B-Cell Lymphoma ICYMI

A supplemental new drug application (sNDA) for venetoclax (Venclexta) used in combination with either a hypomethylating agent or low-dose cytarabine (LDAC) for previously untreated acute myeloid leukemia has been submitted to the Food and Drug Administration by Genentech, which developed it.

Specifically, the sNDA is for these drug combinations in the treatment of AML patients ineligible for intensive chemotherapy, according to the announcement from Genentech.

The sNDA is based on results of two trials that included patients in this population. In the phase 1b M14-358 (NCT02203773), venetoclax was combined with either azacitidine or decitabine; patients treated with 400 mg of venetoclax had a complete remission rate of 73%, and the median overall survival across all doses of venetoclax was 17.5 months. Low white blood cell count with fever, low white blood cell count, anemia, low platelet count, and decreased potassium levels were the most common grade 3/4 adverse events (occurring in 10% or more of patients). In the phase 1b/2 study M14-387 (NCT02287233), venetoclax was used in combination with LDAC; patients treated with a 600-mg dose of venetoclax showed a complete response rate of 62%, and a median overall survival of 11.4 months. Low white blood cell count with fever, decreased potassium levels, pneumonia, disease progression, decreased phosphate levels, high blood pressure, and sepsis were the most common grade 3/4 adverse events seen in this study.

This sNDA follows FDA breakthrough therapy designations, based on these same trials, for these uses of venetoclax with either hypomethylating agents or LDAC. The FDA also recently approved venetoclax in combination with rituximab (Rituxan) for treatment of patients who have chronic lymphocytic leukemia or small lymphocytic lymphoma, with or without 17p depletion, and have been treated with at least one prior therapy.

“AML is an aggressive disease with the lowest survival rate of all leukemias, and we look forward to working closely with the FDA to bring this potential option to patients with this very difficult-to-treat blood cancer as soon as possible,” said Sandra Horning, MD, chief medical officer at Genentech.

More information is included in the full release.

cpalmer@mdedge.com

A supplemental new drug application (sNDA) for venetoclax (Venclexta) used in combination with either a hypomethylating agent or low-dose cytarabine (LDAC) for previously untreated acute myeloid leukemia has been submitted to the Food and Drug Administration by Genentech, which developed it.

Specifically, the sNDA is for these drug combinations in the treatment of AML patients ineligible for intensive chemotherapy, according to the announcement from Genentech.

The sNDA is based on results of two trials that included patients in this population. In the phase 1b M14-358 (NCT02203773), venetoclax was combined with either azacitidine or decitabine; patients treated with 400 mg of venetoclax had a complete remission rate of 73%, and the median overall survival across all doses of venetoclax was 17.5 months. Low white blood cell count with fever, low white blood cell count, anemia, low platelet count, and decreased potassium levels were the most common grade 3/4 adverse events (occurring in 10% or more of patients). In the phase 1b/2 study M14-387 (NCT02287233), venetoclax was used in combination with LDAC; patients treated with a 600-mg dose of venetoclax showed a complete response rate of 62%, and a median overall survival of 11.4 months. Low white blood cell count with fever, decreased potassium levels, pneumonia, disease progression, decreased phosphate levels, high blood pressure, and sepsis were the most common grade 3/4 adverse events seen in this study.

This sNDA follows FDA breakthrough therapy designations, based on these same trials, for these uses of venetoclax with either hypomethylating agents or LDAC. The FDA also recently approved venetoclax in combination with rituximab (Rituxan) for treatment of patients who have chronic lymphocytic leukemia or small lymphocytic lymphoma, with or without 17p depletion, and have been treated with at least one prior therapy.

“AML is an aggressive disease with the lowest survival rate of all leukemias, and we look forward to working closely with the FDA to bring this potential option to patients with this very difficult-to-treat blood cancer as soon as possible,” said Sandra Horning, MD, chief medical officer at Genentech.

More information is included in the full release.

cpalmer@mdedge.com

A supplemental new drug application (sNDA) for venetoclax (Venclexta) used in combination with either a hypomethylating agent or low-dose cytarabine (LDAC) for previously untreated acute myeloid leukemia has been submitted to the Food and Drug Administration by Genentech, which developed it.

Specifically, the sNDA is for these drug combinations in the treatment of AML patients ineligible for intensive chemotherapy, according to the announcement from Genentech.

The sNDA is based on results of two trials that included patients in this population. In the phase 1b M14-358 (NCT02203773), venetoclax was combined with either azacitidine or decitabine; patients treated with 400 mg of venetoclax had a complete remission rate of 73%, and the median overall survival across all doses of venetoclax was 17.5 months. Low white blood cell count with fever, low white blood cell count, anemia, low platelet count, and decreased potassium levels were the most common grade 3/4 adverse events (occurring in 10% or more of patients). In the phase 1b/2 study M14-387 (NCT02287233), venetoclax was used in combination with LDAC; patients treated with a 600-mg dose of venetoclax showed a complete response rate of 62%, and a median overall survival of 11.4 months. Low white blood cell count with fever, decreased potassium levels, pneumonia, disease progression, decreased phosphate levels, high blood pressure, and sepsis were the most common grade 3/4 adverse events seen in this study.

This sNDA follows FDA breakthrough therapy designations, based on these same trials, for these uses of venetoclax with either hypomethylating agents or LDAC. The FDA also recently approved venetoclax in combination with rituximab (Rituxan) for treatment of patients who have chronic lymphocytic leukemia or small lymphocytic lymphoma, with or without 17p depletion, and have been treated with at least one prior therapy.

“AML is an aggressive disease with the lowest survival rate of all leukemias, and we look forward to working closely with the FDA to bring this potential option to patients with this very difficult-to-treat blood cancer as soon as possible,” said Sandra Horning, MD, chief medical officer at Genentech.

More information is included in the full release.

cpalmer@mdedge.com

 

STOCKHOLM – A chemotherapy-free regimen of ibrutinib plus venetoclax was generally safe and showed promising early efficacy in patients with relapsed or refractory chronic lymphocytic leukemia, investigators reported.

A planned interim analysis performed after the first 15 patients who had received two cycles of ibrutinib plus one of ibrutinib and venetoclax showed no treatment-related deaths or treatment interruptions, and all patients had clinical responses, including 8 with complete clinical remission (CR), reported Carsten U. Niemann, MD, PhD, from Rigshospitalet in Copenhagen, and his colleagues.

Neil Osterweil/MDedge News

The goal of the ongoing VISION/HOVEN 141 study is to evaluate whether minimal residual disease (MRD)–guided therapy with the Bruton tyrosine kinase inhibitor ibrutinib and the BCL2 inhibitor venetoclax could lead to MRD negativity and allow select patients to stop treatment, Dr. Niemann said in an interview at the annual congress of the European Hematology Association.

“It’s a 100% clinical response rate and 53% CR. Obviously these are clinical responses, so we don’t have the CT scans, we don’t have the bone marrow biopsies, but we’re very happy to see even in the relapsed/refractory setting such good response rates,” he said.

The investigators are enrolling patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic leukemia requiring treatment and starting all patients on ibrutinib 420 mg daily for the first 2 cycles, with venetoclax added in a 5-week ramp-up from 20 mg beginning with cycle 3 to a final dose of 400 mg daily for 15 total treatment cycles.

At the end of the induction phase, patients who are determined to be MRD-negative by flow cytometry at cycles 12 and 15, and by bone marrow at cycle 15, are randomized on a 1:2 basis to ibrutinib maintenance until disease progression or intolerable toxicity, or to observation until progression or loss of MRD negativity, at which time they start maintenance with ibrutinib until progression or toxicity, plus 12 months of venetoclax.

All 15 patients who were followed for 3 months had clinical responses, including 8 CRs (53%), 6 partial remissions (40%), and 1 partial remission with lymphocytosis (7%).

Three patients had ibrutinib dose reductions and two had venetoclax dose reductions, but no patients stopped treatment. Three patients had grade 2 adverse events (AEs), three had grade 3 AEs, and two had grade 4 AEs. There were no grade 5 AEs.

Two patients had serious AEs during the first two cycles with ibrutinib alone, one of which was a case of febrile neutropenia and one which was an adenocarcinoma of the lung. There were no serious AEs reported during venetoclax ramp-up. To date, there have been no cases of tumor lysis syndrome, atrial fibrillation, or bleeding events reported.

The results suggest that treatment with ibrutinib and venetoclax ramp-up is manageable in this patient population, and the study is ongoing, with further results expected to be reported at either the 2018 annual meeting of the American Society of Hematology or the 2019 annual meeting of the American Society of Clinical Oncology, Dr. Niemann said.

The study is supported by AbbVie and Janssen, which supplied the drugs and had the right to comment on the presentation. Dr. Niemann has previously disclosed consultancy fees from those companies and others.

 

SOURCE: Niemann CU et al. EHA Congress, Abstract PF346.


 

 

STOCKHOLM – A chemotherapy-free regimen of ibrutinib plus venetoclax was generally safe and showed promising early efficacy in patients with relapsed or refractory chronic lymphocytic leukemia, investigators reported.

A planned interim analysis performed after the first 15 patients who had received two cycles of ibrutinib plus one of ibrutinib and venetoclax showed no treatment-related deaths or treatment interruptions, and all patients had clinical responses, including 8 with complete clinical remission (CR), reported Carsten U. Niemann, MD, PhD, from Rigshospitalet in Copenhagen, and his colleagues.

Neil Osterweil/MDedge News

The goal of the ongoing VISION/HOVEN 141 study is to evaluate whether minimal residual disease (MRD)–guided therapy with the Bruton tyrosine kinase inhibitor ibrutinib and the BCL2 inhibitor venetoclax could lead to MRD negativity and allow select patients to stop treatment, Dr. Niemann said in an interview at the annual congress of the European Hematology Association.

“It’s a 100% clinical response rate and 53% CR. Obviously these are clinical responses, so we don’t have the CT scans, we don’t have the bone marrow biopsies, but we’re very happy to see even in the relapsed/refractory setting such good response rates,” he said.

The investigators are enrolling patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic leukemia requiring treatment and starting all patients on ibrutinib 420 mg daily for the first 2 cycles, with venetoclax added in a 5-week ramp-up from 20 mg beginning with cycle 3 to a final dose of 400 mg daily for 15 total treatment cycles.

At the end of the induction phase, patients who are determined to be MRD-negative by flow cytometry at cycles 12 and 15, and by bone marrow at cycle 15, are randomized on a 1:2 basis to ibrutinib maintenance until disease progression or intolerable toxicity, or to observation until progression or loss of MRD negativity, at which time they start maintenance with ibrutinib until progression or toxicity, plus 12 months of venetoclax.

All 15 patients who were followed for 3 months had clinical responses, including 8 CRs (53%), 6 partial remissions (40%), and 1 partial remission with lymphocytosis (7%).

Three patients had ibrutinib dose reductions and two had venetoclax dose reductions, but no patients stopped treatment. Three patients had grade 2 adverse events (AEs), three had grade 3 AEs, and two had grade 4 AEs. There were no grade 5 AEs.

Two patients had serious AEs during the first two cycles with ibrutinib alone, one of which was a case of febrile neutropenia and one which was an adenocarcinoma of the lung. There were no serious AEs reported during venetoclax ramp-up. To date, there have been no cases of tumor lysis syndrome, atrial fibrillation, or bleeding events reported.

The results suggest that treatment with ibrutinib and venetoclax ramp-up is manageable in this patient population, and the study is ongoing, with further results expected to be reported at either the 2018 annual meeting of the American Society of Hematology or the 2019 annual meeting of the American Society of Clinical Oncology, Dr. Niemann said.

The study is supported by AbbVie and Janssen, which supplied the drugs and had the right to comment on the presentation. Dr. Niemann has previously disclosed consultancy fees from those companies and others.

 

SOURCE: Niemann CU et al. EHA Congress, Abstract PF346.


 

 

STOCKHOLM – A chemotherapy-free regimen of ibrutinib plus venetoclax was generally safe and showed promising early efficacy in patients with relapsed or refractory chronic lymphocytic leukemia, investigators reported.

A planned interim analysis performed after the first 15 patients who had received two cycles of ibrutinib plus one of ibrutinib and venetoclax showed no treatment-related deaths or treatment interruptions, and all patients had clinical responses, including 8 with complete clinical remission (CR), reported Carsten U. Niemann, MD, PhD, from Rigshospitalet in Copenhagen, and his colleagues.

Neil Osterweil/MDedge News

The goal of the ongoing VISION/HOVEN 141 study is to evaluate whether minimal residual disease (MRD)–guided therapy with the Bruton tyrosine kinase inhibitor ibrutinib and the BCL2 inhibitor venetoclax could lead to MRD negativity and allow select patients to stop treatment, Dr. Niemann said in an interview at the annual congress of the European Hematology Association.

“It’s a 100% clinical response rate and 53% CR. Obviously these are clinical responses, so we don’t have the CT scans, we don’t have the bone marrow biopsies, but we’re very happy to see even in the relapsed/refractory setting such good response rates,” he said.

The investigators are enrolling patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic leukemia requiring treatment and starting all patients on ibrutinib 420 mg daily for the first 2 cycles, with venetoclax added in a 5-week ramp-up from 20 mg beginning with cycle 3 to a final dose of 400 mg daily for 15 total treatment cycles.

At the end of the induction phase, patients who are determined to be MRD-negative by flow cytometry at cycles 12 and 15, and by bone marrow at cycle 15, are randomized on a 1:2 basis to ibrutinib maintenance until disease progression or intolerable toxicity, or to observation until progression or loss of MRD negativity, at which time they start maintenance with ibrutinib until progression or toxicity, plus 12 months of venetoclax.

All 15 patients who were followed for 3 months had clinical responses, including 8 CRs (53%), 6 partial remissions (40%), and 1 partial remission with lymphocytosis (7%).

Three patients had ibrutinib dose reductions and two had venetoclax dose reductions, but no patients stopped treatment. Three patients had grade 2 adverse events (AEs), three had grade 3 AEs, and two had grade 4 AEs. There were no grade 5 AEs.

Two patients had serious AEs during the first two cycles with ibrutinib alone, one of which was a case of febrile neutropenia and one which was an adenocarcinoma of the lung. There were no serious AEs reported during venetoclax ramp-up. To date, there have been no cases of tumor lysis syndrome, atrial fibrillation, or bleeding events reported.

The results suggest that treatment with ibrutinib and venetoclax ramp-up is manageable in this patient population, and the study is ongoing, with further results expected to be reported at either the 2018 annual meeting of the American Society of Hematology or the 2019 annual meeting of the American Society of Clinical Oncology, Dr. Niemann said.

The study is supported by AbbVie and Janssen, which supplied the drugs and had the right to comment on the presentation. Dr. Niemann has previously disclosed consultancy fees from those companies and others.

 

SOURCE: Niemann CU et al. EHA Congress, Abstract PF346.


 

Case Report

A 19-year-old man first presented to our outpatient dermatology clinic for evaluation of a rash on the elbows and knees of 2 to 3 months’ duration. The lesions were asymptomatic. A review of symptoms including joint pain was largely negative. His medical history was remarkable for terminal ileitis, Crohn disease, anal fissure, rhabdomyolysis, and viral gastroenteritis. Physical examination revealed a well-nourished man with red, scaly, indurated papules and plaques involving approximately 0.5% of the body surface area. A diagnosis of plaque psoriasis was made, and he was treated with topical corticosteroids for 2 weeks and as needed thereafter.

The patient remained stable for 5 years before presenting again to the dermatology clinic for psoriasis that had now spread to the scalp. Clinical examination revealed a very thin, faintly erythematous, scaly patch associated with increased hair density of the right frontal and parietal scalp (Figure). The patient denied any trauma or injury to the area or application of hair dye. We prescribed clobetasol solution 0.05% twice daily to the affected area of the scalp for 2 weeks, which resulted in minimal resolution of the psoriatic scalp lesion.

Comment

The scalp is a site of predilection in psoriasis, as approximately 80% of psoriasis patients report involvement of the scalp.¹ Scalp involvement can dramatically affect a patient’s quality of life and often poses considerable therapeutic challenges for dermatologists.¹ Alopecia in the setting of scalp psoriasis is common but is not well understood.² First described by Shuster³ in 1972, psoriatic alopecia is associated with diminished hair density, follicular miniaturization, sebaceous gland atrophy, and an increased number of dystrophic bulbs in psoriatic plaques.⁴ It clinically presents as pink scaly plaques consistent with psoriasis with overlying alopecia. There are few instances of psoriatic alopecia reported as cicatricial hair loss and generalized telogen effluvium.² It is known that a higher proportion of telogen and catagen hairs exist in patients with psoriatic alopecia.⁵ Additionally, psoriasis patients have more dystrophic hairs in affected and unaffected skin despite no differences in skin when compared to unaffected patients. Many patients achieve hair regrowth following treatment of psoriasis.²

We described a patient with scalp psoriasis who had increased and preserved hair density. Our case suggests that while most patients with scalp psoriasis experience psoriatic alopecia of the lesional skin, some may unconventionally experience increased hair density, which is contradictory to propositions that the friction associated with the application of topical treatments results in breakage of telogen hairs.² Additionally, the presence of increased hair density in scalp psoriasis can further complicate antipsoriatic treatment by making the scalp inaccessible and topical therapies even more difficult to apply.

Case Report

A 19-year-old man first presented to our outpatient dermatology clinic for evaluation of a rash on the elbows and knees of 2 to 3 months’ duration. The lesions were asymptomatic. A review of symptoms including joint pain was largely negative. His medical history was remarkable for terminal ileitis, Crohn disease, anal fissure, rhabdomyolysis, and viral gastroenteritis. Physical examination revealed a well-nourished man with red, scaly, indurated papules and plaques involving approximately 0.5% of the body surface area. A diagnosis of plaque psoriasis was made, and he was treated with topical corticosteroids for 2 weeks and as needed thereafter.

The patient remained stable for 5 years before presenting again to the dermatology clinic for psoriasis that had now spread to the scalp. Clinical examination revealed a very thin, faintly erythematous, scaly patch associated with increased hair density of the right frontal and parietal scalp (Figure). The patient denied any trauma or injury to the area or application of hair dye. We prescribed clobetasol solution 0.05% twice daily to the affected area of the scalp for 2 weeks, which resulted in minimal resolution of the psoriatic scalp lesion.

Comment

The scalp is a site of predilection in psoriasis, as approximately 80% of psoriasis patients report involvement of the scalp.¹ Scalp involvement can dramatically affect a patient’s quality of life and often poses considerable therapeutic challenges for dermatologists.¹ Alopecia in the setting of scalp psoriasis is common but is not well understood.² First described by Shuster³ in 1972, psoriatic alopecia is associated with diminished hair density, follicular miniaturization, sebaceous gland atrophy, and an increased number of dystrophic bulbs in psoriatic plaques.⁴ It clinically presents as pink scaly plaques consistent with psoriasis with overlying alopecia. There are few instances of psoriatic alopecia reported as cicatricial hair loss and generalized telogen effluvium.² It is known that a higher proportion of telogen and catagen hairs exist in patients with psoriatic alopecia.⁵ Additionally, psoriasis patients have more dystrophic hairs in affected and unaffected skin despite no differences in skin when compared to unaffected patients. Many patients achieve hair regrowth following treatment of psoriasis.²

We described a patient with scalp psoriasis who had increased and preserved hair density. Our case suggests that while most patients with scalp psoriasis experience psoriatic alopecia of the lesional skin, some may unconventionally experience increased hair density, which is contradictory to propositions that the friction associated with the application of topical treatments results in breakage of telogen hairs.² Additionally, the presence of increased hair density in scalp psoriasis can further complicate antipsoriatic treatment by making the scalp inaccessible and topical therapies even more difficult to apply.

Case Report

A 19-year-old man first presented to our outpatient dermatology clinic for evaluation of a rash on the elbows and knees of 2 to 3 months’ duration. The lesions were asymptomatic. A review of symptoms including joint pain was largely negative. His medical history was remarkable for terminal ileitis, Crohn disease, anal fissure, rhabdomyolysis, and viral gastroenteritis. Physical examination revealed a well-nourished man with red, scaly, indurated papules and plaques involving approximately 0.5% of the body surface area. A diagnosis of plaque psoriasis was made, and he was treated with topical corticosteroids for 2 weeks and as needed thereafter.

The patient remained stable for 5 years before presenting again to the dermatology clinic for psoriasis that had now spread to the scalp. Clinical examination revealed a very thin, faintly erythematous, scaly patch associated with increased hair density of the right frontal and parietal scalp (Figure). The patient denied any trauma or injury to the area or application of hair dye. We prescribed clobetasol solution 0.05% twice daily to the affected area of the scalp for 2 weeks, which resulted in minimal resolution of the psoriatic scalp lesion.

Comment

The scalp is a site of predilection in psoriasis, as approximately 80% of psoriasis patients report involvement of the scalp.¹ Scalp involvement can dramatically affect a patient’s quality of life and often poses considerable therapeutic challenges for dermatologists.¹ Alopecia in the setting of scalp psoriasis is common but is not well understood.² First described by Shuster³ in 1972, psoriatic alopecia is associated with diminished hair density, follicular miniaturization, sebaceous gland atrophy, and an increased number of dystrophic bulbs in psoriatic plaques.⁴ It clinically presents as pink scaly plaques consistent with psoriasis with overlying alopecia. There are few instances of psoriatic alopecia reported as cicatricial hair loss and generalized telogen effluvium.² It is known that a higher proportion of telogen and catagen hairs exist in patients with psoriatic alopecia.⁵ Additionally, psoriasis patients have more dystrophic hairs in affected and unaffected skin despite no differences in skin when compared to unaffected patients. Many patients achieve hair regrowth following treatment of psoriasis.²

We described a patient with scalp psoriasis who had increased and preserved hair density. Our case suggests that while most patients with scalp psoriasis experience psoriatic alopecia of the lesional skin, some may unconventionally experience increased hair density, which is contradictory to propositions that the friction associated with the application of topical treatments results in breakage of telogen hairs.² Additionally, the presence of increased hair density in scalp psoriasis can further complicate antipsoriatic treatment by making the scalp inaccessible and topical therapies even more difficult to apply.

 

Obinutuzumab (Gazyva)

 

Health Canada has expanded the approved use of obinutuzumab (Gazyva®).

 

The anti-CD20 monoclonal antibody is now approved for use in combination with chemotherapy to treat patients with previously untreated follicular lymphoma (FL) that is advanced (stage II bulky, stage III, or stage IV).

 

In patients who respond to this treatment, obinutuzumab monotherapy can be given as maintenance.

 

Health Canada previously approved obinutuzumab for the following indications:

 

 

 

 

• In combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia
• First in combination with bendamustine, then as monotherapy, in FL patients who relapsed after or are refractory to a rituximab-containing regimen.

Phase 3 results

 

Health Canada’s latest approval of obinutuzumab is based on results from the phase 3 GALLIUM study, which were published in NEJM in October 2017. The following are updated data from the product monograph.

 

GALLIUM included 1385 patients with previously untreated non-Hodgkin lymphoma, and 1202 of these patients had previously untreated, advanced FL.

 

Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).

 

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), and bendamustine.

 

At a median observation time of 41.1 months, the overall response rate was 91% in the obinutuzumab arm and 88% in the rituximab arm. The complete response rates were 28% and 27%, respectively.

 

The median progression-free survival was not reached in either arm. The hazard ratio, for obinutuzumab compared to rituximab, was 0.72 (95% CI, 0.56-0.93, P=0.0118).

 

The estimated 3-year progression-free survival was 78.9% in the rituximab arm and 83.4% in the obinutuzumab arm.

 

Safety was evaluated based on all 1385 patients in the study, 86% of whom had FL and 14% of whom had marginal zone lymphoma.

 

Serious adverse events (AEs) occurred in 50% of patients in the obinutuzumab arm and 43% in the rituximab arm. Fatal AEs occurred in 5% and 4%, respectively. Infections and second malignancies were the leading causes of these deaths.

 

During the monotherapy period, the most common AEs (≥ 5%) in patients treated with obinutuzumab were cough (21%), neutropenia (19%), upper respiratory tract infection (15%), viral upper respiratory tract infection (15%), diarrhea (13%), arthralgia (10%), fatigue (9%), sinusitis (9%), infusion reactions (8%), pneumonia (8%), herpes zoster (8%), lower respiratory tract infection (7%), pyrexia (7%), back pain (6%), headache (6%), urinary tract infection (6%), nausea (6%), bronchitis (5%), and vomiting (5%).

 

Grade 3-4 AEs (≥1%) in patients treated with obinutuzumab included neutropenia (17%), pneumonia (3%), and febrile neutropenia (2%). There were 2 deaths due to pneumonia in the obinutuzumab arm.

 

Obinutuzumab (Gazyva)

 

Health Canada has expanded the approved use of obinutuzumab (Gazyva®).

 

The anti-CD20 monoclonal antibody is now approved for use in combination with chemotherapy to treat patients with previously untreated follicular lymphoma (FL) that is advanced (stage II bulky, stage III, or stage IV).

 

In patients who respond to this treatment, obinutuzumab monotherapy can be given as maintenance.

 

Health Canada previously approved obinutuzumab for the following indications:

 

 

 

 

• In combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia
• First in combination with bendamustine, then as monotherapy, in FL patients who relapsed after or are refractory to a rituximab-containing regimen.

Phase 3 results

 

Health Canada’s latest approval of obinutuzumab is based on results from the phase 3 GALLIUM study, which were published in NEJM in October 2017. The following are updated data from the product monograph.

 

GALLIUM included 1385 patients with previously untreated non-Hodgkin lymphoma, and 1202 of these patients had previously untreated, advanced FL.

 

Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).

 

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), and bendamustine.

 

At a median observation time of 41.1 months, the overall response rate was 91% in the obinutuzumab arm and 88% in the rituximab arm. The complete response rates were 28% and 27%, respectively.

 

The median progression-free survival was not reached in either arm. The hazard ratio, for obinutuzumab compared to rituximab, was 0.72 (95% CI, 0.56-0.93, P=0.0118).

 

The estimated 3-year progression-free survival was 78.9% in the rituximab arm and 83.4% in the obinutuzumab arm.

 

Safety was evaluated based on all 1385 patients in the study, 86% of whom had FL and 14% of whom had marginal zone lymphoma.

 

Serious adverse events (AEs) occurred in 50% of patients in the obinutuzumab arm and 43% in the rituximab arm. Fatal AEs occurred in 5% and 4%, respectively. Infections and second malignancies were the leading causes of these deaths.

 

During the monotherapy period, the most common AEs (≥ 5%) in patients treated with obinutuzumab were cough (21%), neutropenia (19%), upper respiratory tract infection (15%), viral upper respiratory tract infection (15%), diarrhea (13%), arthralgia (10%), fatigue (9%), sinusitis (9%), infusion reactions (8%), pneumonia (8%), herpes zoster (8%), lower respiratory tract infection (7%), pyrexia (7%), back pain (6%), headache (6%), urinary tract infection (6%), nausea (6%), bronchitis (5%), and vomiting (5%).

 

Grade 3-4 AEs (≥1%) in patients treated with obinutuzumab included neutropenia (17%), pneumonia (3%), and febrile neutropenia (2%). There were 2 deaths due to pneumonia in the obinutuzumab arm.

 

Obinutuzumab (Gazyva)

 

Health Canada has expanded the approved use of obinutuzumab (Gazyva®).

 

The anti-CD20 monoclonal antibody is now approved for use in combination with chemotherapy to treat patients with previously untreated follicular lymphoma (FL) that is advanced (stage II bulky, stage III, or stage IV).

 

In patients who respond to this treatment, obinutuzumab monotherapy can be given as maintenance.

 

Health Canada previously approved obinutuzumab for the following indications:

 

 

 

 

• In combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia
• First in combination with bendamustine, then as monotherapy, in FL patients who relapsed after or are refractory to a rituximab-containing regimen.

Phase 3 results

 

Health Canada’s latest approval of obinutuzumab is based on results from the phase 3 GALLIUM study, which were published in NEJM in October 2017. The following are updated data from the product monograph.

 

GALLIUM included 1385 patients with previously untreated non-Hodgkin lymphoma, and 1202 of these patients had previously untreated, advanced FL.

 

Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).

 

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), and bendamustine.

 

At a median observation time of 41.1 months, the overall response rate was 91% in the obinutuzumab arm and 88% in the rituximab arm. The complete response rates were 28% and 27%, respectively.

 

The median progression-free survival was not reached in either arm. The hazard ratio, for obinutuzumab compared to rituximab, was 0.72 (95% CI, 0.56-0.93, P=0.0118).

 

The estimated 3-year progression-free survival was 78.9% in the rituximab arm and 83.4% in the obinutuzumab arm.

 

Safety was evaluated based on all 1385 patients in the study, 86% of whom had FL and 14% of whom had marginal zone lymphoma.

 

Serious adverse events (AEs) occurred in 50% of patients in the obinutuzumab arm and 43% in the rituximab arm. Fatal AEs occurred in 5% and 4%, respectively. Infections and second malignancies were the leading causes of these deaths.

 

During the monotherapy period, the most common AEs (≥ 5%) in patients treated with obinutuzumab were cough (21%), neutropenia (19%), upper respiratory tract infection (15%), viral upper respiratory tract infection (15%), diarrhea (13%), arthralgia (10%), fatigue (9%), sinusitis (9%), infusion reactions (8%), pneumonia (8%), herpes zoster (8%), lower respiratory tract infection (7%), pyrexia (7%), back pain (6%), headache (6%), urinary tract infection (6%), nausea (6%), bronchitis (5%), and vomiting (5%).

 

Grade 3-4 AEs (≥1%) in patients treated with obinutuzumab included neutropenia (17%), pneumonia (3%), and febrile neutropenia (2%). There were 2 deaths due to pneumonia in the obinutuzumab arm.

 

The medical marijuana landscape is changing so fast that Colorado Neurological Institute neurologist Allen C. Bowling, MD, PhD, already needs to update a presentation he gave about cannabis in multiple sclerosis in late May.

That’s when Dr. Bowling spoke about the topic in a presentation at the 2018 annual meeting of the Consortium of Multiple Sclerosis Centers. At the time, 29 states allowed the medical use of marijuana, and not a single cannabis-derived medication could boast Food and Drug Administration approval.

Since then, both those facts became history over a span of 2 days.

First, on June 25, the FDA announced its approval of Epidiolex (cannabidiol) for the treatment of seizures in two rare forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome. It’s the first time the FDA has approved a drug with a purified ingredient – cannabidiol, a nonpsychoactive substance – that’s derived from marijuana.

Then, on June 26, voters in Oklahoma approved a ballot measure that allows the possession of marijuana for medical use; users must register with the state. Thirty states and the District of Columbia have made medical marijuana legal, according to the procon.org website, although the two newest ones (Oklahoma and West Virginia) are still developing procedures.

The laws vary widely. Some states don’t allow patients to smoke medical marijuana, and some don’t allow visitors to use out-of-state registry ID cards. And certain states limit the use of medical marijuana to specific conditions. Medical marijuana use by patients with MS is specifically allowed in many states, including Alaska, Arizona, Florida, Minnesota, and several others.

There’s another complexity: According to procon.org, 17 states have laws about the use of cannabidiol. In Georgia, for instance, the use of some cannabis oil is allowed for the treatment of MS and other conditions.

In the wake of the FDA ruling, Dr. Bowling spoke in an interview about cannabis, MS, and the questions that neurologists should be asking themselves.

Q: What are studies telling us about cannabis and MS?

A: There are lots of clinical studies – 19 randomized controlled trials. A consistent finding is that there’s benefit in terms of pain and people’s subjective sense of spasticity (Neurology. 2014 Apr 29;82(17):1556-63).

Q: During your CMSC presentation, you talked about how “fidelity” has been a problem in cannabis research. Could you elaborate on what you mean?

A: The products used in these studies are generally standardized, research-grade products that you can’t buy in any U.S. dispensary.

Cannabis is complex and contains more than 100 different potentially pharmacologically active molecules. You can’t conclude that if you see a product in clinical trials, you’ll then be able to walk into a dispensary for recreational or medical cannabis and get a product that produces the same effect.

Q: What have you seen in your own patient population in terms of cannabis use?

A: I find what’s been found with the studies: It helps with pain and people’s sense of muscle stiffness.

It’s especially helpful in people with pain and spasticity that breaks through in the late afternoon or at night when they’re trying to go to sleep. Just a little bit of cannabis can get them through those difficult times and improve their quality of life.

 

Q: What choices do patients make regarding whether to get high from the cannabis they use?

A: Some have absolutely zero interest in getting high, and they try to avoid the THC-containing products. Other like getting high in addition to getting help with pain and spasticity.

Q: Who should not use medical marijuana in the MS community?

A: Patients who don’t have symptoms that could respond.

I’m also very concerned about patients who are 25 years and younger because of the effects that cannabis can have on brain development out to age 25 and the higher risk of addiction in people who are younger.

Q: What do you think the future will hold on the cannabis front?

A: Now that it’s less of a taboo topic, there’s an ever-growing number of trials each year, including very high-quality studies.

Pharmaceutically produced, cannabis-based medicines will be a growing area. Epidiolex is a perfect example of that.

It’s important for physicians to know that the way cannabis-based medicine is produced by a pharmaceutical company is different in so many levels than the cannabis in states with recreational and medical marijuana.

Q: What are some ways that the pharmaceutical products are different?

A: The rigor of the production process, the standardization, the purity, the correct labeling and expiration dates. Plus, the lack of the use of pesticides and other contaminants. And they’re distributed by pharmacists.

Q: What should neurologists be thinking if they’re considering whether to recommend cannabis to their patients?

A: This is a very complex topic, and it’s not something that most of us have training in. You can’t sit down for 1 or 2 hours, get up to speed, and have your own well-informed opinion on it. You really need to put more time and effort.

Q: What are some issues that neurologists should consider?

A: You really need to find out what your state is doing about it and see how you feel about that.

How is your state administering medical and/or recreational marijuana? The administration of these programs is extremely different from state to state. Do these details satisfy you, and are you content having your patients interface with these programs?

Dr. Bowling reports no relevant disclosures.

 

The medical marijuana landscape is changing so fast that Colorado Neurological Institute neurologist Allen C. Bowling, MD, PhD, already needs to update a presentation he gave about cannabis in multiple sclerosis in late May.

That’s when Dr. Bowling spoke about the topic in a presentation at the 2018 annual meeting of the Consortium of Multiple Sclerosis Centers. At the time, 29 states allowed the medical use of marijuana, and not a single cannabis-derived medication could boast Food and Drug Administration approval.

Since then, both those facts became history over a span of 2 days.

First, on June 25, the FDA announced its approval of Epidiolex (cannabidiol) for the treatment of seizures in two rare forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome. It’s the first time the FDA has approved a drug with a purified ingredient – cannabidiol, a nonpsychoactive substance – that’s derived from marijuana.

Then, on June 26, voters in Oklahoma approved a ballot measure that allows the possession of marijuana for medical use; users must register with the state. Thirty states and the District of Columbia have made medical marijuana legal, according to the procon.org website, although the two newest ones (Oklahoma and West Virginia) are still developing procedures.

The laws vary widely. Some states don’t allow patients to smoke medical marijuana, and some don’t allow visitors to use out-of-state registry ID cards. And certain states limit the use of medical marijuana to specific conditions. Medical marijuana use by patients with MS is specifically allowed in many states, including Alaska, Arizona, Florida, Minnesota, and several others.

There’s another complexity: According to procon.org, 17 states have laws about the use of cannabidiol. In Georgia, for instance, the use of some cannabis oil is allowed for the treatment of MS and other conditions.

In the wake of the FDA ruling, Dr. Bowling spoke in an interview about cannabis, MS, and the questions that neurologists should be asking themselves.

Q: What are studies telling us about cannabis and MS?

A: There are lots of clinical studies – 19 randomized controlled trials. A consistent finding is that there’s benefit in terms of pain and people’s subjective sense of spasticity (Neurology. 2014 Apr 29;82(17):1556-63).

Q: During your CMSC presentation, you talked about how “fidelity” has been a problem in cannabis research. Could you elaborate on what you mean?

A: The products used in these studies are generally standardized, research-grade products that you can’t buy in any U.S. dispensary.

Cannabis is complex and contains more than 100 different potentially pharmacologically active molecules. You can’t conclude that if you see a product in clinical trials, you’ll then be able to walk into a dispensary for recreational or medical cannabis and get a product that produces the same effect.

Q: What have you seen in your own patient population in terms of cannabis use?

A: I find what’s been found with the studies: It helps with pain and people’s sense of muscle stiffness.

It’s especially helpful in people with pain and spasticity that breaks through in the late afternoon or at night when they’re trying to go to sleep. Just a little bit of cannabis can get them through those difficult times and improve their quality of life.

 

Q: What choices do patients make regarding whether to get high from the cannabis they use?

A: Some have absolutely zero interest in getting high, and they try to avoid the THC-containing products. Other like getting high in addition to getting help with pain and spasticity.

Q: Who should not use medical marijuana in the MS community?

A: Patients who don’t have symptoms that could respond.

I’m also very concerned about patients who are 25 years and younger because of the effects that cannabis can have on brain development out to age 25 and the higher risk of addiction in people who are younger.

Q: What do you think the future will hold on the cannabis front?

A: Now that it’s less of a taboo topic, there’s an ever-growing number of trials each year, including very high-quality studies.

Pharmaceutically produced, cannabis-based medicines will be a growing area. Epidiolex is a perfect example of that.

It’s important for physicians to know that the way cannabis-based medicine is produced by a pharmaceutical company is different in so many levels than the cannabis in states with recreational and medical marijuana.

Q: What are some ways that the pharmaceutical products are different?

A: The rigor of the production process, the standardization, the purity, the correct labeling and expiration dates. Plus, the lack of the use of pesticides and other contaminants. And they’re distributed by pharmacists.

Q: What should neurologists be thinking if they’re considering whether to recommend cannabis to their patients?

A: This is a very complex topic, and it’s not something that most of us have training in. You can’t sit down for 1 or 2 hours, get up to speed, and have your own well-informed opinion on it. You really need to put more time and effort.

Q: What are some issues that neurologists should consider?

A: You really need to find out what your state is doing about it and see how you feel about that.

How is your state administering medical and/or recreational marijuana? The administration of these programs is extremely different from state to state. Do these details satisfy you, and are you content having your patients interface with these programs?

Dr. Bowling reports no relevant disclosures.

 

The medical marijuana landscape is changing so fast that Colorado Neurological Institute neurologist Allen C. Bowling, MD, PhD, already needs to update a presentation he gave about cannabis in multiple sclerosis in late May.

That’s when Dr. Bowling spoke about the topic in a presentation at the 2018 annual meeting of the Consortium of Multiple Sclerosis Centers. At the time, 29 states allowed the medical use of marijuana, and not a single cannabis-derived medication could boast Food and Drug Administration approval.

Since then, both those facts became history over a span of 2 days.

First, on June 25, the FDA announced its approval of Epidiolex (cannabidiol) for the treatment of seizures in two rare forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome. It’s the first time the FDA has approved a drug with a purified ingredient – cannabidiol, a nonpsychoactive substance – that’s derived from marijuana.

Then, on June 26, voters in Oklahoma approved a ballot measure that allows the possession of marijuana for medical use; users must register with the state. Thirty states and the District of Columbia have made medical marijuana legal, according to the procon.org website, although the two newest ones (Oklahoma and West Virginia) are still developing procedures.

The laws vary widely. Some states don’t allow patients to smoke medical marijuana, and some don’t allow visitors to use out-of-state registry ID cards. And certain states limit the use of medical marijuana to specific conditions. Medical marijuana use by patients with MS is specifically allowed in many states, including Alaska, Arizona, Florida, Minnesota, and several others.

There’s another complexity: According to procon.org, 17 states have laws about the use of cannabidiol. In Georgia, for instance, the use of some cannabis oil is allowed for the treatment of MS and other conditions.

In the wake of the FDA ruling, Dr. Bowling spoke in an interview about cannabis, MS, and the questions that neurologists should be asking themselves.

Q: What are studies telling us about cannabis and MS?

A: There are lots of clinical studies – 19 randomized controlled trials. A consistent finding is that there’s benefit in terms of pain and people’s subjective sense of spasticity (Neurology. 2014 Apr 29;82(17):1556-63).

Q: During your CMSC presentation, you talked about how “fidelity” has been a problem in cannabis research. Could you elaborate on what you mean?

A: The products used in these studies are generally standardized, research-grade products that you can’t buy in any U.S. dispensary.

Cannabis is complex and contains more than 100 different potentially pharmacologically active molecules. You can’t conclude that if you see a product in clinical trials, you’ll then be able to walk into a dispensary for recreational or medical cannabis and get a product that produces the same effect.

Q: What have you seen in your own patient population in terms of cannabis use?

A: I find what’s been found with the studies: It helps with pain and people’s sense of muscle stiffness.

It’s especially helpful in people with pain and spasticity that breaks through in the late afternoon or at night when they’re trying to go to sleep. Just a little bit of cannabis can get them through those difficult times and improve their quality of life.

 

Q: What choices do patients make regarding whether to get high from the cannabis they use?

A: Some have absolutely zero interest in getting high, and they try to avoid the THC-containing products. Other like getting high in addition to getting help with pain and spasticity.

Q: Who should not use medical marijuana in the MS community?

A: Patients who don’t have symptoms that could respond.

I’m also very concerned about patients who are 25 years and younger because of the effects that cannabis can have on brain development out to age 25 and the higher risk of addiction in people who are younger.

Q: What do you think the future will hold on the cannabis front?

A: Now that it’s less of a taboo topic, there’s an ever-growing number of trials each year, including very high-quality studies.

Pharmaceutically produced, cannabis-based medicines will be a growing area. Epidiolex is a perfect example of that.

It’s important for physicians to know that the way cannabis-based medicine is produced by a pharmaceutical company is different in so many levels than the cannabis in states with recreational and medical marijuana.

Q: What are some ways that the pharmaceutical products are different?

A: The rigor of the production process, the standardization, the purity, the correct labeling and expiration dates. Plus, the lack of the use of pesticides and other contaminants. And they’re distributed by pharmacists.

Q: What should neurologists be thinking if they’re considering whether to recommend cannabis to their patients?

A: This is a very complex topic, and it’s not something that most of us have training in. You can’t sit down for 1 or 2 hours, get up to speed, and have your own well-informed opinion on it. You really need to put more time and effort.

Q: What are some issues that neurologists should consider?

A: You really need to find out what your state is doing about it and see how you feel about that.

How is your state administering medical and/or recreational marijuana? The administration of these programs is extremely different from state to state. Do these details satisfy you, and are you content having your patients interface with these programs?

Dr. Bowling reports no relevant disclosures.

 

Photo by Chad McNeeley

 

Transplant with radioimmunotherapy (RIT)-based conditioning is a viable treatment option for patients with indolent—but not aggressive—B-cell non-Hodgkin lymphomas (NHLs), according to researchers.

 

Long-term follow-up data showed “excellent” outcomes in patients with indolent B-NHL who received conditioning with ⁹⁰Y-ibritumomab tiuxetan plus fludarabine and low-dose total body irradiation (TBI) prior to HLA-matched hematopoietic stem cell transplant (HSCT).

 

However, long-term outcomes were inferior in patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).

 

Camille E. Puronen, MD, of the University of Washington in Seattle, and her colleagues reported these results in Biology of Blood and Marrow Transplantation.

 

The study enrolled 40 patients with high-risk B-NHL. This included DLBCL (n=14), chronic lymphocytic leukemia (CLL; n=10), MCL (n=8), follicular lymphoma (FL; n=6); hairy cell leukemia (HCL; n=1), and marginal zone lymphoma (MZL; n=1).

 

Patients were treated with 0.4 mCi/kg ⁹⁰Y-ibritumomab tiuxetan, given 2 weeks prior to HSCT, to a maximum dose of 32 mCi.

 

Patients also received fludarabine at 30 mg/m² on day 5, 6, and 7 prior to HSCT and 2 Gy TBI given on the day of transplant.

 

In an earlier report, the objective response rate (ORR) was 60%, and 35% of patients had a complete response (CR) or unconfirmed CR.

 

The researchers said early responses were not associated with disease bulk or chemoresistance, as the ORR was 59% in patients with bulky or chemoresistant disease.

 

However, responses were associated with histology, as the ORR was 38% in patients with DLBCL, 50% in those with MCL, 83% in those with FL, and 90% in those with CLL.

 

Long-term survival

 

In the current report, 11 of 40 patients were still alive at a median follow up of 9 years (range, 5.3 to 10.2). Fourteen patients died of disease progression, and 14 died from complications of HSCT.

 

The 5-year overall survival (OS) was 40%, and the 5-year progression-free survival (PFS) was 28%.

 

The best survival rates were in patients with indolent histology. The 5-year PFS was 44% in these patients, and the 5-year OS was 67%.

 

The researchers said early CR was not associated with long-term survival. However, patients who had at least stable disease (SD) at earlier time points did have the opportunity to achieve long-term survival. All patients who progressed before day 84 were dead by the 1-year mark.

 

Of the 11 patients who were still alive at a median follow up of 9 years, 4 had a CR or unconfirmed CR at day 84 (FL: 1; CLL: 2; MCL: 1); 6 were in partial response (CLL: 3; FL: 1; MCL: 1; MZL: 1); and 1 patient with FL had SD.

 

Among the 18 patients with indolent NHL, long-term PFS was observed in 5 of the 7 patients who achieved early CR and 8 of the 11 patients who did not achieve early CR.

 

Two of the 4 MCL patients who achieved an early CR had long-term PFS, but none of the MCL patients without an early CR had long-term PFS.

 

Among DLBCL patients, 1 of the 4 who achieved early CR had long-term PFS, but none of the patients without an early CR had long-term PFS. Only 1 DLBCL patient survived beyond 5 years. None survived beyond 8 years.

 

The researchers said the favorable outcomes in patients with indolent B-NHL are consistent with the known efficacy of RIT and the graft-versus-leukemia effect in these patients.

 

The team also noted that, since this trial began, several novel agents have been approved for the treatment of indolent B-NHL, which means allogeneic HSCT is often moved to later in the disease course.

 

 

The researchers concluded that ⁹⁰Y-ibritumomab tiuxetan-based conditioning could “continue to play an important role in these settings,” but “improved strategies are needed” for patients with MCL and DLBCL.

 

Photo by Chad McNeeley

 

Transplant with radioimmunotherapy (RIT)-based conditioning is a viable treatment option for patients with indolent—but not aggressive—B-cell non-Hodgkin lymphomas (NHLs), according to researchers.

 

Long-term follow-up data showed “excellent” outcomes in patients with indolent B-NHL who received conditioning with ⁹⁰Y-ibritumomab tiuxetan plus fludarabine and low-dose total body irradiation (TBI) prior to HLA-matched hematopoietic stem cell transplant (HSCT).

 

However, long-term outcomes were inferior in patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).

 

Camille E. Puronen, MD, of the University of Washington in Seattle, and her colleagues reported these results in Biology of Blood and Marrow Transplantation.

 

The study enrolled 40 patients with high-risk B-NHL. This included DLBCL (n=14), chronic lymphocytic leukemia (CLL; n=10), MCL (n=8), follicular lymphoma (FL; n=6); hairy cell leukemia (HCL; n=1), and marginal zone lymphoma (MZL; n=1).

 

Patients were treated with 0.4 mCi/kg ⁹⁰Y-ibritumomab tiuxetan, given 2 weeks prior to HSCT, to a maximum dose of 32 mCi.

 

Patients also received fludarabine at 30 mg/m² on day 5, 6, and 7 prior to HSCT and 2 Gy TBI given on the day of transplant.

 

In an earlier report, the objective response rate (ORR) was 60%, and 35% of patients had a complete response (CR) or unconfirmed CR.

 

The researchers said early responses were not associated with disease bulk or chemoresistance, as the ORR was 59% in patients with bulky or chemoresistant disease.

 

However, responses were associated with histology, as the ORR was 38% in patients with DLBCL, 50% in those with MCL, 83% in those with FL, and 90% in those with CLL.

 

Long-term survival

 

In the current report, 11 of 40 patients were still alive at a median follow up of 9 years (range, 5.3 to 10.2). Fourteen patients died of disease progression, and 14 died from complications of HSCT.

 

The 5-year overall survival (OS) was 40%, and the 5-year progression-free survival (PFS) was 28%.

 

The best survival rates were in patients with indolent histology. The 5-year PFS was 44% in these patients, and the 5-year OS was 67%.

 

The researchers said early CR was not associated with long-term survival. However, patients who had at least stable disease (SD) at earlier time points did have the opportunity to achieve long-term survival. All patients who progressed before day 84 were dead by the 1-year mark.

 

Of the 11 patients who were still alive at a median follow up of 9 years, 4 had a CR or unconfirmed CR at day 84 (FL: 1; CLL: 2; MCL: 1); 6 were in partial response (CLL: 3; FL: 1; MCL: 1; MZL: 1); and 1 patient with FL had SD.

 

Among the 18 patients with indolent NHL, long-term PFS was observed in 5 of the 7 patients who achieved early CR and 8 of the 11 patients who did not achieve early CR.

 

Two of the 4 MCL patients who achieved an early CR had long-term PFS, but none of the MCL patients without an early CR had long-term PFS.

 

Among DLBCL patients, 1 of the 4 who achieved early CR had long-term PFS, but none of the patients without an early CR had long-term PFS. Only 1 DLBCL patient survived beyond 5 years. None survived beyond 8 years.

 

The researchers said the favorable outcomes in patients with indolent B-NHL are consistent with the known efficacy of RIT and the graft-versus-leukemia effect in these patients.

 

The team also noted that, since this trial began, several novel agents have been approved for the treatment of indolent B-NHL, which means allogeneic HSCT is often moved to later in the disease course.

 

 

The researchers concluded that ⁹⁰Y-ibritumomab tiuxetan-based conditioning could “continue to play an important role in these settings,” but “improved strategies are needed” for patients with MCL and DLBCL.

 

Photo by Chad McNeeley

 

Transplant with radioimmunotherapy (RIT)-based conditioning is a viable treatment option for patients with indolent—but not aggressive—B-cell non-Hodgkin lymphomas (NHLs), according to researchers.

 

Long-term follow-up data showed “excellent” outcomes in patients with indolent B-NHL who received conditioning with ⁹⁰Y-ibritumomab tiuxetan plus fludarabine and low-dose total body irradiation (TBI) prior to HLA-matched hematopoietic stem cell transplant (HSCT).

 

However, long-term outcomes were inferior in patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).

 

Camille E. Puronen, MD, of the University of Washington in Seattle, and her colleagues reported these results in Biology of Blood and Marrow Transplantation.

 

The study enrolled 40 patients with high-risk B-NHL. This included DLBCL (n=14), chronic lymphocytic leukemia (CLL; n=10), MCL (n=8), follicular lymphoma (FL; n=6); hairy cell leukemia (HCL; n=1), and marginal zone lymphoma (MZL; n=1).

 

Patients were treated with 0.4 mCi/kg ⁹⁰Y-ibritumomab tiuxetan, given 2 weeks prior to HSCT, to a maximum dose of 32 mCi.

 

Patients also received fludarabine at 30 mg/m² on day 5, 6, and 7 prior to HSCT and 2 Gy TBI given on the day of transplant.

 

In an earlier report, the objective response rate (ORR) was 60%, and 35% of patients had a complete response (CR) or unconfirmed CR.

 

The researchers said early responses were not associated with disease bulk or chemoresistance, as the ORR was 59% in patients with bulky or chemoresistant disease.

 

However, responses were associated with histology, as the ORR was 38% in patients with DLBCL, 50% in those with MCL, 83% in those with FL, and 90% in those with CLL.

 

Long-term survival

 

In the current report, 11 of 40 patients were still alive at a median follow up of 9 years (range, 5.3 to 10.2). Fourteen patients died of disease progression, and 14 died from complications of HSCT.

 

The 5-year overall survival (OS) was 40%, and the 5-year progression-free survival (PFS) was 28%.

 

The best survival rates were in patients with indolent histology. The 5-year PFS was 44% in these patients, and the 5-year OS was 67%.

 

The researchers said early CR was not associated with long-term survival. However, patients who had at least stable disease (SD) at earlier time points did have the opportunity to achieve long-term survival. All patients who progressed before day 84 were dead by the 1-year mark.

 

Of the 11 patients who were still alive at a median follow up of 9 years, 4 had a CR or unconfirmed CR at day 84 (FL: 1; CLL: 2; MCL: 1); 6 were in partial response (CLL: 3; FL: 1; MCL: 1; MZL: 1); and 1 patient with FL had SD.

 

Among the 18 patients with indolent NHL, long-term PFS was observed in 5 of the 7 patients who achieved early CR and 8 of the 11 patients who did not achieve early CR.

 

Two of the 4 MCL patients who achieved an early CR had long-term PFS, but none of the MCL patients without an early CR had long-term PFS.

 

Among DLBCL patients, 1 of the 4 who achieved early CR had long-term PFS, but none of the patients without an early CR had long-term PFS. Only 1 DLBCL patient survived beyond 5 years. None survived beyond 8 years.

 

The researchers said the favorable outcomes in patients with indolent B-NHL are consistent with the known efficacy of RIT and the graft-versus-leukemia effect in these patients.

 

The team also noted that, since this trial began, several novel agents have been approved for the treatment of indolent B-NHL, which means allogeneic HSCT is often moved to later in the disease course.

 

 

The researchers concluded that ⁹⁰Y-ibritumomab tiuxetan-based conditioning could “continue to play an important role in these settings,” but “improved strategies are needed” for patients with MCL and DLBCL.

 

STOCKHOLM – Patients with chronic lymphocytic leukemia (CLL) who experience relapse after therapy with a B-cell receptor signaling inhibitor tend to have a swiftly progressive disease course that requires immediate intervention. For these patients, a rapid venetoclax dose-escalation protocol may be a safe way to quickly regain disease control, and possibly bridge to salvage therapies, investigators reported.

Of 15 patients with CLL who relapsed after treatment with a B-cell receptor inhibitor (BCRi), all were able to get to their target dose of venetoclax under close inpatient monitoring at a median of 12 days, compared with the 35 days usually required for venetoclax dose escalation, reported Farrukh T. Awan, MD, of Ohio State University Comprehensive Cancer Center in Columbus, and his colleagues.

Only two patients developed clinical tumor lysis syndrome (TLS), a common occurrence with venetoclax therapy, and this adverse event was manageable, Dr. Awan said at the annual congress of the European Hematology Association.

“The reason why we have been doing a slow ramp up on venetoclax is the original toxicity issues that we saw early on,” he said in an interview. “But unfortunately, a lot of patients are progressing on these new agents and have very rapid disease progression, and what we have seen is that if you stop the ibrutinib, the disease progresses very quickly, and by the time they can get up to the effective dose of venetoclax, they’re too sick to continue, or they might even die from disease progression.”

Neil Osterweil/MDedge News

To combat this problem, Dr. Awan and his colleagues developed a rapid dose escalation protocol that would ramp up from 20 mg to 400 mg, with increases every 1 or 2 days depending on tolerability and incident TLS. Lab tests for TLS were evaluated every 4-8 hours.

All patients were closely monitored in the hospital, and all were started on allopurinol or other uric acid–lowering agents before starting on venetoclax.

The investigators reported safety and efficacy outcomes for the patients in a retrospective analysis.

The median age of the patients, 12 men and 3 women, was 65 years (range, 58-86 years). Seven patients had Eastern Cooperative Oncology Group Performance Status of 0, seven had an ECOG score of 1, and one had a score of 2-4.

Ten patients had most recently been treated with a BCRi, either a Bruton’s tyrosine kinase inhibitor (ibrutinib or acalabrutinib), idelalisib, or entospletinib. Three patients received ibrutinib plus chemotherapy, and two received rituximab and dexamethasone followed by rituximab maintenance.

The median time to full venetoclax dose was 12 days (range, 5-21 days) and all 15 patients reached the target dose. The mean length of stay during the ramp-up period was 9.5 days (range, 6-22 days).
 

The incidence of clinical TLS was 13.2%, occurring in two patients, one at the initial 20-mg dose, and one at the 200-mg dose level. Another five patients had asymptomatic TLS. Other treatment-related adverse events were anemia in seven patients, neutropenia in six patients, thrombocytopenia in five patients, and lung infection in one patient.

 

Twelve patients had a partial response, one had stable disease, and two had progressive disease. The mean time to best response was 71 days.

One-year progression-free survival was 49%, and 1-year overall survival was 68%.

The investigators found that for patients who still have some disease control with a BCRi, it may be possible to keep them on that drug while transitioning to venetoclax. The rapid dose escalation protocol should only be attempted in highly experience comprehensive cancer centers, Dr. Awan said.

“Under very close monitoring in an experienced inpatient setting, where the nurses are very used to doing this on a weekly basis in a very high volume center, I think that our data show that we could do this without affecting toxicity significantly or mortality,” he said.

Venetoclax therapy could buy enough time for patients to bridge to other options, such as chimeric antigen receptor (CAR) T-cell therapy or allogeneic stem cell transplant, he noted.

“But if we had waited 4 weeks, most of these patients would not have made it,” he said.

The study was internally funded. Dr. Awan reported research funding from Gilead, Pharmacyclics, AbbVie, and Janssen.

SOURCE: Koenig K et al. EHA Congress, Abstract PF357.

 

STOCKHOLM – Patients with chronic lymphocytic leukemia (CLL) who experience relapse after therapy with a B-cell receptor signaling inhibitor tend to have a swiftly progressive disease course that requires immediate intervention. For these patients, a rapid venetoclax dose-escalation protocol may be a safe way to quickly regain disease control, and possibly bridge to salvage therapies, investigators reported.

Of 15 patients with CLL who relapsed after treatment with a B-cell receptor inhibitor (BCRi), all were able to get to their target dose of venetoclax under close inpatient monitoring at a median of 12 days, compared with the 35 days usually required for venetoclax dose escalation, reported Farrukh T. Awan, MD, of Ohio State University Comprehensive Cancer Center in Columbus, and his colleagues.

Only two patients developed clinical tumor lysis syndrome (TLS), a common occurrence with venetoclax therapy, and this adverse event was manageable, Dr. Awan said at the annual congress of the European Hematology Association.

“The reason why we have been doing a slow ramp up on venetoclax is the original toxicity issues that we saw early on,” he said in an interview. “But unfortunately, a lot of patients are progressing on these new agents and have very rapid disease progression, and what we have seen is that if you stop the ibrutinib, the disease progresses very quickly, and by the time they can get up to the effective dose of venetoclax, they’re too sick to continue, or they might even die from disease progression.”

Neil Osterweil/MDedge News

To combat this problem, Dr. Awan and his colleagues developed a rapid dose escalation protocol that would ramp up from 20 mg to 400 mg, with increases every 1 or 2 days depending on tolerability and incident TLS. Lab tests for TLS were evaluated every 4-8 hours.

All patients were closely monitored in the hospital, and all were started on allopurinol or other uric acid–lowering agents before starting on venetoclax.

The investigators reported safety and efficacy outcomes for the patients in a retrospective analysis.

The median age of the patients, 12 men and 3 women, was 65 years (range, 58-86 years). Seven patients had Eastern Cooperative Oncology Group Performance Status of 0, seven had an ECOG score of 1, and one had a score of 2-4.

Ten patients had most recently been treated with a BCRi, either a Bruton’s tyrosine kinase inhibitor (ibrutinib or acalabrutinib), idelalisib, or entospletinib. Three patients received ibrutinib plus chemotherapy, and two received rituximab and dexamethasone followed by rituximab maintenance.

The median time to full venetoclax dose was 12 days (range, 5-21 days) and all 15 patients reached the target dose. The mean length of stay during the ramp-up period was 9.5 days (range, 6-22 days).
 

The incidence of clinical TLS was 13.2%, occurring in two patients, one at the initial 20-mg dose, and one at the 200-mg dose level. Another five patients had asymptomatic TLS. Other treatment-related adverse events were anemia in seven patients, neutropenia in six patients, thrombocytopenia in five patients, and lung infection in one patient.

 

Twelve patients had a partial response, one had stable disease, and two had progressive disease. The mean time to best response was 71 days.

One-year progression-free survival was 49%, and 1-year overall survival was 68%.

The investigators found that for patients who still have some disease control with a BCRi, it may be possible to keep them on that drug while transitioning to venetoclax. The rapid dose escalation protocol should only be attempted in highly experience comprehensive cancer centers, Dr. Awan said.

“Under very close monitoring in an experienced inpatient setting, where the nurses are very used to doing this on a weekly basis in a very high volume center, I think that our data show that we could do this without affecting toxicity significantly or mortality,” he said.

Venetoclax therapy could buy enough time for patients to bridge to other options, such as chimeric antigen receptor (CAR) T-cell therapy or allogeneic stem cell transplant, he noted.

“But if we had waited 4 weeks, most of these patients would not have made it,” he said.

The study was internally funded. Dr. Awan reported research funding from Gilead, Pharmacyclics, AbbVie, and Janssen.

SOURCE: Koenig K et al. EHA Congress, Abstract PF357.

 

STOCKHOLM – Patients with chronic lymphocytic leukemia (CLL) who experience relapse after therapy with a B-cell receptor signaling inhibitor tend to have a swiftly progressive disease course that requires immediate intervention. For these patients, a rapid venetoclax dose-escalation protocol may be a safe way to quickly regain disease control, and possibly bridge to salvage therapies, investigators reported.

Of 15 patients with CLL who relapsed after treatment with a B-cell receptor inhibitor (BCRi), all were able to get to their target dose of venetoclax under close inpatient monitoring at a median of 12 days, compared with the 35 days usually required for venetoclax dose escalation, reported Farrukh T. Awan, MD, of Ohio State University Comprehensive Cancer Center in Columbus, and his colleagues.

Only two patients developed clinical tumor lysis syndrome (TLS), a common occurrence with venetoclax therapy, and this adverse event was manageable, Dr. Awan said at the annual congress of the European Hematology Association.

“The reason why we have been doing a slow ramp up on venetoclax is the original toxicity issues that we saw early on,” he said in an interview. “But unfortunately, a lot of patients are progressing on these new agents and have very rapid disease progression, and what we have seen is that if you stop the ibrutinib, the disease progresses very quickly, and by the time they can get up to the effective dose of venetoclax, they’re too sick to continue, or they might even die from disease progression.”

Neil Osterweil/MDedge News

To combat this problem, Dr. Awan and his colleagues developed a rapid dose escalation protocol that would ramp up from 20 mg to 400 mg, with increases every 1 or 2 days depending on tolerability and incident TLS. Lab tests for TLS were evaluated every 4-8 hours.

All patients were closely monitored in the hospital, and all were started on allopurinol or other uric acid–lowering agents before starting on venetoclax.

The investigators reported safety and efficacy outcomes for the patients in a retrospective analysis.

The median age of the patients, 12 men and 3 women, was 65 years (range, 58-86 years). Seven patients had Eastern Cooperative Oncology Group Performance Status of 0, seven had an ECOG score of 1, and one had a score of 2-4.

Ten patients had most recently been treated with a BCRi, either a Bruton’s tyrosine kinase inhibitor (ibrutinib or acalabrutinib), idelalisib, or entospletinib. Three patients received ibrutinib plus chemotherapy, and two received rituximab and dexamethasone followed by rituximab maintenance.

The median time to full venetoclax dose was 12 days (range, 5-21 days) and all 15 patients reached the target dose. The mean length of stay during the ramp-up period was 9.5 days (range, 6-22 days).
 

The incidence of clinical TLS was 13.2%, occurring in two patients, one at the initial 20-mg dose, and one at the 200-mg dose level. Another five patients had asymptomatic TLS. Other treatment-related adverse events were anemia in seven patients, neutropenia in six patients, thrombocytopenia in five patients, and lung infection in one patient.

 

Twelve patients had a partial response, one had stable disease, and two had progressive disease. The mean time to best response was 71 days.

One-year progression-free survival was 49%, and 1-year overall survival was 68%.

The investigators found that for patients who still have some disease control with a BCRi, it may be possible to keep them on that drug while transitioning to venetoclax. The rapid dose escalation protocol should only be attempted in highly experience comprehensive cancer centers, Dr. Awan said.

“Under very close monitoring in an experienced inpatient setting, where the nurses are very used to doing this on a weekly basis in a very high volume center, I think that our data show that we could do this without affecting toxicity significantly or mortality,” he said.

Venetoclax therapy could buy enough time for patients to bridge to other options, such as chimeric antigen receptor (CAR) T-cell therapy or allogeneic stem cell transplant, he noted.

“But if we had waited 4 weeks, most of these patients would not have made it,” he said.

The study was internally funded. Dr. Awan reported research funding from Gilead, Pharmacyclics, AbbVie, and Janssen.

SOURCE: Koenig K et al. EHA Congress, Abstract PF357.

Researching medical information currently is the third most common use of the Internet in the United States,¹ with the majority of adults using the Web as their first source for health information before seeing a physician.² When assessing health-related information online, resources can be grouped into 4 categories: (1) those attributed to self-proclaimed experts, (2) promotional, (3) social media, and (4) educational.³ Access to such a wide range of sources may give readers the opportunity to share personal anecdotes and opinions, thereby serving as a forum for information that essentially cannot be validated. Although such websites may include useful information and cite current literature, in other instances health-related information may be misleading or fabricated.³

In a study evaluating 291 skin conditions and related Google trends, acne, psoriasis, and eczema were among the most burdensome diseases, with acne yielding the highest number of search results.⁴ Results of the study indicated a positive correlation between disease burden and online search interest.⁴ The impact of these online searches and the validity of Google search results are topics worth considering, as more dermatology patients are relying on holistic and nonpharmaceutical approaches to treatment and disease management.⁵ The purpose of this study was to evaluate content on diet and dermatology available on the Internet for acne, psoriasis, and eczema.

Methods

Google searches were performed in December 2017 using the terms diet and acne, diet and psoriasis, and diet and eczema. The first 10 results for each respective search were reviewed for recommendations about which foods to incorporate in the diet and which to avoid. They also were classified according to the following 4 website categories: (1) those attributed to self-proclaimed experts, (2) promotional, (3) social media, and (4) educational. The recommendations gathered from the 30 websites were then compared to the current literature assessing the impact of diet on these respective conditions by conducting PubMed searches of articles indexed for MEDLINE using the same terms.

Results

The results of this study are outlined in the eTable.

Acne
Our Google search using the term diet and acne produced 17,500,000 results. Of the first 10 search results, 40% (4/10) were websites attributed to self-proclaimed experts, 40% (4/10) were educational resources, and 20% (2/10) were promotional websites. Most of the websites advised acne patients to avoid high glycemic index foods (90% [9/10]) and dairy products (90% [9/10]). When discussing which foods to include in the diet, 70% (7/10) of websites recommended that patients incorporate omega-3 fatty acids and antioxidants in the diet.

Research has shown that a low glycemic index diet can lead to a decrease in patients’ acne lesion counts in some instances.^6,7 In a case-controlled study of 2258 patients on a popular weight loss diet that emphasized low glycemic index foods, 87% of participants reported a reduction in acne and 91% reported a decrease in their dosage or number of acne medications.⁷ Still, the exact correlation between acne development and consumption of glycemic index foods has not been confirmed. However, high glycemic index diets have been linked to hyperinsulinemia, indicating that insulin levels may play a role in acne formation.⁸ The majority of other currently available studies evaluated the potential link between dairy consumption and acne. A retrospective analysis of 47,355 women spanning 12 weeks showed a positive link between increased dairy consumption, specifically skim milk, and acne formation. Despite the positive trend, limitations such as recall bias made it difficult to draw a conclusion based on these findings.⁹ However, results of a longitudinal questionnaire-based population study evaluating the impact of dairy consumption on acne in 2489 adolescent patients confirmed a positive correlation.¹⁰ Studies conducted in 2009 and 2011 concluded that milk consumption results in elevated insulinlike growth factor 1 levels, which were linked to comedogenesis.^8,11

Currently, there are well-described mechanisms to explain the association of dairy consumption and glycemic index with acne. Confirming a correlation between acne development and dairy consumption suggests that a dairy-free diet may benefit acne patients.⁵ Other trials indicate that low glycemic index diets are beneficial in treating acne.^6,7 Therefore, some of the recommendations made in our search results may be of merit; however, there is minimal evidence proving the benefits of the other dietary recommendations made in the websites we evaluated.

Psoriasis
Our Google search using the term diet and psoriasis yielded a total of 9,420,000 results. Of the first 10 search results, 40% (4/10) were websites attributed to self-proclaimed experts, 30% (3/10) were promotional, and 30% (3/10) were educational. Seventy percent (7/10) of websites recommended avoiding alcohol and 60% (6/10) recommended avoiding gluten, with others discouraging consumption of red meat. Most of the websites encouraged patients to consume omega-3 fatty acids and antioxidants, while a few also recommended vitamins A, D, and E, as well as evening primrose oil supplements.

Although current research indicates a positive correlation between excessive alcohol use and psoriasis severity, it is still unclear whether alcohol consumption can be directly linked to the disease.^12-14 Likewise, despite belief that increased oxidative stress likely contributes to inflammation in psoriasis, there is little evidence linking antioxidants to improvement in psoriasis symptoms.¹² However, the current literature is inconsistent regarding the effects of fish oil supplementation on psoriasis.¹² In a randomized double-blind study of 145 patients, there was no significant difference in psoriasis area and severity index scores between a control group and a treatment group receiving fish oil supplementation.¹⁵ In another RCT of 45 participants, those given daily very long-chain omega-3 fatty acid supplements saw no difference in psoriasis symptoms.¹⁵ Despite debate, literature assessing the impact of gluten-free diets has described improvement in psoriasis lesions in patients with celiac-specific antibodies.¹⁶ Although some observational studies described vitamin D supplementation to be beneficial in the treatment of psoriatic lesions, a more recent RCT found no significant difference between control and treatment groups.^17-19

Studies also have revealed that certain eating patterns, such as those associated with the Mediterranean diet that is rich in fruits, vegetables, whole grains, and omega-3 fatty acids may be linked to improved endothelial function scores and reduced C-reactive protein and IL-18levels.^20,21 In a double-blind RCT of 75 patients with plaque psoriasis, mean (SD) psoriasis area and severity index scores decreased by 11.2 (9.8) in a group treated with omega-3 fatty acids compared to 7.5 (8.8) with omega-6 fatty acids (P=.048).²²

Although excessive alcohol use may be linked to psoriasis, there is no conclusive evidence indicating causation, thereby discrediting online claims.^12-14 Research has revealed that gluten-free diets in psoriasis patients with celiac disease may improve psoriasis treatment¹⁶; however, sufficient evidence is lacking for diets low in gluten and high in polyunsaturated fatty acids or antioxidant supplementation. Of the dietary supplements recommended in the search results we reviewed, fish oil appears to be the most promising, but no recommendations can be made based on the current research.

Eczema
Our Google search using the term diet and eczema yielded 1,160,000 results, with 50% (5/10) of websites attributed to self-proclaimed experts, 30% (3/10) to educational websites, and 20% (2/10) to promotional sites. Of the first 10 results, 80% (8/10) recommended that patients with eczema avoid milk/dairy and 50% (5/10) advised to avoid soy and wheat/gluten. Other websites indicated to avoid eggs, nuts, and artificial sweeteners. Patients were encouraged to incorporate omega-3 fatty acids in their diets, and a few sites recommended bananas, coconut oil, olive oil, and various teas.

In a review of 11 studies with a total of 596 participants, supplementation with vitamins D and E, fish oil, olive oil, and linoleic acid was evaluated for the treatment of eczema.²³ Although results indicated modest improvement of eczema severity with supplementation of fish oil, evidence favoring this treatment is limited and unconvincing. Furthermore, some evidence indicates that elimination diets are only appropriate for patients with food allergies.²⁴ In a study evaluating an egg-free and dairy-free diet for eczema patients, only participants with positive egg-specific serum IgE levels saw improvement in disease severity.²³ Even though IgE-mediated food allergies have been reported in 40% of children with moderate eczema, the contribution of these allergies to eczema is questionable.²⁵

There is little evidence in the literature to indicate a definitive correlation between the foods mentioned in the search results we evaluated and the development of eczema; however, for patients with food allergies and eczema, elimination diets may decrease disease severity.^25,26 There is insufficient evidence to suggest a benefit from evening primrose oil or fish oil supplementation, thereby debunking claims found online.

 

Comment

Although our Google search results included a wide range of sources and information regarding diet and dermatologic conditions such as acne, psoriasis, and eczema, most of the information we found was either unfounded or misleading. Study limitations in the current literature include small sample size, potential recall bias, lack of appropriate controls, incomplete reported results, and the failure to clearly define skin changes.

When considering the accuracy and type of information regarding skin conditions that is available on the Internet, it is important to note that most of the results we reviewed were webpages attributed to self-proclaimed experts. Although educational websites also were included in the search results, whether or not patients prefer or understand the content of such websites is still unknown; therefore, health organizations should consider revising online patient education materials to allow universal comprehension.²⁷

Furthermore, it is important to consider the impact that widespread Internet access may have on the physician-patient relationship. Having access to health-related information online and being able to potentially self-diagnose could delay or deter patients from seeking professional advice or care.³ A study evaluating the impact of online searches on the physician-patient relationship among 175 patients determined that 36.5% of patients gathered information online prior to their consultation with a physician, while 67.3% chose to complement the information given to them by their physician with online resources.²⁸ Based on these statistics, it is important that physicians be up-to-date with Internet discourse to discredit unfounded recommendations. Ultimately, when it comes to diet and dermatology, patients ought to be skeptical of the information currently available on the Internet, given that most of it is unsubstantiated by medical research.

Researching medical information currently is the third most common use of the Internet in the United States,¹ with the majority of adults using the Web as their first source for health information before seeing a physician.² When assessing health-related information online, resources can be grouped into 4 categories: (1) those attributed to self-proclaimed experts, (2) promotional, (3) social media, and (4) educational.³ Access to such a wide range of sources may give readers the opportunity to share personal anecdotes and opinions, thereby serving as a forum for information that essentially cannot be validated. Although such websites may include useful information and cite current literature, in other instances health-related information may be misleading or fabricated.³

In a study evaluating 291 skin conditions and related Google trends, acne, psoriasis, and eczema were among the most burdensome diseases, with acne yielding the highest number of search results.⁴ Results of the study indicated a positive correlation between disease burden and online search interest.⁴ The impact of these online searches and the validity of Google search results are topics worth considering, as more dermatology patients are relying on holistic and nonpharmaceutical approaches to treatment and disease management.⁵ The purpose of this study was to evaluate content on diet and dermatology available on the Internet for acne, psoriasis, and eczema.

Methods

Google searches were performed in December 2017 using the terms diet and acne, diet and psoriasis, and diet and eczema. The first 10 results for each respective search were reviewed for recommendations about which foods to incorporate in the diet and which to avoid. They also were classified according to the following 4 website categories: (1) those attributed to self-proclaimed experts, (2) promotional, (3) social media, and (4) educational. The recommendations gathered from the 30 websites were then compared to the current literature assessing the impact of diet on these respective conditions by conducting PubMed searches of articles indexed for MEDLINE using the same terms.

Results

The results of this study are outlined in the eTable.

Acne
Our Google search using the term diet and acne produced 17,500,000 results. Of the first 10 search results, 40% (4/10) were websites attributed to self-proclaimed experts, 40% (4/10) were educational resources, and 20% (2/10) were promotional websites. Most of the websites advised acne patients to avoid high glycemic index foods (90% [9/10]) and dairy products (90% [9/10]). When discussing which foods to include in the diet, 70% (7/10) of websites recommended that patients incorporate omega-3 fatty acids and antioxidants in the diet.

Research has shown that a low glycemic index diet can lead to a decrease in patients’ acne lesion counts in some instances.^6,7 In a case-controlled study of 2258 patients on a popular weight loss diet that emphasized low glycemic index foods, 87% of participants reported a reduction in acne and 91% reported a decrease in their dosage or number of acne medications.⁷ Still, the exact correlation between acne development and consumption of glycemic index foods has not been confirmed. However, high glycemic index diets have been linked to hyperinsulinemia, indicating that insulin levels may play a role in acne formation.⁸ The majority of other currently available studies evaluated the potential link between dairy consumption and acne. A retrospective analysis of 47,355 women spanning 12 weeks showed a positive link between increased dairy consumption, specifically skim milk, and acne formation. Despite the positive trend, limitations such as recall bias made it difficult to draw a conclusion based on these findings.⁹ However, results of a longitudinal questionnaire-based population study evaluating the impact of dairy consumption on acne in 2489 adolescent patients confirmed a positive correlation.¹⁰ Studies conducted in 2009 and 2011 concluded that milk consumption results in elevated insulinlike growth factor 1 levels, which were linked to comedogenesis.^8,11

Currently, there are well-described mechanisms to explain the association of dairy consumption and glycemic index with acne. Confirming a correlation between acne development and dairy consumption suggests that a dairy-free diet may benefit acne patients.⁵ Other trials indicate that low glycemic index diets are beneficial in treating acne.^6,7 Therefore, some of the recommendations made in our search results may be of merit; however, there is minimal evidence proving the benefits of the other dietary recommendations made in the websites we evaluated.

Psoriasis
Our Google search using the term diet and psoriasis yielded a total of 9,420,000 results. Of the first 10 search results, 40% (4/10) were websites attributed to self-proclaimed experts, 30% (3/10) were promotional, and 30% (3/10) were educational. Seventy percent (7/10) of websites recommended avoiding alcohol and 60% (6/10) recommended avoiding gluten, with others discouraging consumption of red meat. Most of the websites encouraged patients to consume omega-3 fatty acids and antioxidants, while a few also recommended vitamins A, D, and E, as well as evening primrose oil supplements.

Although current research indicates a positive correlation between excessive alcohol use and psoriasis severity, it is still unclear whether alcohol consumption can be directly linked to the disease.^12-14 Likewise, despite belief that increased oxidative stress likely contributes to inflammation in psoriasis, there is little evidence linking antioxidants to improvement in psoriasis symptoms.¹² However, the current literature is inconsistent regarding the effects of fish oil supplementation on psoriasis.¹² In a randomized double-blind study of 145 patients, there was no significant difference in psoriasis area and severity index scores between a control group and a treatment group receiving fish oil supplementation.¹⁵ In another RCT of 45 participants, those given daily very long-chain omega-3 fatty acid supplements saw no difference in psoriasis symptoms.¹⁵ Despite debate, literature assessing the impact of gluten-free diets has described improvement in psoriasis lesions in patients with celiac-specific antibodies.¹⁶ Although some observational studies described vitamin D supplementation to be beneficial in the treatment of psoriatic lesions, a more recent RCT found no significant difference between control and treatment groups.^17-19

Studies also have revealed that certain eating patterns, such as those associated with the Mediterranean diet that is rich in fruits, vegetables, whole grains, and omega-3 fatty acids may be linked to improved endothelial function scores and reduced C-reactive protein and IL-18levels.^20,21 In a double-blind RCT of 75 patients with plaque psoriasis, mean (SD) psoriasis area and severity index scores decreased by 11.2 (9.8) in a group treated with omega-3 fatty acids compared to 7.5 (8.8) with omega-6 fatty acids (P=.048).²²

Although excessive alcohol use may be linked to psoriasis, there is no conclusive evidence indicating causation, thereby discrediting online claims.^12-14 Research has revealed that gluten-free diets in psoriasis patients with celiac disease may improve psoriasis treatment¹⁶; however, sufficient evidence is lacking for diets low in gluten and high in polyunsaturated fatty acids or antioxidant supplementation. Of the dietary supplements recommended in the search results we reviewed, fish oil appears to be the most promising, but no recommendations can be made based on the current research.

Eczema
Our Google search using the term diet and eczema yielded 1,160,000 results, with 50% (5/10) of websites attributed to self-proclaimed experts, 30% (3/10) to educational websites, and 20% (2/10) to promotional sites. Of the first 10 results, 80% (8/10) recommended that patients with eczema avoid milk/dairy and 50% (5/10) advised to avoid soy and wheat/gluten. Other websites indicated to avoid eggs, nuts, and artificial sweeteners. Patients were encouraged to incorporate omega-3 fatty acids in their diets, and a few sites recommended bananas, coconut oil, olive oil, and various teas.

In a review of 11 studies with a total of 596 participants, supplementation with vitamins D and E, fish oil, olive oil, and linoleic acid was evaluated for the treatment of eczema.²³ Although results indicated modest improvement of eczema severity with supplementation of fish oil, evidence favoring this treatment is limited and unconvincing. Furthermore, some evidence indicates that elimination diets are only appropriate for patients with food allergies.²⁴ In a study evaluating an egg-free and dairy-free diet for eczema patients, only participants with positive egg-specific serum IgE levels saw improvement in disease severity.²³ Even though IgE-mediated food allergies have been reported in 40% of children with moderate eczema, the contribution of these allergies to eczema is questionable.²⁵

There is little evidence in the literature to indicate a definitive correlation between the foods mentioned in the search results we evaluated and the development of eczema; however, for patients with food allergies and eczema, elimination diets may decrease disease severity.^25,26 There is insufficient evidence to suggest a benefit from evening primrose oil or fish oil supplementation, thereby debunking claims found online.

 

Comment

Although our Google search results included a wide range of sources and information regarding diet and dermatologic conditions such as acne, psoriasis, and eczema, most of the information we found was either unfounded or misleading. Study limitations in the current literature include small sample size, potential recall bias, lack of appropriate controls, incomplete reported results, and the failure to clearly define skin changes.

When considering the accuracy and type of information regarding skin conditions that is available on the Internet, it is important to note that most of the results we reviewed were webpages attributed to self-proclaimed experts. Although educational websites also were included in the search results, whether or not patients prefer or understand the content of such websites is still unknown; therefore, health organizations should consider revising online patient education materials to allow universal comprehension.²⁷

Furthermore, it is important to consider the impact that widespread Internet access may have on the physician-patient relationship. Having access to health-related information online and being able to potentially self-diagnose could delay or deter patients from seeking professional advice or care.³ A study evaluating the impact of online searches on the physician-patient relationship among 175 patients determined that 36.5% of patients gathered information online prior to their consultation with a physician, while 67.3% chose to complement the information given to them by their physician with online resources.²⁸ Based on these statistics, it is important that physicians be up-to-date with Internet discourse to discredit unfounded recommendations. Ultimately, when it comes to diet and dermatology, patients ought to be skeptical of the information currently available on the Internet, given that most of it is unsubstantiated by medical research.

Researching medical information currently is the third most common use of the Internet in the United States,¹ with the majority of adults using the Web as their first source for health information before seeing a physician.² When assessing health-related information online, resources can be grouped into 4 categories: (1) those attributed to self-proclaimed experts, (2) promotional, (3) social media, and (4) educational.³ Access to such a wide range of sources may give readers the opportunity to share personal anecdotes and opinions, thereby serving as a forum for information that essentially cannot be validated. Although such websites may include useful information and cite current literature, in other instances health-related information may be misleading or fabricated.³

In a study evaluating 291 skin conditions and related Google trends, acne, psoriasis, and eczema were among the most burdensome diseases, with acne yielding the highest number of search results.⁴ Results of the study indicated a positive correlation between disease burden and online search interest.⁴ The impact of these online searches and the validity of Google search results are topics worth considering, as more dermatology patients are relying on holistic and nonpharmaceutical approaches to treatment and disease management.⁵ The purpose of this study was to evaluate content on diet and dermatology available on the Internet for acne, psoriasis, and eczema.

Methods

Google searches were performed in December 2017 using the terms diet and acne, diet and psoriasis, and diet and eczema. The first 10 results for each respective search were reviewed for recommendations about which foods to incorporate in the diet and which to avoid. They also were classified according to the following 4 website categories: (1) those attributed to self-proclaimed experts, (2) promotional, (3) social media, and (4) educational. The recommendations gathered from the 30 websites were then compared to the current literature assessing the impact of diet on these respective conditions by conducting PubMed searches of articles indexed for MEDLINE using the same terms.

Results

The results of this study are outlined in the eTable.

Acne
Our Google search using the term diet and acne produced 17,500,000 results. Of the first 10 search results, 40% (4/10) were websites attributed to self-proclaimed experts, 40% (4/10) were educational resources, and 20% (2/10) were promotional websites. Most of the websites advised acne patients to avoid high glycemic index foods (90% [9/10]) and dairy products (90% [9/10]). When discussing which foods to include in the diet, 70% (7/10) of websites recommended that patients incorporate omega-3 fatty acids and antioxidants in the diet.

Research has shown that a low glycemic index diet can lead to a decrease in patients’ acne lesion counts in some instances.^6,7 In a case-controlled study of 2258 patients on a popular weight loss diet that emphasized low glycemic index foods, 87% of participants reported a reduction in acne and 91% reported a decrease in their dosage or number of acne medications.⁷ Still, the exact correlation between acne development and consumption of glycemic index foods has not been confirmed. However, high glycemic index diets have been linked to hyperinsulinemia, indicating that insulin levels may play a role in acne formation.⁸ The majority of other currently available studies evaluated the potential link between dairy consumption and acne. A retrospective analysis of 47,355 women spanning 12 weeks showed a positive link between increased dairy consumption, specifically skim milk, and acne formation. Despite the positive trend, limitations such as recall bias made it difficult to draw a conclusion based on these findings.⁹ However, results of a longitudinal questionnaire-based population study evaluating the impact of dairy consumption on acne in 2489 adolescent patients confirmed a positive correlation.¹⁰ Studies conducted in 2009 and 2011 concluded that milk consumption results in elevated insulinlike growth factor 1 levels, which were linked to comedogenesis.^8,11

Currently, there are well-described mechanisms to explain the association of dairy consumption and glycemic index with acne. Confirming a correlation between acne development and dairy consumption suggests that a dairy-free diet may benefit acne patients.⁵ Other trials indicate that low glycemic index diets are beneficial in treating acne.^6,7 Therefore, some of the recommendations made in our search results may be of merit; however, there is minimal evidence proving the benefits of the other dietary recommendations made in the websites we evaluated.

Psoriasis
Our Google search using the term diet and psoriasis yielded a total of 9,420,000 results. Of the first 10 search results, 40% (4/10) were websites attributed to self-proclaimed experts, 30% (3/10) were promotional, and 30% (3/10) were educational. Seventy percent (7/10) of websites recommended avoiding alcohol and 60% (6/10) recommended avoiding gluten, with others discouraging consumption of red meat. Most of the websites encouraged patients to consume omega-3 fatty acids and antioxidants, while a few also recommended vitamins A, D, and E, as well as evening primrose oil supplements.

Although current research indicates a positive correlation between excessive alcohol use and psoriasis severity, it is still unclear whether alcohol consumption can be directly linked to the disease.^12-14 Likewise, despite belief that increased oxidative stress likely contributes to inflammation in psoriasis, there is little evidence linking antioxidants to improvement in psoriasis symptoms.¹² However, the current literature is inconsistent regarding the effects of fish oil supplementation on psoriasis.¹² In a randomized double-blind study of 145 patients, there was no significant difference in psoriasis area and severity index scores between a control group and a treatment group receiving fish oil supplementation.¹⁵ In another RCT of 45 participants, those given daily very long-chain omega-3 fatty acid supplements saw no difference in psoriasis symptoms.¹⁵ Despite debate, literature assessing the impact of gluten-free diets has described improvement in psoriasis lesions in patients with celiac-specific antibodies.¹⁶ Although some observational studies described vitamin D supplementation to be beneficial in the treatment of psoriatic lesions, a more recent RCT found no significant difference between control and treatment groups.^17-19

Studies also have revealed that certain eating patterns, such as those associated with the Mediterranean diet that is rich in fruits, vegetables, whole grains, and omega-3 fatty acids may be linked to improved endothelial function scores and reduced C-reactive protein and IL-18levels.^20,21 In a double-blind RCT of 75 patients with plaque psoriasis, mean (SD) psoriasis area and severity index scores decreased by 11.2 (9.8) in a group treated with omega-3 fatty acids compared to 7.5 (8.8) with omega-6 fatty acids (P=.048).²²

Although excessive alcohol use may be linked to psoriasis, there is no conclusive evidence indicating causation, thereby discrediting online claims.^12-14 Research has revealed that gluten-free diets in psoriasis patients with celiac disease may improve psoriasis treatment¹⁶; however, sufficient evidence is lacking for diets low in gluten and high in polyunsaturated fatty acids or antioxidant supplementation. Of the dietary supplements recommended in the search results we reviewed, fish oil appears to be the most promising, but no recommendations can be made based on the current research.

Eczema
Our Google search using the term diet and eczema yielded 1,160,000 results, with 50% (5/10) of websites attributed to self-proclaimed experts, 30% (3/10) to educational websites, and 20% (2/10) to promotional sites. Of the first 10 results, 80% (8/10) recommended that patients with eczema avoid milk/dairy and 50% (5/10) advised to avoid soy and wheat/gluten. Other websites indicated to avoid eggs, nuts, and artificial sweeteners. Patients were encouraged to incorporate omega-3 fatty acids in their diets, and a few sites recommended bananas, coconut oil, olive oil, and various teas.

In a review of 11 studies with a total of 596 participants, supplementation with vitamins D and E, fish oil, olive oil, and linoleic acid was evaluated for the treatment of eczema.²³ Although results indicated modest improvement of eczema severity with supplementation of fish oil, evidence favoring this treatment is limited and unconvincing. Furthermore, some evidence indicates that elimination diets are only appropriate for patients with food allergies.²⁴ In a study evaluating an egg-free and dairy-free diet for eczema patients, only participants with positive egg-specific serum IgE levels saw improvement in disease severity.²³ Even though IgE-mediated food allergies have been reported in 40% of children with moderate eczema, the contribution of these allergies to eczema is questionable.²⁵

There is little evidence in the literature to indicate a definitive correlation between the foods mentioned in the search results we evaluated and the development of eczema; however, for patients with food allergies and eczema, elimination diets may decrease disease severity.^25,26 There is insufficient evidence to suggest a benefit from evening primrose oil or fish oil supplementation, thereby debunking claims found online.

 

Comment

Although our Google search results included a wide range of sources and information regarding diet and dermatologic conditions such as acne, psoriasis, and eczema, most of the information we found was either unfounded or misleading. Study limitations in the current literature include small sample size, potential recall bias, lack of appropriate controls, incomplete reported results, and the failure to clearly define skin changes.

When considering the accuracy and type of information regarding skin conditions that is available on the Internet, it is important to note that most of the results we reviewed were webpages attributed to self-proclaimed experts. Although educational websites also were included in the search results, whether or not patients prefer or understand the content of such websites is still unknown; therefore, health organizations should consider revising online patient education materials to allow universal comprehension.²⁷

Furthermore, it is important to consider the impact that widespread Internet access may have on the physician-patient relationship. Having access to health-related information online and being able to potentially self-diagnose could delay or deter patients from seeking professional advice or care.³ A study evaluating the impact of online searches on the physician-patient relationship among 175 patients determined that 36.5% of patients gathered information online prior to their consultation with a physician, while 67.3% chose to complement the information given to them by their physician with online resources.²⁸ Based on these statistics, it is important that physicians be up-to-date with Internet discourse to discredit unfounded recommendations. Ultimately, when it comes to diet and dermatology, patients ought to be skeptical of the information currently available on the Internet, given that most of it is unsubstantiated by medical research.

 

Micrograph showing myelofibrosis

 

New research indicates that JAK inhibitors may increase the risk of lymphoma in patients with myelofibrosis (MF).

 

The patients studied had a 15- to 25-fold higher risk of developing B-cell lymphoma if they received treatment with JAK inhibitors.

 

The researchers speculate that screening MF patients for a pre-existing B-cell clone before starting JAK inhibitor therapy may help prevent lymphoma development.

 

Heinz Gisslinger, MD, of the Medical University of Vienna in Austria, and his colleagues conducted this research and reported the findings in Blood.

 

“[W]e started noticing sporadic cases of lymphomas developing in patients being treated for myeloproliferative neoplasms and wanted to know if this phenomenon was connected to treatment,” Dr Gisslinger said.

 

Therefore, he and his colleagues assessed 626 patients receiving treatment for myeloproliferative neoplasms (MPNs) at the Medical University of Vienna.

 

The incidence of B-cell lymphoma was 5.8% (4/69) in patients treated with JAK inhibitors and 0.36% (2/557) in patients who did not receive JAK inhibitors. That amounts to a 16-fold increased risk of lymphoma in patients receiving JAK inhibitors.

 

When the researchers analyzed only patients with primary MF (n=216), the increased risk of B-cell lymphoma was even greater. The incidence of lymphoma was 9.68% (3/31) in patients treated with JAK inhibitors and 0.54% (1/185) in patients who did not receive JAK inhibitors.

 

That corresponds to a 19-fold increased risk of B-cell lymphoma in primary MF patients treated with JAK inhibitors. When the researchers adjusted for age, there was a 21-fold greater risk. When they adjusted for sex, the risk was 25 times higher.

 

In a second cohort of 929 MPN patients, the incidence of B-cell lymphoma was 3.51% (2/57) in patients who received JAK inhibitors and 0.23% (2/872) in patients who did not. This corresponds to a 15-fold increased risk of lymphoma in the JAK inhibitor recipients.

 

Lymphoma cases

 

In all, there were 6 patients who developed lymphoma after JAK inhibitor treatment. Five developed diffuse large B-cell lymphoma, and 1 had high-grade B-cell lymphoma not otherwise specified.

 

Four of the patients had primary MF, 1 had post-polycythemia vera MF, and 1 had post-essential thrombocythemia (ET) MF. Five patients had a JAK2V617F mutation, and 1 (the post-ET MF patient) had a CALR mutation.

 

All 6 patients had received treatment with ruxolitinib. One patient also received fedratinib.

 

B-cell clone

 

The researchers studied bone marrow samples from 54 of the 69 patients treated with JAK inhibitors in the first cohort. The team found a pre-existing B-cell clone in 3 of the 4 patients who developed lymphoma. Further investigation suggested this was the clone that later transformed into lymphoma.

 

The researchers also found an association between JAK inhibition and an increased frequency of aggressive B-cell lymphomas in mouse models.

 

“By replicating this link between this B-cell clone and aggressive lymphoma, we hope to speed the discovery of an alternative therapy for myelofibrosis,” said study author Veronica Sexl, MD, of the University of Veterinary Medicine in Vienna. “These findings are going to be valuable in clinical care.”

 

“We determined that patients with this pre-existing B-cell clone in their bone marrow are most at risk for developing aggressive lymphoma,” added study author Ulrich Jäger, MD, of the Medical University of Vienna.

 

“We also know that up to 16% of people with myelofibrosis have immunoglobulin gene rearrangements like this B-cell clone. Therefore, our findings suggest that all patients with myelofibrosis should be tested for such gene rearrangements before prescribing JAK inhibitors to treat their disease.”

 

Micrograph showing myelofibrosis

 

New research indicates that JAK inhibitors may increase the risk of lymphoma in patients with myelofibrosis (MF).

 

The patients studied had a 15- to 25-fold higher risk of developing B-cell lymphoma if they received treatment with JAK inhibitors.

 

The researchers speculate that screening MF patients for a pre-existing B-cell clone before starting JAK inhibitor therapy may help prevent lymphoma development.

 

Heinz Gisslinger, MD, of the Medical University of Vienna in Austria, and his colleagues conducted this research and reported the findings in Blood.

 

“[W]e started noticing sporadic cases of lymphomas developing in patients being treated for myeloproliferative neoplasms and wanted to know if this phenomenon was connected to treatment,” Dr Gisslinger said.

 

Therefore, he and his colleagues assessed 626 patients receiving treatment for myeloproliferative neoplasms (MPNs) at the Medical University of Vienna.

 

The incidence of B-cell lymphoma was 5.8% (4/69) in patients treated with JAK inhibitors and 0.36% (2/557) in patients who did not receive JAK inhibitors. That amounts to a 16-fold increased risk of lymphoma in patients receiving JAK inhibitors.

 

When the researchers analyzed only patients with primary MF (n=216), the increased risk of B-cell lymphoma was even greater. The incidence of lymphoma was 9.68% (3/31) in patients treated with JAK inhibitors and 0.54% (1/185) in patients who did not receive JAK inhibitors.

 

That corresponds to a 19-fold increased risk of B-cell lymphoma in primary MF patients treated with JAK inhibitors. When the researchers adjusted for age, there was a 21-fold greater risk. When they adjusted for sex, the risk was 25 times higher.

 

In a second cohort of 929 MPN patients, the incidence of B-cell lymphoma was 3.51% (2/57) in patients who received JAK inhibitors and 0.23% (2/872) in patients who did not. This corresponds to a 15-fold increased risk of lymphoma in the JAK inhibitor recipients.

 

Lymphoma cases

 

In all, there were 6 patients who developed lymphoma after JAK inhibitor treatment. Five developed diffuse large B-cell lymphoma, and 1 had high-grade B-cell lymphoma not otherwise specified.

 

Four of the patients had primary MF, 1 had post-polycythemia vera MF, and 1 had post-essential thrombocythemia (ET) MF. Five patients had a JAK2V617F mutation, and 1 (the post-ET MF patient) had a CALR mutation.

 

All 6 patients had received treatment with ruxolitinib. One patient also received fedratinib.

 

B-cell clone

 

The researchers studied bone marrow samples from 54 of the 69 patients treated with JAK inhibitors in the first cohort. The team found a pre-existing B-cell clone in 3 of the 4 patients who developed lymphoma. Further investigation suggested this was the clone that later transformed into lymphoma.

 

The researchers also found an association between JAK inhibition and an increased frequency of aggressive B-cell lymphomas in mouse models.

 

“By replicating this link between this B-cell clone and aggressive lymphoma, we hope to speed the discovery of an alternative therapy for myelofibrosis,” said study author Veronica Sexl, MD, of the University of Veterinary Medicine in Vienna. “These findings are going to be valuable in clinical care.”

 

“We determined that patients with this pre-existing B-cell clone in their bone marrow are most at risk for developing aggressive lymphoma,” added study author Ulrich Jäger, MD, of the Medical University of Vienna.

 

“We also know that up to 16% of people with myelofibrosis have immunoglobulin gene rearrangements like this B-cell clone. Therefore, our findings suggest that all patients with myelofibrosis should be tested for such gene rearrangements before prescribing JAK inhibitors to treat their disease.”

 

Micrograph showing myelofibrosis

 

New research indicates that JAK inhibitors may increase the risk of lymphoma in patients with myelofibrosis (MF).

 

The patients studied had a 15- to 25-fold higher risk of developing B-cell lymphoma if they received treatment with JAK inhibitors.

 

The researchers speculate that screening MF patients for a pre-existing B-cell clone before starting JAK inhibitor therapy may help prevent lymphoma development.

 

Heinz Gisslinger, MD, of the Medical University of Vienna in Austria, and his colleagues conducted this research and reported the findings in Blood.

 

“[W]e started noticing sporadic cases of lymphomas developing in patients being treated for myeloproliferative neoplasms and wanted to know if this phenomenon was connected to treatment,” Dr Gisslinger said.

 

Therefore, he and his colleagues assessed 626 patients receiving treatment for myeloproliferative neoplasms (MPNs) at the Medical University of Vienna.

 

The incidence of B-cell lymphoma was 5.8% (4/69) in patients treated with JAK inhibitors and 0.36% (2/557) in patients who did not receive JAK inhibitors. That amounts to a 16-fold increased risk of lymphoma in patients receiving JAK inhibitors.

 

When the researchers analyzed only patients with primary MF (n=216), the increased risk of B-cell lymphoma was even greater. The incidence of lymphoma was 9.68% (3/31) in patients treated with JAK inhibitors and 0.54% (1/185) in patients who did not receive JAK inhibitors.

 

That corresponds to a 19-fold increased risk of B-cell lymphoma in primary MF patients treated with JAK inhibitors. When the researchers adjusted for age, there was a 21-fold greater risk. When they adjusted for sex, the risk was 25 times higher.

 

In a second cohort of 929 MPN patients, the incidence of B-cell lymphoma was 3.51% (2/57) in patients who received JAK inhibitors and 0.23% (2/872) in patients who did not. This corresponds to a 15-fold increased risk of lymphoma in the JAK inhibitor recipients.

 

Lymphoma cases

 

In all, there were 6 patients who developed lymphoma after JAK inhibitor treatment. Five developed diffuse large B-cell lymphoma, and 1 had high-grade B-cell lymphoma not otherwise specified.

 

Four of the patients had primary MF, 1 had post-polycythemia vera MF, and 1 had post-essential thrombocythemia (ET) MF. Five patients had a JAK2V617F mutation, and 1 (the post-ET MF patient) had a CALR mutation.

 

All 6 patients had received treatment with ruxolitinib. One patient also received fedratinib.

 

B-cell clone

 

The researchers studied bone marrow samples from 54 of the 69 patients treated with JAK inhibitors in the first cohort. The team found a pre-existing B-cell clone in 3 of the 4 patients who developed lymphoma. Further investigation suggested this was the clone that later transformed into lymphoma.

 

The researchers also found an association between JAK inhibition and an increased frequency of aggressive B-cell lymphomas in mouse models.

 

“By replicating this link between this B-cell clone and aggressive lymphoma, we hope to speed the discovery of an alternative therapy for myelofibrosis,” said study author Veronica Sexl, MD, of the University of Veterinary Medicine in Vienna. “These findings are going to be valuable in clinical care.”

 

“We determined that patients with this pre-existing B-cell clone in their bone marrow are most at risk for developing aggressive lymphoma,” added study author Ulrich Jäger, MD, of the Medical University of Vienna.

 

“We also know that up to 16% of people with myelofibrosis have immunoglobulin gene rearrangements like this B-cell clone. Therefore, our findings suggest that all patients with myelofibrosis should be tested for such gene rearrangements before prescribing JAK inhibitors to treat their disease.”

 

Photo from EHA

 

STOCKHOLM—Tagraxofusp (SL-401) has produced “very encouraging” results in a phase 2 trial of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), according to an investigator.

 

Tagraxofusp, a targeted therapy directed to CD123, produced an overall response rate (ORR) of 83% and a complete response (CR) rate of 62% in patients with previously untreated or relapsed/refractory BPDCN.

 

Common adverse events (AEs) related to tagraxofusp include hypoalbuminemia, transaminitis, and thrombocytopenia. There was 1 grade 5 AE—a case of capillary leak syndrome (CLS).

 

Study investigator Naveen Pemmaraju, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S116.

 

The trial was sponsored by Stemline Therapeutics.

 

Dr Pemmaraju noted that there are no approved therapies for BPDCN, so patients may be treated with therapies intended for acute myeloid leukemia (AML), acute lymphoblastic leukemia, or lymphomas.

 

“These are usually quite intense cytotoxic chemotherapy regimens,” he said. “But even with these regimens, most groups report median overall survival times of 8 to 14 months.”

 

And although stem cell transplants can be effective in BPDCN, a “vast majority” of patients are not fit for transplant, according to Dr Pemmaraju.

 

With this in mind, he and his colleagues are conducting this trial of tagraxofusp in BPDCN.

 

The trial has 4 stages. In stage 1, patients received tagraxofusp at 7, 9, 12, or 16 μg/kg on days 1 to 5 of a 21-day cycle. In stages 2 and 3, patients received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle. Stage 4 is still enrolling.

 

Efficacy

 

Dr Pemmaraju presented results in 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN. The patients’ median age at baseline was 70 (range, 22-84), and 82% were male.

 

Three patients received tagraxofusp at 7 μg/kg/day, and the rest received the 12 μg/kg/day dose.

 

Among patients who received the 12 μg/kg/day dose, the ORR was 83% (35/42). The ORR was 90% (26/29) in previously untreated patients and 69% (9/13) in relapsed/refractory patients.

 

“These are very encouraging results—a 90% overall response rate in the frontline setting,” Dr Pemmaraju noted.

 

The composite CR rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.

 

This included 13 patients with a CR (1 relapsed/refractory), 10 with a clinical CR (3 relapsed/refractory), and 3 with a CR with incomplete hematologic recovery (1 relapsed/refractory). A clinical CR was defined as absence of gross disease with minimal residual skin abnormality.

 

Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.

 

Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival has not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).

 

Dr Pemmaraju said this result is important because it contrasts with the historical expectation of a median overall survival of 8 to 14 months.

 

Safety

 

Dr Pemmaraju presented safety results in 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with AML, myelofibrosis, and chronic myelomonocytic leukemia in addition to the 45 patients with BPDCN. However, AEs were similar regardless of disease.

 

Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).

 

 

CLS of any grade was also a common AE, occurring in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.

 

Dr Pemmaraju did note that CLS has proven manageable with monitoring and pre-emptive measures. Specifically, inclusion criteria were changed so that patients must have normal cardiac function, adequate kidney function, and albumin of at least 3.2 g/dl. Investigators also began monitoring patients’ weight, albumin levels, and kidney function.

 

“With the combination of greater understanding of CLS, actual definitive protocol adjustments made by investigators, and monitoring, this has been a highly manageable phenomenon,” Dr Pemmaraju said.

 

Next steps

 

The investigators plan to continue enrolling patients in this study and collect additional safety and survival data, but Dr Pemmaraju and his colleagues also want to evaluate tagraxofusp in combination with other therapies.

 

Tagraxofusp is already under investigation in combination with azacitidine in a phase 1/2 trial of patients with high-risk myelodysplastic syndromes and AML.

 

Dr Pemmaraju is interested in combining hypomethylating agents with tagraxofusp for BPDCN patients as well, to build upon the encouraging results with tagraxofusp alone.

 

“An extraordinarily rare disease that used to not have any therapies at all now has at least one ongoing clinical trial with some encouraging activity,” he said. “I hope that gives hope to people with rare diseases, to let them know they’re not alone. There may be someone out there who’s researching their disease, no matter how rare it is.”

 

Photo from EHA

 

STOCKHOLM—Tagraxofusp (SL-401) has produced “very encouraging” results in a phase 2 trial of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), according to an investigator.

 

Tagraxofusp, a targeted therapy directed to CD123, produced an overall response rate (ORR) of 83% and a complete response (CR) rate of 62% in patients with previously untreated or relapsed/refractory BPDCN.

 

Common adverse events (AEs) related to tagraxofusp include hypoalbuminemia, transaminitis, and thrombocytopenia. There was 1 grade 5 AE—a case of capillary leak syndrome (CLS).

 

Study investigator Naveen Pemmaraju, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S116.

 

The trial was sponsored by Stemline Therapeutics.

 

Dr Pemmaraju noted that there are no approved therapies for BPDCN, so patients may be treated with therapies intended for acute myeloid leukemia (AML), acute lymphoblastic leukemia, or lymphomas.

 

“These are usually quite intense cytotoxic chemotherapy regimens,” he said. “But even with these regimens, most groups report median overall survival times of 8 to 14 months.”

 

And although stem cell transplants can be effective in BPDCN, a “vast majority” of patients are not fit for transplant, according to Dr Pemmaraju.

 

With this in mind, he and his colleagues are conducting this trial of tagraxofusp in BPDCN.

 

The trial has 4 stages. In stage 1, patients received tagraxofusp at 7, 9, 12, or 16 μg/kg on days 1 to 5 of a 21-day cycle. In stages 2 and 3, patients received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle. Stage 4 is still enrolling.

 

Efficacy

 

Dr Pemmaraju presented results in 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN. The patients’ median age at baseline was 70 (range, 22-84), and 82% were male.

 

Three patients received tagraxofusp at 7 μg/kg/day, and the rest received the 12 μg/kg/day dose.

 

Among patients who received the 12 μg/kg/day dose, the ORR was 83% (35/42). The ORR was 90% (26/29) in previously untreated patients and 69% (9/13) in relapsed/refractory patients.

 

“These are very encouraging results—a 90% overall response rate in the frontline setting,” Dr Pemmaraju noted.

 

The composite CR rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.

 

This included 13 patients with a CR (1 relapsed/refractory), 10 with a clinical CR (3 relapsed/refractory), and 3 with a CR with incomplete hematologic recovery (1 relapsed/refractory). A clinical CR was defined as absence of gross disease with minimal residual skin abnormality.

 

Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.

 

Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival has not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).

 

Dr Pemmaraju said this result is important because it contrasts with the historical expectation of a median overall survival of 8 to 14 months.

 

Safety

 

Dr Pemmaraju presented safety results in 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with AML, myelofibrosis, and chronic myelomonocytic leukemia in addition to the 45 patients with BPDCN. However, AEs were similar regardless of disease.

 

Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).

 

 

CLS of any grade was also a common AE, occurring in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.

 

Dr Pemmaraju did note that CLS has proven manageable with monitoring and pre-emptive measures. Specifically, inclusion criteria were changed so that patients must have normal cardiac function, adequate kidney function, and albumin of at least 3.2 g/dl. Investigators also began monitoring patients’ weight, albumin levels, and kidney function.

 

“With the combination of greater understanding of CLS, actual definitive protocol adjustments made by investigators, and monitoring, this has been a highly manageable phenomenon,” Dr Pemmaraju said.

 

Next steps

 

The investigators plan to continue enrolling patients in this study and collect additional safety and survival data, but Dr Pemmaraju and his colleagues also want to evaluate tagraxofusp in combination with other therapies.

 

Tagraxofusp is already under investigation in combination with azacitidine in a phase 1/2 trial of patients with high-risk myelodysplastic syndromes and AML.

 

Dr Pemmaraju is interested in combining hypomethylating agents with tagraxofusp for BPDCN patients as well, to build upon the encouraging results with tagraxofusp alone.

 

“An extraordinarily rare disease that used to not have any therapies at all now has at least one ongoing clinical trial with some encouraging activity,” he said. “I hope that gives hope to people with rare diseases, to let them know they’re not alone. There may be someone out there who’s researching their disease, no matter how rare it is.”

 

Photo from EHA

 

STOCKHOLM—Tagraxofusp (SL-401) has produced “very encouraging” results in a phase 2 trial of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), according to an investigator.

 

Tagraxofusp, a targeted therapy directed to CD123, produced an overall response rate (ORR) of 83% and a complete response (CR) rate of 62% in patients with previously untreated or relapsed/refractory BPDCN.

 

Common adverse events (AEs) related to tagraxofusp include hypoalbuminemia, transaminitis, and thrombocytopenia. There was 1 grade 5 AE—a case of capillary leak syndrome (CLS).

 

Study investigator Naveen Pemmaraju, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S116.

 

The trial was sponsored by Stemline Therapeutics.

 

Dr Pemmaraju noted that there are no approved therapies for BPDCN, so patients may be treated with therapies intended for acute myeloid leukemia (AML), acute lymphoblastic leukemia, or lymphomas.

 

“These are usually quite intense cytotoxic chemotherapy regimens,” he said. “But even with these regimens, most groups report median overall survival times of 8 to 14 months.”

 

And although stem cell transplants can be effective in BPDCN, a “vast majority” of patients are not fit for transplant, according to Dr Pemmaraju.

 

With this in mind, he and his colleagues are conducting this trial of tagraxofusp in BPDCN.

 

The trial has 4 stages. In stage 1, patients received tagraxofusp at 7, 9, 12, or 16 μg/kg on days 1 to 5 of a 21-day cycle. In stages 2 and 3, patients received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle. Stage 4 is still enrolling.

 

Efficacy

 

Dr Pemmaraju presented results in 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN. The patients’ median age at baseline was 70 (range, 22-84), and 82% were male.

 

Three patients received tagraxofusp at 7 μg/kg/day, and the rest received the 12 μg/kg/day dose.

 

Among patients who received the 12 μg/kg/day dose, the ORR was 83% (35/42). The ORR was 90% (26/29) in previously untreated patients and 69% (9/13) in relapsed/refractory patients.

 

“These are very encouraging results—a 90% overall response rate in the frontline setting,” Dr Pemmaraju noted.

 

The composite CR rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.

 

This included 13 patients with a CR (1 relapsed/refractory), 10 with a clinical CR (3 relapsed/refractory), and 3 with a CR with incomplete hematologic recovery (1 relapsed/refractory). A clinical CR was defined as absence of gross disease with minimal residual skin abnormality.

 

Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.

 

Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival has not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).

 

Dr Pemmaraju said this result is important because it contrasts with the historical expectation of a median overall survival of 8 to 14 months.

 

Safety

 

Dr Pemmaraju presented safety results in 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with AML, myelofibrosis, and chronic myelomonocytic leukemia in addition to the 45 patients with BPDCN. However, AEs were similar regardless of disease.

 

Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).

 

 

CLS of any grade was also a common AE, occurring in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.

 

Dr Pemmaraju did note that CLS has proven manageable with monitoring and pre-emptive measures. Specifically, inclusion criteria were changed so that patients must have normal cardiac function, adequate kidney function, and albumin of at least 3.2 g/dl. Investigators also began monitoring patients’ weight, albumin levels, and kidney function.

 

“With the combination of greater understanding of CLS, actual definitive protocol adjustments made by investigators, and monitoring, this has been a highly manageable phenomenon,” Dr Pemmaraju said.

 

Next steps

 

The investigators plan to continue enrolling patients in this study and collect additional safety and survival data, but Dr Pemmaraju and his colleagues also want to evaluate tagraxofusp in combination with other therapies.

 

Tagraxofusp is already under investigation in combination with azacitidine in a phase 1/2 trial of patients with high-risk myelodysplastic syndromes and AML.

 

Dr Pemmaraju is interested in combining hypomethylating agents with tagraxofusp for BPDCN patients as well, to build upon the encouraging results with tagraxofusp alone.

 

“An extraordinarily rare disease that used to not have any therapies at all now has at least one ongoing clinical trial with some encouraging activity,” he said. “I hope that gives hope to people with rare diseases, to let them know they’re not alone. There may be someone out there who’s researching their disease, no matter how rare it is.”