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Individuals who develop acute myeloid leukemia (AML) may have somatic mutations detectable years before diagnosis, a newly published analysis shows.

Mutations in IDH1, IDH2, TP53, DNMT3A, TET2, and spliceosome genes at baseline assessment increased the odds of developing AML with a median follow-up of 9.6 years in the study, which was based on blood samples from participants in the Women’s Health Initiative (WHI).

The findings suggest a “premalignant landscape of mutations” that may precede overt AML by many years, according to Pinkal Desai, MD, assistant professor of medicine at Cornell University and oncologist at New York–Presbyterian/Weill Cornell Medical Center, New York, and her coauthors.

“The ability to detect and identify high-risk mutations suggests that monitoring strategies for patients, as well as clinical trials of potentially preventative or disease-intercepting interventions should be considered,” wrote Dr. Desai and her colleagues. The report was published in Nature Medicine.

Their analysis comprised 212 women who participated in the WHI who were healthy at the baseline evaluation but went on to develop AML during follow-up. They performed deep sequencing on peripheral blood DNA for these cases and for 212 age-matched controls.

Women who developed AML were more likely than were controls to have mutations in baseline assessment (odds ratio, 4.86; 95% confidence interval, 3.07-7.77), and had demonstrated greater clonal complexity versus controls (comutations in 46.8% and 5.5%, respectively; odds ratio, 9.01; 95% CI, 4.1-21.4), investigators found.

©GunarsB/Thinkstock

All 21 patients with TP53 mutations went on to develop AML, as did all 15 with IDH1 or IDH2 mutations and all 3 with RUNX1 mutations. Multivariate analysis showed that TP53, IDH1 and IDH2, TET2, DNMT3A and several spliceosome genes were associated with significantly increased odds of AML versus controls.

Based on these results, Dr. Desai and colleagues proposed that patients at increased AML risk should be followed in long-term monitoring studies that incorporate next-generation sequencing.

“Data from these studies will provide a robust rationale for clinical trials of preventative intervention strategies in populations at high risk of developing AML,” they wrote.

In clinical practice, monitoring individuals for AML-associated mutations will become more feasible as costs decrease and new therapies with favorable toxicity profiles are introduced, they added.

“Molecularly targeted therapy is already available for IDH2 mutations and is under development for mutations in other candidate genes found in this study including IDH1, TP53 and spliceosome genes,” they wrote.

The authors reported having no relevant financial disclosures. The WHI program is funded by the National Institutes of Health.

SOURCE: Desai P et al. Nat Med. 2018;24:1015-23.

Individuals who develop acute myeloid leukemia (AML) may have somatic mutations detectable years before diagnosis, a newly published analysis shows.

Mutations in IDH1, IDH2, TP53, DNMT3A, TET2, and spliceosome genes at baseline assessment increased the odds of developing AML with a median follow-up of 9.6 years in the study, which was based on blood samples from participants in the Women’s Health Initiative (WHI).

The findings suggest a “premalignant landscape of mutations” that may precede overt AML by many years, according to Pinkal Desai, MD, assistant professor of medicine at Cornell University and oncologist at New York–Presbyterian/Weill Cornell Medical Center, New York, and her coauthors.

“The ability to detect and identify high-risk mutations suggests that monitoring strategies for patients, as well as clinical trials of potentially preventative or disease-intercepting interventions should be considered,” wrote Dr. Desai and her colleagues. The report was published in Nature Medicine.

Their analysis comprised 212 women who participated in the WHI who were healthy at the baseline evaluation but went on to develop AML during follow-up. They performed deep sequencing on peripheral blood DNA for these cases and for 212 age-matched controls.

Women who developed AML were more likely than were controls to have mutations in baseline assessment (odds ratio, 4.86; 95% confidence interval, 3.07-7.77), and had demonstrated greater clonal complexity versus controls (comutations in 46.8% and 5.5%, respectively; odds ratio, 9.01; 95% CI, 4.1-21.4), investigators found.

©GunarsB/Thinkstock

All 21 patients with TP53 mutations went on to develop AML, as did all 15 with IDH1 or IDH2 mutations and all 3 with RUNX1 mutations. Multivariate analysis showed that TP53, IDH1 and IDH2, TET2, DNMT3A and several spliceosome genes were associated with significantly increased odds of AML versus controls.

Based on these results, Dr. Desai and colleagues proposed that patients at increased AML risk should be followed in long-term monitoring studies that incorporate next-generation sequencing.

“Data from these studies will provide a robust rationale for clinical trials of preventative intervention strategies in populations at high risk of developing AML,” they wrote.

In clinical practice, monitoring individuals for AML-associated mutations will become more feasible as costs decrease and new therapies with favorable toxicity profiles are introduced, they added.

“Molecularly targeted therapy is already available for IDH2 mutations and is under development for mutations in other candidate genes found in this study including IDH1, TP53 and spliceosome genes,” they wrote.

The authors reported having no relevant financial disclosures. The WHI program is funded by the National Institutes of Health.

SOURCE: Desai P et al. Nat Med. 2018;24:1015-23.

Individuals who develop acute myeloid leukemia (AML) may have somatic mutations detectable years before diagnosis, a newly published analysis shows.

Mutations in IDH1, IDH2, TP53, DNMT3A, TET2, and spliceosome genes at baseline assessment increased the odds of developing AML with a median follow-up of 9.6 years in the study, which was based on blood samples from participants in the Women’s Health Initiative (WHI).

The findings suggest a “premalignant landscape of mutations” that may precede overt AML by many years, according to Pinkal Desai, MD, assistant professor of medicine at Cornell University and oncologist at New York–Presbyterian/Weill Cornell Medical Center, New York, and her coauthors.

“The ability to detect and identify high-risk mutations suggests that monitoring strategies for patients, as well as clinical trials of potentially preventative or disease-intercepting interventions should be considered,” wrote Dr. Desai and her colleagues. The report was published in Nature Medicine.

Their analysis comprised 212 women who participated in the WHI who were healthy at the baseline evaluation but went on to develop AML during follow-up. They performed deep sequencing on peripheral blood DNA for these cases and for 212 age-matched controls.

Women who developed AML were more likely than were controls to have mutations in baseline assessment (odds ratio, 4.86; 95% confidence interval, 3.07-7.77), and had demonstrated greater clonal complexity versus controls (comutations in 46.8% and 5.5%, respectively; odds ratio, 9.01; 95% CI, 4.1-21.4), investigators found.

©GunarsB/Thinkstock

All 21 patients with TP53 mutations went on to develop AML, as did all 15 with IDH1 or IDH2 mutations and all 3 with RUNX1 mutations. Multivariate analysis showed that TP53, IDH1 and IDH2, TET2, DNMT3A and several spliceosome genes were associated with significantly increased odds of AML versus controls.

Based on these results, Dr. Desai and colleagues proposed that patients at increased AML risk should be followed in long-term monitoring studies that incorporate next-generation sequencing.

“Data from these studies will provide a robust rationale for clinical trials of preventative intervention strategies in populations at high risk of developing AML,” they wrote.

In clinical practice, monitoring individuals for AML-associated mutations will become more feasible as costs decrease and new therapies with favorable toxicity profiles are introduced, they added.

“Molecularly targeted therapy is already available for IDH2 mutations and is under development for mutations in other candidate genes found in this study including IDH1, TP53 and spliceosome genes,” they wrote.

The authors reported having no relevant financial disclosures. The WHI program is funded by the National Institutes of Health.

SOURCE: Desai P et al. Nat Med. 2018;24:1015-23.

A 70-year-old man underwent salvage therapy for multiple myeloma (MM). While on maintenance immunotherapy he developed a sternal plasmacytoma. After the fifth cycle of treatment, he developed swelling, erythema, and pain in his right testis.

The main differential diagnoses for those symptoms are infections and tumors; infection is more common, so his clinicians at Indiana University School of Medicine presumed orchitis and started him on IV antibiotics. The pain resolved, but the swelling persisted after the antibiotic course. The clinicians turned to biochemical marker screening for germ cell tumors, but those were negative. Serial ultrasound imaging, which they had begun during his admission, remained unchanged.

Meanwhile, the patient’s chemotherapy was being held back, and he developed another sternal mass, prompting a fluorodeoxyglucose-positron emission tomography–computed tomography (PET/CT) scan to evaluate for relapse of myeloma. The scan revealed an enlarged, diffusely hypermetabolic right testicle. Believing the symptoms were related to the myeloma and not orchitis, the clinicians advised a radical orchiectomy.

A biopsy after the surgery showed tumor cells consistent with testicular plasmacytoma.

While rare, testicular plasmacytoma is commonly associated with MM, especially in the later stages, when cancer cells are more aggressive and not relying on bone marrow for survival, the clinicians say. Unlike myeloma, which typically spreads via blood to bone sites, testicular plasmacytoma may spread via lymphatic channels to the regional lymph nodes and subsequently to distant sites, the clinicians add, similarly to lymphoma or germ cell tumor.

It is hard to diagnose, though. The clinicians say the patient’s case illustrates the challenges. Imaging studies such as ultrasound and CT scans are not specific. And although FDG-PET/CT imaging is a standard staging tool for myeloma and helpful in identifying plasmacytoma when evidenced as intramedullary or extramedullary hypermetabolic lesions, hypermetabolic lesions are not always malignant, they note. FDG-PET/CT can’t differentiate between orchitis and testicular plasmacytoma.  Biopsy remains the diagnostic gold standard.

Source:
Schiavo C, Mann SA, Mer J, Suvannasankha A. BMJ Case Rep. 2018;pii:bcr-2017-222046.
doi: 10.1136/bcr-2017-222046.

A 70-year-old man underwent salvage therapy for multiple myeloma (MM). While on maintenance immunotherapy he developed a sternal plasmacytoma. After the fifth cycle of treatment, he developed swelling, erythema, and pain in his right testis.

The main differential diagnoses for those symptoms are infections and tumors; infection is more common, so his clinicians at Indiana University School of Medicine presumed orchitis and started him on IV antibiotics. The pain resolved, but the swelling persisted after the antibiotic course. The clinicians turned to biochemical marker screening for germ cell tumors, but those were negative. Serial ultrasound imaging, which they had begun during his admission, remained unchanged.

Meanwhile, the patient’s chemotherapy was being held back, and he developed another sternal mass, prompting a fluorodeoxyglucose-positron emission tomography–computed tomography (PET/CT) scan to evaluate for relapse of myeloma. The scan revealed an enlarged, diffusely hypermetabolic right testicle. Believing the symptoms were related to the myeloma and not orchitis, the clinicians advised a radical orchiectomy.

A biopsy after the surgery showed tumor cells consistent with testicular plasmacytoma.

While rare, testicular plasmacytoma is commonly associated with MM, especially in the later stages, when cancer cells are more aggressive and not relying on bone marrow for survival, the clinicians say. Unlike myeloma, which typically spreads via blood to bone sites, testicular plasmacytoma may spread via lymphatic channels to the regional lymph nodes and subsequently to distant sites, the clinicians add, similarly to lymphoma or germ cell tumor.

It is hard to diagnose, though. The clinicians say the patient’s case illustrates the challenges. Imaging studies such as ultrasound and CT scans are not specific. And although FDG-PET/CT imaging is a standard staging tool for myeloma and helpful in identifying plasmacytoma when evidenced as intramedullary or extramedullary hypermetabolic lesions, hypermetabolic lesions are not always malignant, they note. FDG-PET/CT can’t differentiate between orchitis and testicular plasmacytoma.  Biopsy remains the diagnostic gold standard.

Source:
Schiavo C, Mann SA, Mer J, Suvannasankha A. BMJ Case Rep. 2018;pii:bcr-2017-222046.
doi: 10.1136/bcr-2017-222046.

A 70-year-old man underwent salvage therapy for multiple myeloma (MM). While on maintenance immunotherapy he developed a sternal plasmacytoma. After the fifth cycle of treatment, he developed swelling, erythema, and pain in his right testis.

The main differential diagnoses for those symptoms are infections and tumors; infection is more common, so his clinicians at Indiana University School of Medicine presumed orchitis and started him on IV antibiotics. The pain resolved, but the swelling persisted after the antibiotic course. The clinicians turned to biochemical marker screening for germ cell tumors, but those were negative. Serial ultrasound imaging, which they had begun during his admission, remained unchanged.

Meanwhile, the patient’s chemotherapy was being held back, and he developed another sternal mass, prompting a fluorodeoxyglucose-positron emission tomography–computed tomography (PET/CT) scan to evaluate for relapse of myeloma. The scan revealed an enlarged, diffusely hypermetabolic right testicle. Believing the symptoms were related to the myeloma and not orchitis, the clinicians advised a radical orchiectomy.

A biopsy after the surgery showed tumor cells consistent with testicular plasmacytoma.

While rare, testicular plasmacytoma is commonly associated with MM, especially in the later stages, when cancer cells are more aggressive and not relying on bone marrow for survival, the clinicians say. Unlike myeloma, which typically spreads via blood to bone sites, testicular plasmacytoma may spread via lymphatic channels to the regional lymph nodes and subsequently to distant sites, the clinicians add, similarly to lymphoma or germ cell tumor.

It is hard to diagnose, though. The clinicians say the patient’s case illustrates the challenges. Imaging studies such as ultrasound and CT scans are not specific. And although FDG-PET/CT imaging is a standard staging tool for myeloma and helpful in identifying plasmacytoma when evidenced as intramedullary or extramedullary hypermetabolic lesions, hypermetabolic lesions are not always malignant, they note. FDG-PET/CT can’t differentiate between orchitis and testicular plasmacytoma.  Biopsy remains the diagnostic gold standard.

Source:
Schiavo C, Mann SA, Mer J, Suvannasankha A. BMJ Case Rep. 2018;pii:bcr-2017-222046.
doi: 10.1136/bcr-2017-222046.

The Trump administration seeks to reorganize several federal agencies as part of a sweeping reform proposal, issued June 21. Although the plans hits many parts of federal health care, the most dramatic change is a proposed reduction of the Public Health Service (PHS) Commissioned Corps from more than 6,000 officers to no more than 4,500.

“Government in the 21st century is fundamentally a services business, and modern information technology should be at the heart of the U.S. government service delivery model,” according to the administration’s reform proposal. “And yet, today’s Executive branch is still aligned to the stove-piped organizational constructs of the 20th century, which in many cases have grown inefficient and out of date. Consequently, the public and our workforce are frustrated with government’s ability to deliver its mission in an effective, efficient, and secure way.”

tupungato/Thinkstock

If implemented, changes to the Commissioned Corp would be dramatic. The plan directs the Department of Health and Human Services (HHS) to “civilianize officers who do not provide critical public health services” and to ensure that the Corps is deployed at least once every 3 years to positions that either are difficult to fill or respond to a public health emergency. Instead the Commissioned Corps would be replaced with a Reserve Corps. Similar to the armed forces reserves, this group “would consist of Government employees and private citizens who agree to be deployed and serve in times of national need.”  In addition, the plan would change the way federal agencies pay for the retirement benefits of Commissioned Corps members, potentially eliminating one of the fiscal benefits that agencies receive for hiring Commissioned Corps members. 

In addition, under the proposal, nutrition assistance programs currently run out of the U.S. Department of Agriculture (USDA) including the Supplemental Nutrition Assistance Program (SNAP) and the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) would move to the Department of Health and Human Services, which would be rebranded the Department of Health and Public Welfare.

Moving these programs “would allow for better and easier coordination across programs that serve similar populations, ensuring consistent policies and a single point of administration for the major public assistance programs,” according to the proposal. “This single point of administration would lead to reduced duplication in state reporting requirements and other administrative burdens, and a more streamlined process for issuing guidance, writing regulations, and approving waivers.”

Food oversight functions would move from the Food and Drug Administration to the USDA; FDA would be rebranded the Federal Drug Administration and focus on drugs, devices, biologics, tobacco, dietary supplements, and cosmetics.

The administration also proposed to create a Council on Public Assistance comprised of “all federal agencies that administer public benefits, with a statutory authority to set cross-cutting program policies, including uniform work requirements.”

Other functions of the council would include approving service plans and waivers by states under Welfare-to-Work projects; resolving disputes when multiple agencies disagree on a particular policy; and recommending policy changes to eliminate barriers at the federal, state, and local level to getting welfare beneficiaries to work.

The proposal also calls for a restructuring of the National Institutes of Health “to ensure operations are effective and efficient,” with no detail provided. It would also place the Agency for Healthcare Research and Quality under the auspices of NIH.

The Strategic National Stockpile would be managed by the Assistant Secretary for Preparedness and Response “to consolidate strategic decision making around the development and procurement of medical countermeasures, and streamline operational decisions during responses to public health and other emergencies to improve responsiveness.”

Senator Patty Murray (D-WA), the ranking member of the Senate Health, Education, Labor, and Pensions (HELP) Committee, was quick to dismiss the plan, labeling it as “futile” and an “attempt to make government work worse for the people it serves.”

This article originally appeared at Internal Medicine News. It has been edited for Federal Practitioner and includes additional reporting by Reid Paul.

gtwachtman@mdedge.com

The Trump administration seeks to reorganize several federal agencies as part of a sweeping reform proposal, issued June 21. Although the plans hits many parts of federal health care, the most dramatic change is a proposed reduction of the Public Health Service (PHS) Commissioned Corps from more than 6,000 officers to no more than 4,500.

“Government in the 21st century is fundamentally a services business, and modern information technology should be at the heart of the U.S. government service delivery model,” according to the administration’s reform proposal. “And yet, today’s Executive branch is still aligned to the stove-piped organizational constructs of the 20th century, which in many cases have grown inefficient and out of date. Consequently, the public and our workforce are frustrated with government’s ability to deliver its mission in an effective, efficient, and secure way.”

tupungato/Thinkstock

If implemented, changes to the Commissioned Corp would be dramatic. The plan directs the Department of Health and Human Services (HHS) to “civilianize officers who do not provide critical public health services” and to ensure that the Corps is deployed at least once every 3 years to positions that either are difficult to fill or respond to a public health emergency. Instead the Commissioned Corps would be replaced with a Reserve Corps. Similar to the armed forces reserves, this group “would consist of Government employees and private citizens who agree to be deployed and serve in times of national need.”  In addition, the plan would change the way federal agencies pay for the retirement benefits of Commissioned Corps members, potentially eliminating one of the fiscal benefits that agencies receive for hiring Commissioned Corps members. 

In addition, under the proposal, nutrition assistance programs currently run out of the U.S. Department of Agriculture (USDA) including the Supplemental Nutrition Assistance Program (SNAP) and the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) would move to the Department of Health and Human Services, which would be rebranded the Department of Health and Public Welfare.

Moving these programs “would allow for better and easier coordination across programs that serve similar populations, ensuring consistent policies and a single point of administration for the major public assistance programs,” according to the proposal. “This single point of administration would lead to reduced duplication in state reporting requirements and other administrative burdens, and a more streamlined process for issuing guidance, writing regulations, and approving waivers.”

Food oversight functions would move from the Food and Drug Administration to the USDA; FDA would be rebranded the Federal Drug Administration and focus on drugs, devices, biologics, tobacco, dietary supplements, and cosmetics.

The administration also proposed to create a Council on Public Assistance comprised of “all federal agencies that administer public benefits, with a statutory authority to set cross-cutting program policies, including uniform work requirements.”

Other functions of the council would include approving service plans and waivers by states under Welfare-to-Work projects; resolving disputes when multiple agencies disagree on a particular policy; and recommending policy changes to eliminate barriers at the federal, state, and local level to getting welfare beneficiaries to work.

The proposal also calls for a restructuring of the National Institutes of Health “to ensure operations are effective and efficient,” with no detail provided. It would also place the Agency for Healthcare Research and Quality under the auspices of NIH.

The Strategic National Stockpile would be managed by the Assistant Secretary for Preparedness and Response “to consolidate strategic decision making around the development and procurement of medical countermeasures, and streamline operational decisions during responses to public health and other emergencies to improve responsiveness.”

Senator Patty Murray (D-WA), the ranking member of the Senate Health, Education, Labor, and Pensions (HELP) Committee, was quick to dismiss the plan, labeling it as “futile” and an “attempt to make government work worse for the people it serves.”

This article originally appeared at Internal Medicine News. It has been edited for Federal Practitioner and includes additional reporting by Reid Paul.

gtwachtman@mdedge.com

The Trump administration seeks to reorganize several federal agencies as part of a sweeping reform proposal, issued June 21. Although the plans hits many parts of federal health care, the most dramatic change is a proposed reduction of the Public Health Service (PHS) Commissioned Corps from more than 6,000 officers to no more than 4,500.

“Government in the 21st century is fundamentally a services business, and modern information technology should be at the heart of the U.S. government service delivery model,” according to the administration’s reform proposal. “And yet, today’s Executive branch is still aligned to the stove-piped organizational constructs of the 20th century, which in many cases have grown inefficient and out of date. Consequently, the public and our workforce are frustrated with government’s ability to deliver its mission in an effective, efficient, and secure way.”

tupungato/Thinkstock

If implemented, changes to the Commissioned Corp would be dramatic. The plan directs the Department of Health and Human Services (HHS) to “civilianize officers who do not provide critical public health services” and to ensure that the Corps is deployed at least once every 3 years to positions that either are difficult to fill or respond to a public health emergency. Instead the Commissioned Corps would be replaced with a Reserve Corps. Similar to the armed forces reserves, this group “would consist of Government employees and private citizens who agree to be deployed and serve in times of national need.”  In addition, the plan would change the way federal agencies pay for the retirement benefits of Commissioned Corps members, potentially eliminating one of the fiscal benefits that agencies receive for hiring Commissioned Corps members. 

In addition, under the proposal, nutrition assistance programs currently run out of the U.S. Department of Agriculture (USDA) including the Supplemental Nutrition Assistance Program (SNAP) and the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) would move to the Department of Health and Human Services, which would be rebranded the Department of Health and Public Welfare.

Moving these programs “would allow for better and easier coordination across programs that serve similar populations, ensuring consistent policies and a single point of administration for the major public assistance programs,” according to the proposal. “This single point of administration would lead to reduced duplication in state reporting requirements and other administrative burdens, and a more streamlined process for issuing guidance, writing regulations, and approving waivers.”

Food oversight functions would move from the Food and Drug Administration to the USDA; FDA would be rebranded the Federal Drug Administration and focus on drugs, devices, biologics, tobacco, dietary supplements, and cosmetics.

The administration also proposed to create a Council on Public Assistance comprised of “all federal agencies that administer public benefits, with a statutory authority to set cross-cutting program policies, including uniform work requirements.”

Other functions of the council would include approving service plans and waivers by states under Welfare-to-Work projects; resolving disputes when multiple agencies disagree on a particular policy; and recommending policy changes to eliminate barriers at the federal, state, and local level to getting welfare beneficiaries to work.

The proposal also calls for a restructuring of the National Institutes of Health “to ensure operations are effective and efficient,” with no detail provided. It would also place the Agency for Healthcare Research and Quality under the auspices of NIH.

The Strategic National Stockpile would be managed by the Assistant Secretary for Preparedness and Response “to consolidate strategic decision making around the development and procurement of medical countermeasures, and streamline operational decisions during responses to public health and other emergencies to improve responsiveness.”

Senator Patty Murray (D-WA), the ranking member of the Senate Health, Education, Labor, and Pensions (HELP) Committee, was quick to dismiss the plan, labeling it as “futile” and an “attempt to make government work worse for the people it serves.”

This article originally appeared at Internal Medicine News. It has been edited for Federal Practitioner and includes additional reporting by Reid Paul.

gtwachtman@mdedge.com

Median progression-free survival (PFS) based on traditional RECIST criteria did not correlate with overall survival (OS) in a meta-analysis of 12 randomized controlled trials of nivolumab or pembrolizumab monotherapy.

There was no correlation in terms of medians or gains in medians, although hazard ratios for OS and PFS did correlate significantly, said Bishal Gyawali, MD, PhD, of Nagoya (Japan) University Hospital with his associates. “The protective effects of treatment were greater for OS than for PFS,” they concluded in JAMA Network Open. “Progression-free survival cannot adequately capture the benefit of PD-1 inhibitors; thus, OS should remain the gold standard end point for trials of PD-1 inhibitors.”

Progression-free survival often has been used as a surrogate for OS because the latter takes time to ascertain and can be contaminated by crossover or postprogression treatment. However, it can be problematic to assume that the two outcomes correlate. Progression “is defined as an increase in tumor size beyond an arbitrary cutoff and is prone to bias, particularly when the investigators are not blinded,” the researchers noted. Furthermore, PD-1 inhibitors show an “atypical response pattern,” including long durations of response, responses after initial progression (known as pseudoprogression), and even response after treatment cessation.

The analysis, the first to formally compare PFS and OS across PD-1 inhibitors, included 10 randomized, controlled trials comparing nivolumab or pembrolizumab with nonimmunotherapy in adults with solid tumors. Two additional trials evaluated pembrolizumab or nivolumab following treatment with ipilimumab. In all, the studies included 5,417 patients. There was no significant heterogeneity among studies, the researchers said.

Median PFS and median OS correlated poorly, with an R² value of 0.46 (P = .09). Change in PFS also did not correlate with change in OS (R² = 0.23; P = .28). In contrast, hazard ratios for PFS and OS correlated significantly (R2 = 0.41; P = .048). The protective effects of treatment were higher for OS than for PFS (pooled HR, 1.2; 95% confidence interval, 1.1-1.3; P = .002).

This might be because traditional RECIST (response evaluation criteria in solid tumors) criteria predate the era of immunotherapy and do not accurately capture disease progression when patients are on immuno-oncologics. For example, pseudoprogression (in which T-cell infiltrates cause the tumor to grow before it shrinks) could be misconstrued as progression. Also, PD-1 inhibitors can continue working even after treatment cessation, which could affect OS more than PFS, the researchers noted.

Regardless, “PD-1 inhibitors may have larger effects on OS than on PFS, which would be unprecedented in oncology therapeutics,” they concluded. “These results support the rationale of using OS as the primary end point of future phase 3 trials of PD-1 inhibitors and discourage the use of PFS as a sole primary end point as the latter may provide misleading information about the efficacy of these drugs.”

Funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, and the Engelberg Foundation. The investigators reported having no relevant conflicts of interest. One coinvestigator reported research support from the Laura and John Arnold Foundation. The other investigators had no conflicts.

SOURCE: Gyawali B et al. JAMA Network Open. 2018 June 22. doi: 10.1001/jamanetworkopen.2018.0416.

Median progression-free survival (PFS) based on traditional RECIST criteria did not correlate with overall survival (OS) in a meta-analysis of 12 randomized controlled trials of nivolumab or pembrolizumab monotherapy.

There was no correlation in terms of medians or gains in medians, although hazard ratios for OS and PFS did correlate significantly, said Bishal Gyawali, MD, PhD, of Nagoya (Japan) University Hospital with his associates. “The protective effects of treatment were greater for OS than for PFS,” they concluded in JAMA Network Open. “Progression-free survival cannot adequately capture the benefit of PD-1 inhibitors; thus, OS should remain the gold standard end point for trials of PD-1 inhibitors.”

Progression-free survival often has been used as a surrogate for OS because the latter takes time to ascertain and can be contaminated by crossover or postprogression treatment. However, it can be problematic to assume that the two outcomes correlate. Progression “is defined as an increase in tumor size beyond an arbitrary cutoff and is prone to bias, particularly when the investigators are not blinded,” the researchers noted. Furthermore, PD-1 inhibitors show an “atypical response pattern,” including long durations of response, responses after initial progression (known as pseudoprogression), and even response after treatment cessation.

The analysis, the first to formally compare PFS and OS across PD-1 inhibitors, included 10 randomized, controlled trials comparing nivolumab or pembrolizumab with nonimmunotherapy in adults with solid tumors. Two additional trials evaluated pembrolizumab or nivolumab following treatment with ipilimumab. In all, the studies included 5,417 patients. There was no significant heterogeneity among studies, the researchers said.

Median PFS and median OS correlated poorly, with an R² value of 0.46 (P = .09). Change in PFS also did not correlate with change in OS (R² = 0.23; P = .28). In contrast, hazard ratios for PFS and OS correlated significantly (R2 = 0.41; P = .048). The protective effects of treatment were higher for OS than for PFS (pooled HR, 1.2; 95% confidence interval, 1.1-1.3; P = .002).

This might be because traditional RECIST (response evaluation criteria in solid tumors) criteria predate the era of immunotherapy and do not accurately capture disease progression when patients are on immuno-oncologics. For example, pseudoprogression (in which T-cell infiltrates cause the tumor to grow before it shrinks) could be misconstrued as progression. Also, PD-1 inhibitors can continue working even after treatment cessation, which could affect OS more than PFS, the researchers noted.

Regardless, “PD-1 inhibitors may have larger effects on OS than on PFS, which would be unprecedented in oncology therapeutics,” they concluded. “These results support the rationale of using OS as the primary end point of future phase 3 trials of PD-1 inhibitors and discourage the use of PFS as a sole primary end point as the latter may provide misleading information about the efficacy of these drugs.”

Funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, and the Engelberg Foundation. The investigators reported having no relevant conflicts of interest. One coinvestigator reported research support from the Laura and John Arnold Foundation. The other investigators had no conflicts.

SOURCE: Gyawali B et al. JAMA Network Open. 2018 June 22. doi: 10.1001/jamanetworkopen.2018.0416.

Median progression-free survival (PFS) based on traditional RECIST criteria did not correlate with overall survival (OS) in a meta-analysis of 12 randomized controlled trials of nivolumab or pembrolizumab monotherapy.

There was no correlation in terms of medians or gains in medians, although hazard ratios for OS and PFS did correlate significantly, said Bishal Gyawali, MD, PhD, of Nagoya (Japan) University Hospital with his associates. “The protective effects of treatment were greater for OS than for PFS,” they concluded in JAMA Network Open. “Progression-free survival cannot adequately capture the benefit of PD-1 inhibitors; thus, OS should remain the gold standard end point for trials of PD-1 inhibitors.”

Progression-free survival often has been used as a surrogate for OS because the latter takes time to ascertain and can be contaminated by crossover or postprogression treatment. However, it can be problematic to assume that the two outcomes correlate. Progression “is defined as an increase in tumor size beyond an arbitrary cutoff and is prone to bias, particularly when the investigators are not blinded,” the researchers noted. Furthermore, PD-1 inhibitors show an “atypical response pattern,” including long durations of response, responses after initial progression (known as pseudoprogression), and even response after treatment cessation.

The analysis, the first to formally compare PFS and OS across PD-1 inhibitors, included 10 randomized, controlled trials comparing nivolumab or pembrolizumab with nonimmunotherapy in adults with solid tumors. Two additional trials evaluated pembrolizumab or nivolumab following treatment with ipilimumab. In all, the studies included 5,417 patients. There was no significant heterogeneity among studies, the researchers said.

Median PFS and median OS correlated poorly, with an R² value of 0.46 (P = .09). Change in PFS also did not correlate with change in OS (R² = 0.23; P = .28). In contrast, hazard ratios for PFS and OS correlated significantly (R2 = 0.41; P = .048). The protective effects of treatment were higher for OS than for PFS (pooled HR, 1.2; 95% confidence interval, 1.1-1.3; P = .002).

This might be because traditional RECIST (response evaluation criteria in solid tumors) criteria predate the era of immunotherapy and do not accurately capture disease progression when patients are on immuno-oncologics. For example, pseudoprogression (in which T-cell infiltrates cause the tumor to grow before it shrinks) could be misconstrued as progression. Also, PD-1 inhibitors can continue working even after treatment cessation, which could affect OS more than PFS, the researchers noted.

Regardless, “PD-1 inhibitors may have larger effects on OS than on PFS, which would be unprecedented in oncology therapeutics,” they concluded. “These results support the rationale of using OS as the primary end point of future phase 3 trials of PD-1 inhibitors and discourage the use of PFS as a sole primary end point as the latter may provide misleading information about the efficacy of these drugs.”

Funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, and the Engelberg Foundation. The investigators reported having no relevant conflicts of interest. One coinvestigator reported research support from the Laura and John Arnold Foundation. The other investigators had no conflicts.

SOURCE: Gyawali B et al. JAMA Network Open. 2018 June 22. doi: 10.1001/jamanetworkopen.2018.0416.

A 26-year-old man presented to uroligy clinicians with right testicular pain and a right epididymal mass. It was a challenge to diagnose the cause—until he revealed some essential clues.

The differential diagnosis included testicular malignancy and lymphoma. However, tumor markers were within normal limits. Tests for HIV and syphilis were negative. The clinicians also considered granulomatous or chronic orchitis, but after treatment with nonsteroidal anti-inflammatory drugs, the pain and palpable epididymal mass had resolved. Then, follow-up testicular ultrasound images showed new diffuse heterogeneous hypoechoic lesions in the right testis.

The patient elected to have a right radical orchiectomy with sperm cryopreserved. He recovered well, and semen analysis did not show any abnormalities.

Pathology of the surgical specimen revealed necrotizing and nonnecrotizing granulomas. At this point, the patient recollected that he had developed cervical lymphadenopathy and oral ulcers several weeks after traveling to South America, 8 months before presenting with the testicular symptoms.

Combined with another clue—frequent exposure to cats during his South America trip—the patient’s symptoms now created a clearer picture. He had been diagnosed with toxoplasmosis at the time but had not received treatment because he was immunocompetent. The patient’s symptoms had resolved spontaneously, and he said he had  been in his usual health between then and when he developed the testicular pain.

Based on this new information, the clinicians conducted immunohistochemical tests, which revealed isolated cysts about 20 µm in diameter, confirming a diagnosis of testicular toxoplasmosis. They started him on systemic toxoplasmosis treatment; he has been in good health since.

The clinicians note that toxoplasmosis is highly prevalent, infecting up to 30% of the world’s population. Cat feces is one source of infection with Toxoplasma gondii, which is typically asymptomatic. In immunocompetent patients, it tends to present as an acute infection that is benign and self-limited.

Only a few cases of testicular toxoplasmosis have been reported in the literature, and all have been in immunocompromised patients. Because this patient was immunocompetent, the case is  unique, being the only one reported as yet. Given the immunocompetence, the clinicians say, the patient demonstrates the need for clinicians to have a high index of suspicion.

Source:
Wong V, Amarasekera C, Kundu S. BMJ Case Rep. 2018;2018. pii: bcr-2018-224962.

A 26-year-old man presented to uroligy clinicians with right testicular pain and a right epididymal mass. It was a challenge to diagnose the cause—until he revealed some essential clues.

The differential diagnosis included testicular malignancy and lymphoma. However, tumor markers were within normal limits. Tests for HIV and syphilis were negative. The clinicians also considered granulomatous or chronic orchitis, but after treatment with nonsteroidal anti-inflammatory drugs, the pain and palpable epididymal mass had resolved. Then, follow-up testicular ultrasound images showed new diffuse heterogeneous hypoechoic lesions in the right testis.

The patient elected to have a right radical orchiectomy with sperm cryopreserved. He recovered well, and semen analysis did not show any abnormalities.

Pathology of the surgical specimen revealed necrotizing and nonnecrotizing granulomas. At this point, the patient recollected that he had developed cervical lymphadenopathy and oral ulcers several weeks after traveling to South America, 8 months before presenting with the testicular symptoms.

Combined with another clue—frequent exposure to cats during his South America trip—the patient’s symptoms now created a clearer picture. He had been diagnosed with toxoplasmosis at the time but had not received treatment because he was immunocompetent. The patient’s symptoms had resolved spontaneously, and he said he had  been in his usual health between then and when he developed the testicular pain.

Based on this new information, the clinicians conducted immunohistochemical tests, which revealed isolated cysts about 20 µm in diameter, confirming a diagnosis of testicular toxoplasmosis. They started him on systemic toxoplasmosis treatment; he has been in good health since.

The clinicians note that toxoplasmosis is highly prevalent, infecting up to 30% of the world’s population. Cat feces is one source of infection with Toxoplasma gondii, which is typically asymptomatic. In immunocompetent patients, it tends to present as an acute infection that is benign and self-limited.

Only a few cases of testicular toxoplasmosis have been reported in the literature, and all have been in immunocompromised patients. Because this patient was immunocompetent, the case is  unique, being the only one reported as yet. Given the immunocompetence, the clinicians say, the patient demonstrates the need for clinicians to have a high index of suspicion.

Source:
Wong V, Amarasekera C, Kundu S. BMJ Case Rep. 2018;2018. pii: bcr-2018-224962.

A 26-year-old man presented to uroligy clinicians with right testicular pain and a right epididymal mass. It was a challenge to diagnose the cause—until he revealed some essential clues.

The differential diagnosis included testicular malignancy and lymphoma. However, tumor markers were within normal limits. Tests for HIV and syphilis were negative. The clinicians also considered granulomatous or chronic orchitis, but after treatment with nonsteroidal anti-inflammatory drugs, the pain and palpable epididymal mass had resolved. Then, follow-up testicular ultrasound images showed new diffuse heterogeneous hypoechoic lesions in the right testis.

The patient elected to have a right radical orchiectomy with sperm cryopreserved. He recovered well, and semen analysis did not show any abnormalities.

Pathology of the surgical specimen revealed necrotizing and nonnecrotizing granulomas. At this point, the patient recollected that he had developed cervical lymphadenopathy and oral ulcers several weeks after traveling to South America, 8 months before presenting with the testicular symptoms.

Combined with another clue—frequent exposure to cats during his South America trip—the patient’s symptoms now created a clearer picture. He had been diagnosed with toxoplasmosis at the time but had not received treatment because he was immunocompetent. The patient’s symptoms had resolved spontaneously, and he said he had  been in his usual health between then and when he developed the testicular pain.

Based on this new information, the clinicians conducted immunohistochemical tests, which revealed isolated cysts about 20 µm in diameter, confirming a diagnosis of testicular toxoplasmosis. They started him on systemic toxoplasmosis treatment; he has been in good health since.

The clinicians note that toxoplasmosis is highly prevalent, infecting up to 30% of the world’s population. Cat feces is one source of infection with Toxoplasma gondii, which is typically asymptomatic. In immunocompetent patients, it tends to present as an acute infection that is benign and self-limited.

Only a few cases of testicular toxoplasmosis have been reported in the literature, and all have been in immunocompromised patients. Because this patient was immunocompetent, the case is  unique, being the only one reported as yet. Given the immunocompetence, the clinicians say, the patient demonstrates the need for clinicians to have a high index of suspicion.

Source:
Wong V, Amarasekera C, Kundu S. BMJ Case Rep. 2018;2018. pii: bcr-2018-224962.

CHICAGO – Chemoimmunotherapy for chronic lymphocytic leukemia is on the way out, but there’s one scenario where it still plays a key role, according to one leukemia expert.

That scenario is not in relapsed or refractory chronic lymphocytic leukemia (CLL), where the use of fludarabine, cyclophosphamide, and rituximab (FCR) may be hard to justify today. Data supporting use of FCR in relapsed CLL show a median progression-free survival (PFS) of about 21 months, Susan M. O’Brien, MD, of the University of California, Irvine, said at the annual meeting of the American Society of Clinical Oncology. There is also data for bendamustine-rituximab retreatment showing a median event-free survival of about 15 months, she added.

By contrast, the 5-year follow-up data for the Bruton tyrosine kinase inhibitor ibrutinib in the relapsed/refractory setting shows a median PFS of 52 months, which is “extraordinary,” given that the patients had a median of four prior regimens, Dr. O’Brien said.

Similarly, recently published results from the randomized, phase 3 MURANO study of venetoclax plus rituximab in relapsed/refractory CLL showed that median PFS was not reached at a median follow-up of 23.8 months, versus a median of 17 months for the bendamustine-rituximab comparison arm (N Engl J Med. 2018;378[12]:1107-20).

“Thanks to the MURANO study, we likely will have an expanded label for venetoclax that includes the combination of venetoclax and rituximab,” Dr. O’Brien said. “I think it’s quite clear that either of these is dramatically better than what you get with retreatment with chemotherapy, so I personally don’t think there is a role for chemoimmunotherapy in the relapsed patient.”

On June 8, 2018, the Food and Drug Administration granted regular approval for venetoclax for patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who have received at least one prior therapy. The FDA also approved its use in combination with rituximab.*

But frontline CLL treatment is currently a little bit more complicated, Dr. O’Brien said.

Recent studies show favorable long-term outcomes with FCR frontline therapy in the immunoglobulin heavy chain variable gene (IgHV) –mutated subgroup of patients, she noted.

The longest follow-up comes from a study from investigators at the University of Texas MD Anderson Cancer Center, Houston, published in 2016. In that study, the 12.8-year PFS was 53.9% for IgHV-mutated patients, versus just 8.7% for patients with unmutated IgHV. Of the IgHV-mutated group, more than half achieved minimal residual disease (MRD) negativity after treatment (Blood. 2016 Jan 21; 127[3]: 303-9).

“I’m going to go out on a limb and I’m going to suggest that I think there is a cure fraction here,” Dr. O’Brien said. “On the other hand, if there’s not a cure fraction and they’re going to relapse after 17 years, that’s a pretty attractive endpoint, even if it’s not a cure fraction.”

Clinical practice guidelines now recognize IgHV mutation status as an important marker that should be obtained when deciding on treatment, Dr. O’Brien noted.

For unmutated patients, the RESONATE-2 trial showed that ibrutinib was superior to chlorambucil in older patients, many of whom had comorbid conditions. In the 3-year update, median PFS was approximately 15 months for chlorambucil, while for ibrutinib the median PFS was “nowhere near” being reached, Dr. O’Brien said.

Those data may not be so relevant for fit, unmutated patients, and two randomized trials comparing FCR with bendamustine and rituximab have yet to report data. However, one recent cross-trial comparison found fairly overlapping survival curves for the two chemoimmunotherapy approaches.

Dr. O’Brien said she would put older patients with comorbidities on ibrutinib if a clinical trial was not available, and for fit, unmutated patients, while more data are needed, she would also use ibrutinib. However, patient preference sometimes tips the scale in favor of FCR.

“The discussions sometimes are quite long about whether the patient should opt to take ibrutinib or FCR,” Dr. O’Brien said. “The last patient I had that discussion with elected to take FCR. When I asked him why, he said because he liked the idea of being finished in six cycles, off all therapy, and hopefully in remission.”

While Dr. O’Brien said she views chemoimmunotherapy as still relevant in IgHV-mutated patients, eventually it will go away, she concluded. Toward that end, there is considerable interest in venetoclax plus ibrutinib, a combination that, in early reports, has yielded very encouraging MRD results in first-line CLL.

“We have no long-term data, but very, very exciting MRD negativity data,” Dr. O’Brien said.

Dr. O’Brien reported relationships with Abbvie, Amgen, Celgene, Gilead Sciences, Janssen, Pfizer, Pharmacyclics, Sunesis Pharmaceuticals, and others.

*This story was updated 6/25/2018.

CHICAGO – Chemoimmunotherapy for chronic lymphocytic leukemia is on the way out, but there’s one scenario where it still plays a key role, according to one leukemia expert.

That scenario is not in relapsed or refractory chronic lymphocytic leukemia (CLL), where the use of fludarabine, cyclophosphamide, and rituximab (FCR) may be hard to justify today. Data supporting use of FCR in relapsed CLL show a median progression-free survival (PFS) of about 21 months, Susan M. O’Brien, MD, of the University of California, Irvine, said at the annual meeting of the American Society of Clinical Oncology. There is also data for bendamustine-rituximab retreatment showing a median event-free survival of about 15 months, she added.

By contrast, the 5-year follow-up data for the Bruton tyrosine kinase inhibitor ibrutinib in the relapsed/refractory setting shows a median PFS of 52 months, which is “extraordinary,” given that the patients had a median of four prior regimens, Dr. O’Brien said.

Similarly, recently published results from the randomized, phase 3 MURANO study of venetoclax plus rituximab in relapsed/refractory CLL showed that median PFS was not reached at a median follow-up of 23.8 months, versus a median of 17 months for the bendamustine-rituximab comparison arm (N Engl J Med. 2018;378[12]:1107-20).

“Thanks to the MURANO study, we likely will have an expanded label for venetoclax that includes the combination of venetoclax and rituximab,” Dr. O’Brien said. “I think it’s quite clear that either of these is dramatically better than what you get with retreatment with chemotherapy, so I personally don’t think there is a role for chemoimmunotherapy in the relapsed patient.”

On June 8, 2018, the Food and Drug Administration granted regular approval for venetoclax for patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who have received at least one prior therapy. The FDA also approved its use in combination with rituximab.*

But frontline CLL treatment is currently a little bit more complicated, Dr. O’Brien said.

Recent studies show favorable long-term outcomes with FCR frontline therapy in the immunoglobulin heavy chain variable gene (IgHV) –mutated subgroup of patients, she noted.

The longest follow-up comes from a study from investigators at the University of Texas MD Anderson Cancer Center, Houston, published in 2016. In that study, the 12.8-year PFS was 53.9% for IgHV-mutated patients, versus just 8.7% for patients with unmutated IgHV. Of the IgHV-mutated group, more than half achieved minimal residual disease (MRD) negativity after treatment (Blood. 2016 Jan 21; 127[3]: 303-9).

“I’m going to go out on a limb and I’m going to suggest that I think there is a cure fraction here,” Dr. O’Brien said. “On the other hand, if there’s not a cure fraction and they’re going to relapse after 17 years, that’s a pretty attractive endpoint, even if it’s not a cure fraction.”

Clinical practice guidelines now recognize IgHV mutation status as an important marker that should be obtained when deciding on treatment, Dr. O’Brien noted.

For unmutated patients, the RESONATE-2 trial showed that ibrutinib was superior to chlorambucil in older patients, many of whom had comorbid conditions. In the 3-year update, median PFS was approximately 15 months for chlorambucil, while for ibrutinib the median PFS was “nowhere near” being reached, Dr. O’Brien said.

Those data may not be so relevant for fit, unmutated patients, and two randomized trials comparing FCR with bendamustine and rituximab have yet to report data. However, one recent cross-trial comparison found fairly overlapping survival curves for the two chemoimmunotherapy approaches.

Dr. O’Brien said she would put older patients with comorbidities on ibrutinib if a clinical trial was not available, and for fit, unmutated patients, while more data are needed, she would also use ibrutinib. However, patient preference sometimes tips the scale in favor of FCR.

“The discussions sometimes are quite long about whether the patient should opt to take ibrutinib or FCR,” Dr. O’Brien said. “The last patient I had that discussion with elected to take FCR. When I asked him why, he said because he liked the idea of being finished in six cycles, off all therapy, and hopefully in remission.”

While Dr. O’Brien said she views chemoimmunotherapy as still relevant in IgHV-mutated patients, eventually it will go away, she concluded. Toward that end, there is considerable interest in venetoclax plus ibrutinib, a combination that, in early reports, has yielded very encouraging MRD results in first-line CLL.

“We have no long-term data, but very, very exciting MRD negativity data,” Dr. O’Brien said.

Dr. O’Brien reported relationships with Abbvie, Amgen, Celgene, Gilead Sciences, Janssen, Pfizer, Pharmacyclics, Sunesis Pharmaceuticals, and others.

*This story was updated 6/25/2018.

CHICAGO – Chemoimmunotherapy for chronic lymphocytic leukemia is on the way out, but there’s one scenario where it still plays a key role, according to one leukemia expert.

That scenario is not in relapsed or refractory chronic lymphocytic leukemia (CLL), where the use of fludarabine, cyclophosphamide, and rituximab (FCR) may be hard to justify today. Data supporting use of FCR in relapsed CLL show a median progression-free survival (PFS) of about 21 months, Susan M. O’Brien, MD, of the University of California, Irvine, said at the annual meeting of the American Society of Clinical Oncology. There is also data for bendamustine-rituximab retreatment showing a median event-free survival of about 15 months, she added.

By contrast, the 5-year follow-up data for the Bruton tyrosine kinase inhibitor ibrutinib in the relapsed/refractory setting shows a median PFS of 52 months, which is “extraordinary,” given that the patients had a median of four prior regimens, Dr. O’Brien said.

Similarly, recently published results from the randomized, phase 3 MURANO study of venetoclax plus rituximab in relapsed/refractory CLL showed that median PFS was not reached at a median follow-up of 23.8 months, versus a median of 17 months for the bendamustine-rituximab comparison arm (N Engl J Med. 2018;378[12]:1107-20).

“Thanks to the MURANO study, we likely will have an expanded label for venetoclax that includes the combination of venetoclax and rituximab,” Dr. O’Brien said. “I think it’s quite clear that either of these is dramatically better than what you get with retreatment with chemotherapy, so I personally don’t think there is a role for chemoimmunotherapy in the relapsed patient.”

On June 8, 2018, the Food and Drug Administration granted regular approval for venetoclax for patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who have received at least one prior therapy. The FDA also approved its use in combination with rituximab.*

But frontline CLL treatment is currently a little bit more complicated, Dr. O’Brien said.

Recent studies show favorable long-term outcomes with FCR frontline therapy in the immunoglobulin heavy chain variable gene (IgHV) –mutated subgroup of patients, she noted.

The longest follow-up comes from a study from investigators at the University of Texas MD Anderson Cancer Center, Houston, published in 2016. In that study, the 12.8-year PFS was 53.9% for IgHV-mutated patients, versus just 8.7% for patients with unmutated IgHV. Of the IgHV-mutated group, more than half achieved minimal residual disease (MRD) negativity after treatment (Blood. 2016 Jan 21; 127[3]: 303-9).

“I’m going to go out on a limb and I’m going to suggest that I think there is a cure fraction here,” Dr. O’Brien said. “On the other hand, if there’s not a cure fraction and they’re going to relapse after 17 years, that’s a pretty attractive endpoint, even if it’s not a cure fraction.”

Clinical practice guidelines now recognize IgHV mutation status as an important marker that should be obtained when deciding on treatment, Dr. O’Brien noted.

For unmutated patients, the RESONATE-2 trial showed that ibrutinib was superior to chlorambucil in older patients, many of whom had comorbid conditions. In the 3-year update, median PFS was approximately 15 months for chlorambucil, while for ibrutinib the median PFS was “nowhere near” being reached, Dr. O’Brien said.

Those data may not be so relevant for fit, unmutated patients, and two randomized trials comparing FCR with bendamustine and rituximab have yet to report data. However, one recent cross-trial comparison found fairly overlapping survival curves for the two chemoimmunotherapy approaches.

Dr. O’Brien said she would put older patients with comorbidities on ibrutinib if a clinical trial was not available, and for fit, unmutated patients, while more data are needed, she would also use ibrutinib. However, patient preference sometimes tips the scale in favor of FCR.

“The discussions sometimes are quite long about whether the patient should opt to take ibrutinib or FCR,” Dr. O’Brien said. “The last patient I had that discussion with elected to take FCR. When I asked him why, he said because he liked the idea of being finished in six cycles, off all therapy, and hopefully in remission.”

While Dr. O’Brien said she views chemoimmunotherapy as still relevant in IgHV-mutated patients, eventually it will go away, she concluded. Toward that end, there is considerable interest in venetoclax plus ibrutinib, a combination that, in early reports, has yielded very encouraging MRD results in first-line CLL.

“We have no long-term data, but very, very exciting MRD negativity data,” Dr. O’Brien said.

Dr. O’Brien reported relationships with Abbvie, Amgen, Celgene, Gilead Sciences, Janssen, Pfizer, Pharmacyclics, Sunesis Pharmaceuticals, and others.

*This story was updated 6/25/2018.

CHICAGO – The 10-year incidence rates for both squamous cell carcinoma and basal cell carcinoma arising after hematopoietic cell transplantation are impressively high at 17%-plus for each, but the malignancies occur on two very different timelines, according to Jeffrey F. Scott, MD, a fellow in micrographic surgery and dermatologic oncology at Case Western Reserve University in Cleveland.

Most of the squamous cell carcinomas (SCCs) in a large multicenter retrospective study developed within the first 5 years following hematopoietic cell transplantation (HCT), while the majority of the basal cell carcinomas (BCCs) occurred after that point, Dr. Scott reported at the annual meeting of the American College of Mohs Surgery.

He presented the results of the study, which included 876 HCT recipients followed for a mean of 6.1 years. The study objective was to pin down the risk factors for skin cancer after HCT, especially the patient-specific ones. This has become a pressing issue because the use of HCT is steadily growing, and the 5-year survival rate now exceeds 50%.

The transplant-specific risk factors have previously been fairly well described by others. They include the donor source, type of disease, the conditioning regimen, whether whole body irradiation was used, immunosuppression, graft versus host disease (GVHD), and others.

The patient-centric risk factors, in contrast, have not been well characterized. And it’s critical to thoroughly understand these risk factors in order to develop targeted prevention and surveillance strategies, Dr. Scott said.

“There remains a significant knowledge gap within our field. I would venture that the majority of this audience has treated a patient with skin cancer who has had a transplant,” he said. “Yet when a patient asks us, ‘Doc, what is my risk for skin cancer after my HCT?’ we’re really unable to give them an accurate and complete assessment of that risk. That’s because we’re missing the second major category of risk factors: the patient-specific risk factors.”

The reason for that, he added, is that the major population-based studies and national HCT registries are run by hematologists and oncologists, and they haven’t adequately captured the patient-specific skin cancer risk factors. But these are variables very familiar to dermatologists. They include skin phenotype, history of UV radiation exposure, and history of pre-HCT skin cancer.

Dr. Scott said the multicenter study he presented has two major advantages over prior studies: its large size and thorough followup. Nearly all 876 patients were followed by both an oncologist and a dermatologist at the same institution.

During followup, the HCT recipients collectively developed 63 SCCs, 55 BCCs, and 16 malignant melanomas. The 5- and 10-year incidence rates for SCC were 10.6% and 17.2%. For BCC, the 5- and 10-year rates were 5.7% and 17.6%. All 16 cases of melanoma occurred within 5 years after HCT.

In multivariate Cox proportional hazard analyses, photodamage documented on examination was independently associated with a 3.2-fold increased risk of post-HCT SCC and a 3.5-fold increased risk of BCC.

A pre-transplant history of BCC was associated with a 3.9-fold increased likelihood of developing a BCC afterwards. Similarly, a pre-HCT history of SCC conferred a 4.2-fold increased risk of post-transplant SCC and was also independently associated with a 6.6-fold increased risk of developing melanoma post-HCT.

Fitzpatrick skin types I and II were respectively associated with 9.3- and 7.2-fold increased risks of post-HCT nonmelanoma skin cancer, compared with skin types III-VI.

Acute GVHD wasn’t associated with an increased risk of nonmelanoma skin cancer after HCT. However, in an observation that hasn’t previously been reported by others, chronic GVHD with skin involvement was associated with a 2.7-fold increased likelihood of SCC post-HCT, Dr. Scott noted.

What’s next for Dr. Scott and his coinvestigators? “Our ultimate goal with this project is to develop an interactive risk assessment tool like the National Cancer Institute’s Breast Cancer Risk Assessment Tool that can be online and used by patients and providers to estimate their individualized risk of basal cell carcinoma, squamous cell carcinoma, and melanoma after HCT,” he said.

Dr. Scott reported having no financial conflicts related to the study.

bjancin@mdedge.com

CHICAGO – The 10-year incidence rates for both squamous cell carcinoma and basal cell carcinoma arising after hematopoietic cell transplantation are impressively high at 17%-plus for each, but the malignancies occur on two very different timelines, according to Jeffrey F. Scott, MD, a fellow in micrographic surgery and dermatologic oncology at Case Western Reserve University in Cleveland.

Most of the squamous cell carcinomas (SCCs) in a large multicenter retrospective study developed within the first 5 years following hematopoietic cell transplantation (HCT), while the majority of the basal cell carcinomas (BCCs) occurred after that point, Dr. Scott reported at the annual meeting of the American College of Mohs Surgery.

He presented the results of the study, which included 876 HCT recipients followed for a mean of 6.1 years. The study objective was to pin down the risk factors for skin cancer after HCT, especially the patient-specific ones. This has become a pressing issue because the use of HCT is steadily growing, and the 5-year survival rate now exceeds 50%.

The transplant-specific risk factors have previously been fairly well described by others. They include the donor source, type of disease, the conditioning regimen, whether whole body irradiation was used, immunosuppression, graft versus host disease (GVHD), and others.

The patient-centric risk factors, in contrast, have not been well characterized. And it’s critical to thoroughly understand these risk factors in order to develop targeted prevention and surveillance strategies, Dr. Scott said.

“There remains a significant knowledge gap within our field. I would venture that the majority of this audience has treated a patient with skin cancer who has had a transplant,” he said. “Yet when a patient asks us, ‘Doc, what is my risk for skin cancer after my HCT?’ we’re really unable to give them an accurate and complete assessment of that risk. That’s because we’re missing the second major category of risk factors: the patient-specific risk factors.”

The reason for that, he added, is that the major population-based studies and national HCT registries are run by hematologists and oncologists, and they haven’t adequately captured the patient-specific skin cancer risk factors. But these are variables very familiar to dermatologists. They include skin phenotype, history of UV radiation exposure, and history of pre-HCT skin cancer.

Dr. Scott said the multicenter study he presented has two major advantages over prior studies: its large size and thorough followup. Nearly all 876 patients were followed by both an oncologist and a dermatologist at the same institution.

During followup, the HCT recipients collectively developed 63 SCCs, 55 BCCs, and 16 malignant melanomas. The 5- and 10-year incidence rates for SCC were 10.6% and 17.2%. For BCC, the 5- and 10-year rates were 5.7% and 17.6%. All 16 cases of melanoma occurred within 5 years after HCT.

In multivariate Cox proportional hazard analyses, photodamage documented on examination was independently associated with a 3.2-fold increased risk of post-HCT SCC and a 3.5-fold increased risk of BCC.

A pre-transplant history of BCC was associated with a 3.9-fold increased likelihood of developing a BCC afterwards. Similarly, a pre-HCT history of SCC conferred a 4.2-fold increased risk of post-transplant SCC and was also independently associated with a 6.6-fold increased risk of developing melanoma post-HCT.

Fitzpatrick skin types I and II were respectively associated with 9.3- and 7.2-fold increased risks of post-HCT nonmelanoma skin cancer, compared with skin types III-VI.

Acute GVHD wasn’t associated with an increased risk of nonmelanoma skin cancer after HCT. However, in an observation that hasn’t previously been reported by others, chronic GVHD with skin involvement was associated with a 2.7-fold increased likelihood of SCC post-HCT, Dr. Scott noted.

What’s next for Dr. Scott and his coinvestigators? “Our ultimate goal with this project is to develop an interactive risk assessment tool like the National Cancer Institute’s Breast Cancer Risk Assessment Tool that can be online and used by patients and providers to estimate their individualized risk of basal cell carcinoma, squamous cell carcinoma, and melanoma after HCT,” he said.

Dr. Scott reported having no financial conflicts related to the study.

bjancin@mdedge.com

CHICAGO – The 10-year incidence rates for both squamous cell carcinoma and basal cell carcinoma arising after hematopoietic cell transplantation are impressively high at 17%-plus for each, but the malignancies occur on two very different timelines, according to Jeffrey F. Scott, MD, a fellow in micrographic surgery and dermatologic oncology at Case Western Reserve University in Cleveland.

Most of the squamous cell carcinomas (SCCs) in a large multicenter retrospective study developed within the first 5 years following hematopoietic cell transplantation (HCT), while the majority of the basal cell carcinomas (BCCs) occurred after that point, Dr. Scott reported at the annual meeting of the American College of Mohs Surgery.

He presented the results of the study, which included 876 HCT recipients followed for a mean of 6.1 years. The study objective was to pin down the risk factors for skin cancer after HCT, especially the patient-specific ones. This has become a pressing issue because the use of HCT is steadily growing, and the 5-year survival rate now exceeds 50%.

The transplant-specific risk factors have previously been fairly well described by others. They include the donor source, type of disease, the conditioning regimen, whether whole body irradiation was used, immunosuppression, graft versus host disease (GVHD), and others.

The patient-centric risk factors, in contrast, have not been well characterized. And it’s critical to thoroughly understand these risk factors in order to develop targeted prevention and surveillance strategies, Dr. Scott said.

“There remains a significant knowledge gap within our field. I would venture that the majority of this audience has treated a patient with skin cancer who has had a transplant,” he said. “Yet when a patient asks us, ‘Doc, what is my risk for skin cancer after my HCT?’ we’re really unable to give them an accurate and complete assessment of that risk. That’s because we’re missing the second major category of risk factors: the patient-specific risk factors.”

The reason for that, he added, is that the major population-based studies and national HCT registries are run by hematologists and oncologists, and they haven’t adequately captured the patient-specific skin cancer risk factors. But these are variables very familiar to dermatologists. They include skin phenotype, history of UV radiation exposure, and history of pre-HCT skin cancer.

Dr. Scott said the multicenter study he presented has two major advantages over prior studies: its large size and thorough followup. Nearly all 876 patients were followed by both an oncologist and a dermatologist at the same institution.

During followup, the HCT recipients collectively developed 63 SCCs, 55 BCCs, and 16 malignant melanomas. The 5- and 10-year incidence rates for SCC were 10.6% and 17.2%. For BCC, the 5- and 10-year rates were 5.7% and 17.6%. All 16 cases of melanoma occurred within 5 years after HCT.

In multivariate Cox proportional hazard analyses, photodamage documented on examination was independently associated with a 3.2-fold increased risk of post-HCT SCC and a 3.5-fold increased risk of BCC.

A pre-transplant history of BCC was associated with a 3.9-fold increased likelihood of developing a BCC afterwards. Similarly, a pre-HCT history of SCC conferred a 4.2-fold increased risk of post-transplant SCC and was also independently associated with a 6.6-fold increased risk of developing melanoma post-HCT.

Fitzpatrick skin types I and II were respectively associated with 9.3- and 7.2-fold increased risks of post-HCT nonmelanoma skin cancer, compared with skin types III-VI.

Acute GVHD wasn’t associated with an increased risk of nonmelanoma skin cancer after HCT. However, in an observation that hasn’t previously been reported by others, chronic GVHD with skin involvement was associated with a 2.7-fold increased likelihood of SCC post-HCT, Dr. Scott noted.

What’s next for Dr. Scott and his coinvestigators? “Our ultimate goal with this project is to develop an interactive risk assessment tool like the National Cancer Institute’s Breast Cancer Risk Assessment Tool that can be online and used by patients and providers to estimate their individualized risk of basal cell carcinoma, squamous cell carcinoma, and melanoma after HCT,” he said.

Dr. Scott reported having no financial conflicts related to the study.

bjancin@mdedge.com

Platinum-based chemotherapy is effective in metastatic triple negative breast cancer (mTNBC), but predictive biomarkers would help identify the best candidates for the treatment. Two sets of parameters—neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR)—have already demonstrated their prognostic prowess in many malignancies, but how well will they do in platinum-treated mTNBC patients? Researchers from Fondazione IRCCS Istituto Nazionale dei Tumori, in Milan, Italy conducted a retrospective, single-center study to evaluate the association between baseline NLR or PLR and progression-free survival (PFS) in 57 mTNBC patients treated with carboplatin-paclitaxel or carboplatin-gemcitabine between 2007 and 2017, compared with 148 patients with hormone receptor-positive HER2-negative metastatic breast cancer.

Response was assessed every 3 chemotherapy cycles. Among platinum-treated patients, high NLR and PLR were associated with significantly lower PFS. Median PFS was 304 days in patients with NLR < 2.5, and 158 days in those with NLR ≥ 2.5. Progression-free survival was longer in patients with baseline PLR < 200, compared with PLR ≥ 200. The researchers found no significant association between NLR or PLR and the PFS of control patients.

When the same parameters were evaluated before the administration of the third treatment cycle, NLR < 2.5 was still associated with reduced risk of disease progression, although PLR < 200 was not.

In patients with mTNBC, median overall survival was significantly longer in patients with NLR < 2.5 compared with NLR ≥ 2.5. Platelet-to-lymphocyte ratio values were not associated with overall survival. The ratios also appeared to have a generally prognostic role independently from tumor biology.

The hormone receptors for NLR and PLR in multivariable analysis for PFS were similar, and the parameters correlated with each other, the researchers say, suggesting that both NLR and PLR “well reflect the inflammatory/immune contexture in mTNBC, and may be redundant as predictive biomarkers.”

Source:
Vernieri C, Mennitto A, Prisciandaro M, et al. Sci Rep. 2018;8(1):8703.

Platinum-based chemotherapy is effective in metastatic triple negative breast cancer (mTNBC), but predictive biomarkers would help identify the best candidates for the treatment. Two sets of parameters—neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR)—have already demonstrated their prognostic prowess in many malignancies, but how well will they do in platinum-treated mTNBC patients? Researchers from Fondazione IRCCS Istituto Nazionale dei Tumori, in Milan, Italy conducted a retrospective, single-center study to evaluate the association between baseline NLR or PLR and progression-free survival (PFS) in 57 mTNBC patients treated with carboplatin-paclitaxel or carboplatin-gemcitabine between 2007 and 2017, compared with 148 patients with hormone receptor-positive HER2-negative metastatic breast cancer.

Response was assessed every 3 chemotherapy cycles. Among platinum-treated patients, high NLR and PLR were associated with significantly lower PFS. Median PFS was 304 days in patients with NLR < 2.5, and 158 days in those with NLR ≥ 2.5. Progression-free survival was longer in patients with baseline PLR < 200, compared with PLR ≥ 200. The researchers found no significant association between NLR or PLR and the PFS of control patients.

When the same parameters were evaluated before the administration of the third treatment cycle, NLR < 2.5 was still associated with reduced risk of disease progression, although PLR < 200 was not.

In patients with mTNBC, median overall survival was significantly longer in patients with NLR < 2.5 compared with NLR ≥ 2.5. Platelet-to-lymphocyte ratio values were not associated with overall survival. The ratios also appeared to have a generally prognostic role independently from tumor biology.

The hormone receptors for NLR and PLR in multivariable analysis for PFS were similar, and the parameters correlated with each other, the researchers say, suggesting that both NLR and PLR “well reflect the inflammatory/immune contexture in mTNBC, and may be redundant as predictive biomarkers.”

Source:
Vernieri C, Mennitto A, Prisciandaro M, et al. Sci Rep. 2018;8(1):8703.

Platinum-based chemotherapy is effective in metastatic triple negative breast cancer (mTNBC), but predictive biomarkers would help identify the best candidates for the treatment. Two sets of parameters—neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR)—have already demonstrated their prognostic prowess in many malignancies, but how well will they do in platinum-treated mTNBC patients? Researchers from Fondazione IRCCS Istituto Nazionale dei Tumori, in Milan, Italy conducted a retrospective, single-center study to evaluate the association between baseline NLR or PLR and progression-free survival (PFS) in 57 mTNBC patients treated with carboplatin-paclitaxel or carboplatin-gemcitabine between 2007 and 2017, compared with 148 patients with hormone receptor-positive HER2-negative metastatic breast cancer.

Response was assessed every 3 chemotherapy cycles. Among platinum-treated patients, high NLR and PLR were associated with significantly lower PFS. Median PFS was 304 days in patients with NLR < 2.5, and 158 days in those with NLR ≥ 2.5. Progression-free survival was longer in patients with baseline PLR < 200, compared with PLR ≥ 200. The researchers found no significant association between NLR or PLR and the PFS of control patients.

When the same parameters were evaluated before the administration of the third treatment cycle, NLR < 2.5 was still associated with reduced risk of disease progression, although PLR < 200 was not.

In patients with mTNBC, median overall survival was significantly longer in patients with NLR < 2.5 compared with NLR ≥ 2.5. Platelet-to-lymphocyte ratio values were not associated with overall survival. The ratios also appeared to have a generally prognostic role independently from tumor biology.

The hormone receptors for NLR and PLR in multivariable analysis for PFS were similar, and the parameters correlated with each other, the researchers say, suggesting that both NLR and PLR “well reflect the inflammatory/immune contexture in mTNBC, and may be redundant as predictive biomarkers.”

Source:
Vernieri C, Mennitto A, Prisciandaro M, et al. Sci Rep. 2018;8(1):8703.

Venetoclax (Venclexta) has received regular approval from the Food and Drug Administration for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy.

The approval was based results from the MURANO trial of 389 patients, which was a randomized, multicenter, open-label trial of venetoclax plus rituximab versus bendamustine plus rituximab.

cpalmer@mdedge.com

Venetoclax (Venclexta) has received regular approval from the Food and Drug Administration for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy.

The approval was based results from the MURANO trial of 389 patients, which was a randomized, multicenter, open-label trial of venetoclax plus rituximab versus bendamustine plus rituximab.

cpalmer@mdedge.com

Venetoclax (Venclexta) has received regular approval from the Food and Drug Administration for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy.

The approval was based results from the MURANO trial of 389 patients, which was a randomized, multicenter, open-label trial of venetoclax plus rituximab versus bendamustine plus rituximab.

cpalmer@mdedge.com