BEST PRACTICES IN: Management of Patients With T2DM: The Risk and Role of Chronic Kidney Disease

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BEST PRACTICES IN: Management of Patients With T2DM: The Risk and Role of Chronic Kidney Disease

A supplement to Internal Medicine News®. This supplement was sponsored by Boehringer Ingelheim Pharmaceuticals, Inc. and Eli Lilly and Company.

 


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Topics

 

  • Epidemiology of CKD/RI With DM
  • Risk Factors for CKD/RI in Patients With T2DM
  • Early Identification and Screening
  • CKD Strongly Effects CV Outcomes in Patients With DM
  • Awareness of the Importance of CKD/RI Is Lacking
  • CKD/RI Increases the Risk for Hypoglycemia in DM Treatment
  • Multifactorial Therapy May Benefit Outcomes in Patients With T2DM and CKD

Faculty/Faculty Disclosure Mark Stolar, MD
Associate Professor of Clinical Medicine
Northwestern University Medical School
Chicago, IL

Michael Kodack, PharmD
Vice President, Medical
BlueSpark Healthcare Communications LLC
Basking Ridge, NJ

Mark Stolar, MD, has served on the Speakers Bureau of Takeda Pharmaceutical Company Limited and has developed educational programs for the TCL Institute and NACE. Michael Kodack, PharmD, is an employee of BlueSpark Healthcare Communications LLC.

Copyright © 2011 Elsevier Inc.

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A supplement to Internal Medicine News®. This supplement was sponsored by Boehringer Ingelheim Pharmaceuticals, Inc. and Eli Lilly and Company.

 


To view the supplement, click the image above.

Topics

 

  • Epidemiology of CKD/RI With DM
  • Risk Factors for CKD/RI in Patients With T2DM
  • Early Identification and Screening
  • CKD Strongly Effects CV Outcomes in Patients With DM
  • Awareness of the Importance of CKD/RI Is Lacking
  • CKD/RI Increases the Risk for Hypoglycemia in DM Treatment
  • Multifactorial Therapy May Benefit Outcomes in Patients With T2DM and CKD

Faculty/Faculty Disclosure Mark Stolar, MD
Associate Professor of Clinical Medicine
Northwestern University Medical School
Chicago, IL

Michael Kodack, PharmD
Vice President, Medical
BlueSpark Healthcare Communications LLC
Basking Ridge, NJ

Mark Stolar, MD, has served on the Speakers Bureau of Takeda Pharmaceutical Company Limited and has developed educational programs for the TCL Institute and NACE. Michael Kodack, PharmD, is an employee of BlueSpark Healthcare Communications LLC.

Copyright © 2011 Elsevier Inc.

A supplement to Internal Medicine News®. This supplement was sponsored by Boehringer Ingelheim Pharmaceuticals, Inc. and Eli Lilly and Company.

 


To view the supplement, click the image above.

Topics

 

  • Epidemiology of CKD/RI With DM
  • Risk Factors for CKD/RI in Patients With T2DM
  • Early Identification and Screening
  • CKD Strongly Effects CV Outcomes in Patients With DM
  • Awareness of the Importance of CKD/RI Is Lacking
  • CKD/RI Increases the Risk for Hypoglycemia in DM Treatment
  • Multifactorial Therapy May Benefit Outcomes in Patients With T2DM and CKD

Faculty/Faculty Disclosure Mark Stolar, MD
Associate Professor of Clinical Medicine
Northwestern University Medical School
Chicago, IL

Michael Kodack, PharmD
Vice President, Medical
BlueSpark Healthcare Communications LLC
Basking Ridge, NJ

Mark Stolar, MD, has served on the Speakers Bureau of Takeda Pharmaceutical Company Limited and has developed educational programs for the TCL Institute and NACE. Michael Kodack, PharmD, is an employee of BlueSpark Healthcare Communications LLC.

Copyright © 2011 Elsevier Inc.

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BEST PRACTICES IN: Management of Patients With T2DM: The Risk and Role of Chronic Kidney Disease
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Pomalidomide in lenalidomide-refractory multiple myeloma and carfilzomib in refractory and newly diagnosed multiple myeloma

From the Oncologist's Perspective - Evolving therapies for multiple myeloma
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Pomalidomide in lenalidomide-refractory multiple myeloma and carfilzomib in refractory and newly diagnosed multiple myeloma
Pomalidomide and carfilzomib represent active and well-tolerated new options in combination regimens.

What's new, what's important

Treatment of multiple myeloma is evolving rapidly. It is tough to keep up with the rapid pace of new drugs, updates, and changes in the standard of care. In this issue of Community Oncology we bring to you two new exciting drugs on the horizon, pomalidomide and carfilzomib. In addition to introducing these two new drugs, we have asked Dr. Noopur Raje to explain how she treats a newly diagnosed patient with multiple myeloma.

Pomalidomide, a thalidomide (Thalomid) analog, is a promising myeloma drug with encouraging responses in relapsed/refractory myeloma patients. Carfilzomib is a novel proteasome inhibitor. When combined with lenalidomide (Revlimid) in the first-line setting, it produced a 100% response rate. Phase III studies are in progress or being completed. It will be exciting to see the final results of these studies. 

With this issue we are changing the format of Community Translations to incorporate the mechanism of action or pathophysiology of some of these new advances so that a clinician can relate to them in a clinical setting. 

--Jame Abraham, MD, Editor

Two of the most promising drugs on the horizon for patients with multiple myeloma (MM) are pomalidomide and carfilzomib. Both agents have shown significant single-agent activity in clinical trials. They seem to work in patients whose MM is resistant to other treatments and are being studied in combination regimens.

Pomalidomide

Pomalidomide is a new immunomodulatory drug (IMiD) with high in vitro potency. In initial experience with pomalidomide and low-dose dexamethasone in relapsed MM, Lacy and colleagues found an overall response rate of 63% and observed responses in some patients who were refractory to lenalidomide (Revlimid), suggesting an absence of cross-resistance between pomalidomide and other IMiDs. In a recently reported phase II study,1 these investigators assessed the combination of pomalidomide and low-dose dexamethasone in patients with lenalidomide-refractory MM, finding the combination to be highly active and well tolerated.

In this study, 34 patients with lenalidomide-refractory MM were treated with oral pomalidomide (2 mg daily) and dexamethasone (40 mg once weekly) in 28-day cycles. Patients had a median age of 61.5 years, 68% were male, 85% had an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1, and 41% were categorized as high risk. The median time from diagnosis was 62 months. The median number of prior chemotherapy regimens was four. In addition to lenalidomide, 58% of patients had received prior thalidomide (Thalomid), and 59% had received prior bortezomib (Velcade); 68% of patients had undergone prior autologous stem cell transplantation, and 53% had prior radiation therapy. Twenty patients (59%) had peripheral neuropathy at baseline.

Patients received a median of 5 cycles (range, 1−14) of pomalidomide plus low-dose dexamethasone. Prophylaxis for venous thromboembolism was given in 204 of 209 treatment cycles (aspirin in 150 cycles and warfarin in 54 cycles). Treatment responses consisted of a very good partial response in 9%, a partial response in 23%, and a minimal response in 15%, for an overall clinical benefit rate of 47%; 35% of patients had stable disease, and 18% had disease progression. The median time to response was 2 months. Response was observed in 8 of 14 (57%) high-risk patients, in 8 of 19 (42%) who received previous thalidomide treatment, and in 9 of 20 (45%) who were given previous bortezomib treatment. In eight patients with stable disease, the pomalidomide dose was increased to 4 mg/d, with one patient improving to a partial response. The median duration of response in 11 patients with a partial response or better was 9.1 months. The median progression-free survival was 4.8 months, and progression-free survival did not differ between high-risk and standard-risk patients. The median overall survival was 13.9 months. During follow-up, treatment was stopped due to disease progression in 23 patients, 3 withdrew from the study due to patient/physician discretion, and 8 continued to receive treatment. Seven patients died, all due to disease progression. The median follow-up of patients remaining alive was 8.3 months.

Pomalidomide/dexamethasone treatment was well tolerated. Toxicity consisted mostly of myelosuppression. Grade 3 or 4 hematologic toxicity at least possibly related to treatment occurred in 38% of patients, including neutropenia in 29%, anemia in 12%, and thrombocytopenia in 9%. The most common grade 3/4 nonhematologic toxicity was fatigue, which occurred in 9% of patients (all grade 3); grade 3 pneumonitis, edema, pneumonia, and folliculitis were each observed in one patient. Nine patients (26%) had neuropathy during treatment (six grade 1, three grade 2); they included six patients with neuropathy at baseline, three of whom had a worsening of grade.
 

 

Carfilzomib

Carfilzomib is a highly selective epoxyketone proteasome inhibitor with minimal affinity for nontarget proteases. In a recent phase II trial in patients with relapsed/refractory MM, reported at the 2010 American Society of Hematology (ASH) meeting, carfilzomib produced durable responses and was well tolerated.2 An ongoing phase I/II trial assessing carfilzomib, lenalidomide, and dexamethasone in newly diagnosed MM, also reported at the 2010 ASH meeting, has shown good activity and tolerability of the regimen.3 A phase III trial comparing carfilzomib plus lenalidomide and low-dose dexamethasone versus lenalidomide and low-dose dexamethasone in relapsed MM has been initiated.

Relapsed/refractory MM

In the trial in patients with relapsed/refractory MM, 266 patients with multiply relapsed MM who had disease refractory to their last treatment received carfilzomib (20 mg/m2 IV on days 1, 2, 8, 9, 15, and 16) every 28 days for the first cycle, with the dose then being escalated to 27 mg/m2 on the same schedule for up to 12 cycles.2 Prior therapies included bortezomib, either lenalidomide or thalidomide, and an alkylating agent. Patients had a median duration of MM of 5.4 years and had received a median of 5 prior lines of chemotherapy and a median of 13 antimyeloma treatments; prior treatments included bortezomib in 99.6% of patients (a median of two prior regimens containing bortezomib), lenalidomide in 94%, thalidomide in 74%, corticosteroids in 98%, alkylating agents in 91%, and stem cell transplantation in 74%. Overall, 65% of patients were refractory to bortezomib prior to study entry.

At the time of reporting, 79 patients (30%) had completed at least 6 cycles of study treatment, approximately 11% had completed 12 cycles (with most entering an extension phase of the study), and 15 patients remained on study (all with more than 10 cycles of study treatment). Among 257 patients evaluable for response, 0.4% (one patient) had a complete response, 4.7% had a very good partial response, and 19% had a partial response, for an overall response rate of 24%; an additional 12% of patients had a minimal response, yielding an overall clinical benefit rate of 36%. Stable disease for at least 6 weeks was achieved in 32%. Among patients with a partial response or better, the median duration of response was 7.4 months. Among patients with a minimal response, the median duration of response was 6.3 months, indicating durable minor responses.

Toxicity consisted mainly of myelosuppression. Grade 3/4 hematologic toxicities consisted of thrombocytopenia in 18% of patients, lymphopenia in 11%, neutropenia in 8%, and anemia in 7%.4 Grade 3/4 nonhematologic toxicities included fatigue in 6% of patients; pneumonia and congestive cardiac failure in 3% each; nausea, dyspnea, increased blood creatinine levels, and increased blood uric acid levels in 1% each; and diarrhea in 0.4%. Grade 1/2 peripheral neuropathy was present in 77% of patients at baseline; new-onset neuropathy was infrequent, with grade 3 or lower neuropathy occurring in less than 1% of patients.2

Newly diagnosed MM

In an ongoing phase I/II trial, patients with newly diagnosed MM are receiving carfilzomib, lenalidomide, and dexamethasone.3 Carfilzomib is started at 20 mg/m2 (dose level 1) and increased to 27 mg/m2 (dose level 2) and 36 mg/m2 (dose level 3) given IV on days 1, 2, 8, 9, 15, and 16 in 28-day cycles. Lenalidomide is given at 25 mg/d on days 1−21 in each cycle, and dexamethasone is given weekly at 40 mg during cycles 1−4 and at 20 mg during cycles 5−8. Patients with a partial response or better are eligible to proceed to stem cell collection and autologous stem cell transplantation after at least 4 cycles and can continue study treatment after transplantation. After completion of 8 cycles, patients are to receive maintenance cycles consisting of carfilzomib on days 1, 2, 15, and 16; lenalidomide on days 1−21; and weekly dexamethasone at doses tolerated at the end of 8 cycles. A planned 36 patients are to be treated at the carfilzomib maximum tolerated dose.

At the time of reporting, 24 patients had been enrolled, 4 at dose level 1, 14 at dose level 2, and 6 at dose level 3. Toxicity data were available for 21 patients, including 19 who completed at least 1 cycle of treatment. A single dose-limiting toxicity event was observed, consisting of nonfebrile neutropenia in a patient at dose level 2. The maximum tolerated dose had not yet been reached. Grade 3/4 hematologic toxicities consisted of neutropenia in three patients, thrombocytopenia in three patients, and anemia in one patient. Grade 3 nonhematologic toxicities included five cases of elevated blood glucose levels, deep vein thrombosis during aspirin prophylaxis in one patient, and fatigue in one patient. Emergent peripheral neuropathy was observed in two patients, who developed grade 1 neuropathy.
 

 

At the time of reporting, 23 patients continued on treatment, with 20 having no need for dose modifications. After a median of 4 months of treatment (range, 1−8 months), the preliminary response rate in 19 evaluable patients completing at least 1 cycle was 100% with at least a partial response, including 63% with a very good partial response and 37% with a complete response or near-complete response. Partial responses were observed in 17 of 19 patients after 1 cycle, with responses improving in all patients with continuing treatment. Seven patients had proceeded to stem cell collection using growth factors only after a median of 4 cycles, and all resumed study treatment after stem cell collection. No disease progression had been observed in any of the evaluable patients, and all remained alive.

References

1. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia 2010;24:1934−1939.

2. Siegel DSD, Martin T, Wang M, et al. Results of PX-171-003-A1, an open-label, single-arm, phase 2 study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). Blood 2010;116:985.

3. Jakubowiak AJ, Dytfeld D, Jagannath S, et al. Carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma: initial results of phase I/II MMRC trial. Blood 2010;116:862.

4. Singhal SB, Siegel DSD, Martin T, et al. Pooled safety analysis from phase 1 and 2 studies of carfilzomib (CFZ) in patients with relapsed and/or refractory multiple myeloma (MM). Blood 2010;116:1954.

Body

Noopur Raje, MD, Massachusetts General Hospital Cancer Center; Division of Hematology and Oncology, Massachusetts General Hospital; and Harvard Medical School, Boston, MA

Although multiple myeloma (MM) remains an incurable bone marrow

cancer, survival rates have improved markedly over the past decade. An

understanding of MM pathobiology (Figure 1) and improvement in stem cell

transplantation, better supportive care, and novel therapies with

higher efficacy and lower toxicity are all responsible for this

improvement. The availability of a rich pipeline of novel agents

undergoing early-phase clinical trials in MM is an exciting and active

area of research.1

Current treatment

Over the past several years, five therapeutic strategies have

received US Food and Drug Administration (FDA) approval either as

monotherapy or in combination for treating MM, with thalidomide

(Thalomid), lenalidomide (Revlimid), and bortezomib (Velcade) as

important backbone drugs in these approaches. In the upfront setting,

thalidomide with dexamethasone2 and bortezomib in combination with melphalan and prednisone3

increased the overall response rate and significantly prolonged time to

disease progression and are FDA approved. For treatment of relapsed MM,

bortezomib alone4 and in combination with pegylated liposomal doxorubicin (Doxil),5 as well as lenalidomide/dexamethasone,6

have been approved. Results of a recent phase III randomized clinical

trial suggest that lower doses of dexamethasone provide a survival

advantage, at least in the upfront setting, mainly due to the increased

toxicity of high doses of dexamethasone.7

The availability of these novel agents has not only provided us

with several treatment options but has had an important impact on the

overall survival of our patients. To improve upon current outcomes,

optimal combinations of bortezomib, thalidomide, and lenalidomide are

currently under evaluation in phase II/III clinical trials.

Novel approaches

The preceding review refers to recent data on pomalidomide, the

newest immunomodulatory drug (IMiD) analog, which has shown single-agent

activity in phase I studies and was subsequently tested in a phase II

trial in combination with low-dose dexamethasone in patients with

relapsed or refractory MM. Pomalidomide/dexamethasone was found to be

highly active and well tolerated, providing a clinical benefit in 47% of

patients and no grade 3 neuropathy. These findings have led to a large

phase II study, which has completed accrual and is awaiting analysis.

Another promising agent discussed here is the novel proteasome

inhibitor carfilzomib. Although bortezomib is an effective agent in MM,

about 20% of newly diagnosed patients are resistant to bortezomib, and,

ultimately, all patients relapse and develop resistance to the drug.

Carfilzomib irreversibly blocks chymotrypsin-like activity and in phase I

studies achieved more than 80% proteasome inhibition. Encouraging data

presented at the 2010 annual meeting of the American Society of

Hematology demonstrated that it was well tolerated and had an overall

clinical benefit rate of 36% in relapsed/refractory MM.8 In the upfront setting, carfilzomib combined with lenalidomide led to a 100% response rate.9

This combination with low-dose dexamethasone is currently

undergoing testing in a phase III registration trial. These data,

therefore, provide important therapeutic options among the armamentarium

of current and future antimyeloma therapies, helping transform MM into

an even more chronic disease than it is today and ultimately leading to a

cure.

References

1. Cirstea D, Vallet S, Raje N. Future novel single agent and combination therapies. Cancer J 2009;15:511-518.

2. Rajkumar

SV, Rosinol L, Hussein M, et al. Multicenter, randomized, double-blind,

placebo-controlled study of thalidomide plus dexamethasone compared

with dexamethasone as initial therapy for newly diagnosed multiple

myeloma. J Clin Oncol 2008;26:2171-2177.

3. San

Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and

prednisone for initial treatment of multiple myeloma. N Engl J Med

2008;359:906-917.

4. Richardson

PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose

dexamethasone for relapsed multiple myeloma. N Engl J Med

2005;352:2487-2498.

5. Orlowski

RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of

pegylated liposomal doxorubicin plus bortezomib compared with bortezomib

alone in relapsed or refractory multiple myeloma: combination therapy

improves time to progression. J Clin Oncol 2007;25:3892-3901.

6. Dimopoulos

MA, Chen C, Spencer A, et al. Long-term follow-up on overall survival

from the MM-009 and MM-010 phase III trials of lenalidomide plus

dexamethasone in patients with relapsed or refractory multiple myeloma.

Leukemia 2009;23:2147-2152.

7. Rajkumar

SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose

dexamethasone versus lenalidomide plus low-dose dexamethasone as initial

therapy for newly diagnosed multiple myeloma: an open-label randomised

controlled trial. Lancet Oncol 2010;11:29-37.

8. Siegel

DSD, Martin T, Wang M, et al. Results of PX-171-003-A1, an open-label,

single-arm, phase 2 study of carfilzomib (CFZ) in patients (pts) with

relapsed and refractory multiple myeloma (MM). Blood 2010;116:985.

9. Jakubowiak

AJ, Dytfeld D, Jagannath S, et al. Carfilzomib, lenalidomide, and

dexamethasone in newly diagnosed multiple myeloma: initial results of

phase I/II MMRC trial. Blood 2010;116:862.

Dr. Raje can be reached at nraje@partners.org.

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Pomalidomide and carfilzomib represent active and well-tolerated new options in combination regimens.
Pomalidomide and carfilzomib represent active and well-tolerated new options in combination regimens.
Body

Noopur Raje, MD, Massachusetts General Hospital Cancer Center; Division of Hematology and Oncology, Massachusetts General Hospital; and Harvard Medical School, Boston, MA

Although multiple myeloma (MM) remains an incurable bone marrow

cancer, survival rates have improved markedly over the past decade. An

understanding of MM pathobiology (Figure 1) and improvement in stem cell

transplantation, better supportive care, and novel therapies with

higher efficacy and lower toxicity are all responsible for this

improvement. The availability of a rich pipeline of novel agents

undergoing early-phase clinical trials in MM is an exciting and active

area of research.1

Current treatment

Over the past several years, five therapeutic strategies have

received US Food and Drug Administration (FDA) approval either as

monotherapy or in combination for treating MM, with thalidomide

(Thalomid), lenalidomide (Revlimid), and bortezomib (Velcade) as

important backbone drugs in these approaches. In the upfront setting,

thalidomide with dexamethasone2 and bortezomib in combination with melphalan and prednisone3

increased the overall response rate and significantly prolonged time to

disease progression and are FDA approved. For treatment of relapsed MM,

bortezomib alone4 and in combination with pegylated liposomal doxorubicin (Doxil),5 as well as lenalidomide/dexamethasone,6

have been approved. Results of a recent phase III randomized clinical

trial suggest that lower doses of dexamethasone provide a survival

advantage, at least in the upfront setting, mainly due to the increased

toxicity of high doses of dexamethasone.7

The availability of these novel agents has not only provided us

with several treatment options but has had an important impact on the

overall survival of our patients. To improve upon current outcomes,

optimal combinations of bortezomib, thalidomide, and lenalidomide are

currently under evaluation in phase II/III clinical trials.

Novel approaches

The preceding review refers to recent data on pomalidomide, the

newest immunomodulatory drug (IMiD) analog, which has shown single-agent

activity in phase I studies and was subsequently tested in a phase II

trial in combination with low-dose dexamethasone in patients with

relapsed or refractory MM. Pomalidomide/dexamethasone was found to be

highly active and well tolerated, providing a clinical benefit in 47% of

patients and no grade 3 neuropathy. These findings have led to a large

phase II study, which has completed accrual and is awaiting analysis.

Another promising agent discussed here is the novel proteasome

inhibitor carfilzomib. Although bortezomib is an effective agent in MM,

about 20% of newly diagnosed patients are resistant to bortezomib, and,

ultimately, all patients relapse and develop resistance to the drug.

Carfilzomib irreversibly blocks chymotrypsin-like activity and in phase I

studies achieved more than 80% proteasome inhibition. Encouraging data

presented at the 2010 annual meeting of the American Society of

Hematology demonstrated that it was well tolerated and had an overall

clinical benefit rate of 36% in relapsed/refractory MM.8 In the upfront setting, carfilzomib combined with lenalidomide led to a 100% response rate.9

This combination with low-dose dexamethasone is currently

undergoing testing in a phase III registration trial. These data,

therefore, provide important therapeutic options among the armamentarium

of current and future antimyeloma therapies, helping transform MM into

an even more chronic disease than it is today and ultimately leading to a

cure.

References

1. Cirstea D, Vallet S, Raje N. Future novel single agent and combination therapies. Cancer J 2009;15:511-518.

2. Rajkumar

SV, Rosinol L, Hussein M, et al. Multicenter, randomized, double-blind,

placebo-controlled study of thalidomide plus dexamethasone compared

with dexamethasone as initial therapy for newly diagnosed multiple

myeloma. J Clin Oncol 2008;26:2171-2177.

3. San

Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and

prednisone for initial treatment of multiple myeloma. N Engl J Med

2008;359:906-917.

4. Richardson

PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose

dexamethasone for relapsed multiple myeloma. N Engl J Med

2005;352:2487-2498.

5. Orlowski

RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of

pegylated liposomal doxorubicin plus bortezomib compared with bortezomib

alone in relapsed or refractory multiple myeloma: combination therapy

improves time to progression. J Clin Oncol 2007;25:3892-3901.

6. Dimopoulos

MA, Chen C, Spencer A, et al. Long-term follow-up on overall survival

from the MM-009 and MM-010 phase III trials of lenalidomide plus

dexamethasone in patients with relapsed or refractory multiple myeloma.

Leukemia 2009;23:2147-2152.

7. Rajkumar

SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose

dexamethasone versus lenalidomide plus low-dose dexamethasone as initial

therapy for newly diagnosed multiple myeloma: an open-label randomised

controlled trial. Lancet Oncol 2010;11:29-37.

8. Siegel

DSD, Martin T, Wang M, et al. Results of PX-171-003-A1, an open-label,

single-arm, phase 2 study of carfilzomib (CFZ) in patients (pts) with

relapsed and refractory multiple myeloma (MM). Blood 2010;116:985.

9. Jakubowiak

AJ, Dytfeld D, Jagannath S, et al. Carfilzomib, lenalidomide, and

dexamethasone in newly diagnosed multiple myeloma: initial results of

phase I/II MMRC trial. Blood 2010;116:862.

Dr. Raje can be reached at nraje@partners.org.

Body

Noopur Raje, MD, Massachusetts General Hospital Cancer Center; Division of Hematology and Oncology, Massachusetts General Hospital; and Harvard Medical School, Boston, MA

Although multiple myeloma (MM) remains an incurable bone marrow

cancer, survival rates have improved markedly over the past decade. An

understanding of MM pathobiology (Figure 1) and improvement in stem cell

transplantation, better supportive care, and novel therapies with

higher efficacy and lower toxicity are all responsible for this

improvement. The availability of a rich pipeline of novel agents

undergoing early-phase clinical trials in MM is an exciting and active

area of research.1

Current treatment

Over the past several years, five therapeutic strategies have

received US Food and Drug Administration (FDA) approval either as

monotherapy or in combination for treating MM, with thalidomide

(Thalomid), lenalidomide (Revlimid), and bortezomib (Velcade) as

important backbone drugs in these approaches. In the upfront setting,

thalidomide with dexamethasone2 and bortezomib in combination with melphalan and prednisone3

increased the overall response rate and significantly prolonged time to

disease progression and are FDA approved. For treatment of relapsed MM,

bortezomib alone4 and in combination with pegylated liposomal doxorubicin (Doxil),5 as well as lenalidomide/dexamethasone,6

have been approved. Results of a recent phase III randomized clinical

trial suggest that lower doses of dexamethasone provide a survival

advantage, at least in the upfront setting, mainly due to the increased

toxicity of high doses of dexamethasone.7

The availability of these novel agents has not only provided us

with several treatment options but has had an important impact on the

overall survival of our patients. To improve upon current outcomes,

optimal combinations of bortezomib, thalidomide, and lenalidomide are

currently under evaluation in phase II/III clinical trials.

Novel approaches

The preceding review refers to recent data on pomalidomide, the

newest immunomodulatory drug (IMiD) analog, which has shown single-agent

activity in phase I studies and was subsequently tested in a phase II

trial in combination with low-dose dexamethasone in patients with

relapsed or refractory MM. Pomalidomide/dexamethasone was found to be

highly active and well tolerated, providing a clinical benefit in 47% of

patients and no grade 3 neuropathy. These findings have led to a large

phase II study, which has completed accrual and is awaiting analysis.

Another promising agent discussed here is the novel proteasome

inhibitor carfilzomib. Although bortezomib is an effective agent in MM,

about 20% of newly diagnosed patients are resistant to bortezomib, and,

ultimately, all patients relapse and develop resistance to the drug.

Carfilzomib irreversibly blocks chymotrypsin-like activity and in phase I

studies achieved more than 80% proteasome inhibition. Encouraging data

presented at the 2010 annual meeting of the American Society of

Hematology demonstrated that it was well tolerated and had an overall

clinical benefit rate of 36% in relapsed/refractory MM.8 In the upfront setting, carfilzomib combined with lenalidomide led to a 100% response rate.9

This combination with low-dose dexamethasone is currently

undergoing testing in a phase III registration trial. These data,

therefore, provide important therapeutic options among the armamentarium

of current and future antimyeloma therapies, helping transform MM into

an even more chronic disease than it is today and ultimately leading to a

cure.

References

1. Cirstea D, Vallet S, Raje N. Future novel single agent and combination therapies. Cancer J 2009;15:511-518.

2. Rajkumar

SV, Rosinol L, Hussein M, et al. Multicenter, randomized, double-blind,

placebo-controlled study of thalidomide plus dexamethasone compared

with dexamethasone as initial therapy for newly diagnosed multiple

myeloma. J Clin Oncol 2008;26:2171-2177.

3. San

Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and

prednisone for initial treatment of multiple myeloma. N Engl J Med

2008;359:906-917.

4. Richardson

PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose

dexamethasone for relapsed multiple myeloma. N Engl J Med

2005;352:2487-2498.

5. Orlowski

RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of

pegylated liposomal doxorubicin plus bortezomib compared with bortezomib

alone in relapsed or refractory multiple myeloma: combination therapy

improves time to progression. J Clin Oncol 2007;25:3892-3901.

6. Dimopoulos

MA, Chen C, Spencer A, et al. Long-term follow-up on overall survival

from the MM-009 and MM-010 phase III trials of lenalidomide plus

dexamethasone in patients with relapsed or refractory multiple myeloma.

Leukemia 2009;23:2147-2152.

7. Rajkumar

SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose

dexamethasone versus lenalidomide plus low-dose dexamethasone as initial

therapy for newly diagnosed multiple myeloma: an open-label randomised

controlled trial. Lancet Oncol 2010;11:29-37.

8. Siegel

DSD, Martin T, Wang M, et al. Results of PX-171-003-A1, an open-label,

single-arm, phase 2 study of carfilzomib (CFZ) in patients (pts) with

relapsed and refractory multiple myeloma (MM). Blood 2010;116:985.

9. Jakubowiak

AJ, Dytfeld D, Jagannath S, et al. Carfilzomib, lenalidomide, and

dexamethasone in newly diagnosed multiple myeloma: initial results of

phase I/II MMRC trial. Blood 2010;116:862.

Dr. Raje can be reached at nraje@partners.org.

Title
From the Oncologist's Perspective - Evolving therapies for multiple myeloma
From the Oncologist's Perspective - Evolving therapies for multiple myeloma

What's new, what's important

Treatment of multiple myeloma is evolving rapidly. It is tough to keep up with the rapid pace of new drugs, updates, and changes in the standard of care. In this issue of Community Oncology we bring to you two new exciting drugs on the horizon, pomalidomide and carfilzomib. In addition to introducing these two new drugs, we have asked Dr. Noopur Raje to explain how she treats a newly diagnosed patient with multiple myeloma.

Pomalidomide, a thalidomide (Thalomid) analog, is a promising myeloma drug with encouraging responses in relapsed/refractory myeloma patients. Carfilzomib is a novel proteasome inhibitor. When combined with lenalidomide (Revlimid) in the first-line setting, it produced a 100% response rate. Phase III studies are in progress or being completed. It will be exciting to see the final results of these studies. 

With this issue we are changing the format of Community Translations to incorporate the mechanism of action or pathophysiology of some of these new advances so that a clinician can relate to them in a clinical setting. 

--Jame Abraham, MD, Editor

Two of the most promising drugs on the horizon for patients with multiple myeloma (MM) are pomalidomide and carfilzomib. Both agents have shown significant single-agent activity in clinical trials. They seem to work in patients whose MM is resistant to other treatments and are being studied in combination regimens.

Pomalidomide

Pomalidomide is a new immunomodulatory drug (IMiD) with high in vitro potency. In initial experience with pomalidomide and low-dose dexamethasone in relapsed MM, Lacy and colleagues found an overall response rate of 63% and observed responses in some patients who were refractory to lenalidomide (Revlimid), suggesting an absence of cross-resistance between pomalidomide and other IMiDs. In a recently reported phase II study,1 these investigators assessed the combination of pomalidomide and low-dose dexamethasone in patients with lenalidomide-refractory MM, finding the combination to be highly active and well tolerated.

In this study, 34 patients with lenalidomide-refractory MM were treated with oral pomalidomide (2 mg daily) and dexamethasone (40 mg once weekly) in 28-day cycles. Patients had a median age of 61.5 years, 68% were male, 85% had an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1, and 41% were categorized as high risk. The median time from diagnosis was 62 months. The median number of prior chemotherapy regimens was four. In addition to lenalidomide, 58% of patients had received prior thalidomide (Thalomid), and 59% had received prior bortezomib (Velcade); 68% of patients had undergone prior autologous stem cell transplantation, and 53% had prior radiation therapy. Twenty patients (59%) had peripheral neuropathy at baseline.

Patients received a median of 5 cycles (range, 1−14) of pomalidomide plus low-dose dexamethasone. Prophylaxis for venous thromboembolism was given in 204 of 209 treatment cycles (aspirin in 150 cycles and warfarin in 54 cycles). Treatment responses consisted of a very good partial response in 9%, a partial response in 23%, and a minimal response in 15%, for an overall clinical benefit rate of 47%; 35% of patients had stable disease, and 18% had disease progression. The median time to response was 2 months. Response was observed in 8 of 14 (57%) high-risk patients, in 8 of 19 (42%) who received previous thalidomide treatment, and in 9 of 20 (45%) who were given previous bortezomib treatment. In eight patients with stable disease, the pomalidomide dose was increased to 4 mg/d, with one patient improving to a partial response. The median duration of response in 11 patients with a partial response or better was 9.1 months. The median progression-free survival was 4.8 months, and progression-free survival did not differ between high-risk and standard-risk patients. The median overall survival was 13.9 months. During follow-up, treatment was stopped due to disease progression in 23 patients, 3 withdrew from the study due to patient/physician discretion, and 8 continued to receive treatment. Seven patients died, all due to disease progression. The median follow-up of patients remaining alive was 8.3 months.

Pomalidomide/dexamethasone treatment was well tolerated. Toxicity consisted mostly of myelosuppression. Grade 3 or 4 hematologic toxicity at least possibly related to treatment occurred in 38% of patients, including neutropenia in 29%, anemia in 12%, and thrombocytopenia in 9%. The most common grade 3/4 nonhematologic toxicity was fatigue, which occurred in 9% of patients (all grade 3); grade 3 pneumonitis, edema, pneumonia, and folliculitis were each observed in one patient. Nine patients (26%) had neuropathy during treatment (six grade 1, three grade 2); they included six patients with neuropathy at baseline, three of whom had a worsening of grade.
 

 

Carfilzomib

Carfilzomib is a highly selective epoxyketone proteasome inhibitor with minimal affinity for nontarget proteases. In a recent phase II trial in patients with relapsed/refractory MM, reported at the 2010 American Society of Hematology (ASH) meeting, carfilzomib produced durable responses and was well tolerated.2 An ongoing phase I/II trial assessing carfilzomib, lenalidomide, and dexamethasone in newly diagnosed MM, also reported at the 2010 ASH meeting, has shown good activity and tolerability of the regimen.3 A phase III trial comparing carfilzomib plus lenalidomide and low-dose dexamethasone versus lenalidomide and low-dose dexamethasone in relapsed MM has been initiated.

Relapsed/refractory MM

In the trial in patients with relapsed/refractory MM, 266 patients with multiply relapsed MM who had disease refractory to their last treatment received carfilzomib (20 mg/m2 IV on days 1, 2, 8, 9, 15, and 16) every 28 days for the first cycle, with the dose then being escalated to 27 mg/m2 on the same schedule for up to 12 cycles.2 Prior therapies included bortezomib, either lenalidomide or thalidomide, and an alkylating agent. Patients had a median duration of MM of 5.4 years and had received a median of 5 prior lines of chemotherapy and a median of 13 antimyeloma treatments; prior treatments included bortezomib in 99.6% of patients (a median of two prior regimens containing bortezomib), lenalidomide in 94%, thalidomide in 74%, corticosteroids in 98%, alkylating agents in 91%, and stem cell transplantation in 74%. Overall, 65% of patients were refractory to bortezomib prior to study entry.

At the time of reporting, 79 patients (30%) had completed at least 6 cycles of study treatment, approximately 11% had completed 12 cycles (with most entering an extension phase of the study), and 15 patients remained on study (all with more than 10 cycles of study treatment). Among 257 patients evaluable for response, 0.4% (one patient) had a complete response, 4.7% had a very good partial response, and 19% had a partial response, for an overall response rate of 24%; an additional 12% of patients had a minimal response, yielding an overall clinical benefit rate of 36%. Stable disease for at least 6 weeks was achieved in 32%. Among patients with a partial response or better, the median duration of response was 7.4 months. Among patients with a minimal response, the median duration of response was 6.3 months, indicating durable minor responses.

Toxicity consisted mainly of myelosuppression. Grade 3/4 hematologic toxicities consisted of thrombocytopenia in 18% of patients, lymphopenia in 11%, neutropenia in 8%, and anemia in 7%.4 Grade 3/4 nonhematologic toxicities included fatigue in 6% of patients; pneumonia and congestive cardiac failure in 3% each; nausea, dyspnea, increased blood creatinine levels, and increased blood uric acid levels in 1% each; and diarrhea in 0.4%. Grade 1/2 peripheral neuropathy was present in 77% of patients at baseline; new-onset neuropathy was infrequent, with grade 3 or lower neuropathy occurring in less than 1% of patients.2

Newly diagnosed MM

In an ongoing phase I/II trial, patients with newly diagnosed MM are receiving carfilzomib, lenalidomide, and dexamethasone.3 Carfilzomib is started at 20 mg/m2 (dose level 1) and increased to 27 mg/m2 (dose level 2) and 36 mg/m2 (dose level 3) given IV on days 1, 2, 8, 9, 15, and 16 in 28-day cycles. Lenalidomide is given at 25 mg/d on days 1−21 in each cycle, and dexamethasone is given weekly at 40 mg during cycles 1−4 and at 20 mg during cycles 5−8. Patients with a partial response or better are eligible to proceed to stem cell collection and autologous stem cell transplantation after at least 4 cycles and can continue study treatment after transplantation. After completion of 8 cycles, patients are to receive maintenance cycles consisting of carfilzomib on days 1, 2, 15, and 16; lenalidomide on days 1−21; and weekly dexamethasone at doses tolerated at the end of 8 cycles. A planned 36 patients are to be treated at the carfilzomib maximum tolerated dose.

At the time of reporting, 24 patients had been enrolled, 4 at dose level 1, 14 at dose level 2, and 6 at dose level 3. Toxicity data were available for 21 patients, including 19 who completed at least 1 cycle of treatment. A single dose-limiting toxicity event was observed, consisting of nonfebrile neutropenia in a patient at dose level 2. The maximum tolerated dose had not yet been reached. Grade 3/4 hematologic toxicities consisted of neutropenia in three patients, thrombocytopenia in three patients, and anemia in one patient. Grade 3 nonhematologic toxicities included five cases of elevated blood glucose levels, deep vein thrombosis during aspirin prophylaxis in one patient, and fatigue in one patient. Emergent peripheral neuropathy was observed in two patients, who developed grade 1 neuropathy.
 

 

At the time of reporting, 23 patients continued on treatment, with 20 having no need for dose modifications. After a median of 4 months of treatment (range, 1−8 months), the preliminary response rate in 19 evaluable patients completing at least 1 cycle was 100% with at least a partial response, including 63% with a very good partial response and 37% with a complete response or near-complete response. Partial responses were observed in 17 of 19 patients after 1 cycle, with responses improving in all patients with continuing treatment. Seven patients had proceeded to stem cell collection using growth factors only after a median of 4 cycles, and all resumed study treatment after stem cell collection. No disease progression had been observed in any of the evaluable patients, and all remained alive.

References

1. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia 2010;24:1934−1939.

2. Siegel DSD, Martin T, Wang M, et al. Results of PX-171-003-A1, an open-label, single-arm, phase 2 study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). Blood 2010;116:985.

3. Jakubowiak AJ, Dytfeld D, Jagannath S, et al. Carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma: initial results of phase I/II MMRC trial. Blood 2010;116:862.

4. Singhal SB, Siegel DSD, Martin T, et al. Pooled safety analysis from phase 1 and 2 studies of carfilzomib (CFZ) in patients with relapsed and/or refractory multiple myeloma (MM). Blood 2010;116:1954.

What's new, what's important

Treatment of multiple myeloma is evolving rapidly. It is tough to keep up with the rapid pace of new drugs, updates, and changes in the standard of care. In this issue of Community Oncology we bring to you two new exciting drugs on the horizon, pomalidomide and carfilzomib. In addition to introducing these two new drugs, we have asked Dr. Noopur Raje to explain how she treats a newly diagnosed patient with multiple myeloma.

Pomalidomide, a thalidomide (Thalomid) analog, is a promising myeloma drug with encouraging responses in relapsed/refractory myeloma patients. Carfilzomib is a novel proteasome inhibitor. When combined with lenalidomide (Revlimid) in the first-line setting, it produced a 100% response rate. Phase III studies are in progress or being completed. It will be exciting to see the final results of these studies. 

With this issue we are changing the format of Community Translations to incorporate the mechanism of action or pathophysiology of some of these new advances so that a clinician can relate to them in a clinical setting. 

--Jame Abraham, MD, Editor

Two of the most promising drugs on the horizon for patients with multiple myeloma (MM) are pomalidomide and carfilzomib. Both agents have shown significant single-agent activity in clinical trials. They seem to work in patients whose MM is resistant to other treatments and are being studied in combination regimens.

Pomalidomide

Pomalidomide is a new immunomodulatory drug (IMiD) with high in vitro potency. In initial experience with pomalidomide and low-dose dexamethasone in relapsed MM, Lacy and colleagues found an overall response rate of 63% and observed responses in some patients who were refractory to lenalidomide (Revlimid), suggesting an absence of cross-resistance between pomalidomide and other IMiDs. In a recently reported phase II study,1 these investigators assessed the combination of pomalidomide and low-dose dexamethasone in patients with lenalidomide-refractory MM, finding the combination to be highly active and well tolerated.

In this study, 34 patients with lenalidomide-refractory MM were treated with oral pomalidomide (2 mg daily) and dexamethasone (40 mg once weekly) in 28-day cycles. Patients had a median age of 61.5 years, 68% were male, 85% had an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1, and 41% were categorized as high risk. The median time from diagnosis was 62 months. The median number of prior chemotherapy regimens was four. In addition to lenalidomide, 58% of patients had received prior thalidomide (Thalomid), and 59% had received prior bortezomib (Velcade); 68% of patients had undergone prior autologous stem cell transplantation, and 53% had prior radiation therapy. Twenty patients (59%) had peripheral neuropathy at baseline.

Patients received a median of 5 cycles (range, 1−14) of pomalidomide plus low-dose dexamethasone. Prophylaxis for venous thromboembolism was given in 204 of 209 treatment cycles (aspirin in 150 cycles and warfarin in 54 cycles). Treatment responses consisted of a very good partial response in 9%, a partial response in 23%, and a minimal response in 15%, for an overall clinical benefit rate of 47%; 35% of patients had stable disease, and 18% had disease progression. The median time to response was 2 months. Response was observed in 8 of 14 (57%) high-risk patients, in 8 of 19 (42%) who received previous thalidomide treatment, and in 9 of 20 (45%) who were given previous bortezomib treatment. In eight patients with stable disease, the pomalidomide dose was increased to 4 mg/d, with one patient improving to a partial response. The median duration of response in 11 patients with a partial response or better was 9.1 months. The median progression-free survival was 4.8 months, and progression-free survival did not differ between high-risk and standard-risk patients. The median overall survival was 13.9 months. During follow-up, treatment was stopped due to disease progression in 23 patients, 3 withdrew from the study due to patient/physician discretion, and 8 continued to receive treatment. Seven patients died, all due to disease progression. The median follow-up of patients remaining alive was 8.3 months.

Pomalidomide/dexamethasone treatment was well tolerated. Toxicity consisted mostly of myelosuppression. Grade 3 or 4 hematologic toxicity at least possibly related to treatment occurred in 38% of patients, including neutropenia in 29%, anemia in 12%, and thrombocytopenia in 9%. The most common grade 3/4 nonhematologic toxicity was fatigue, which occurred in 9% of patients (all grade 3); grade 3 pneumonitis, edema, pneumonia, and folliculitis were each observed in one patient. Nine patients (26%) had neuropathy during treatment (six grade 1, three grade 2); they included six patients with neuropathy at baseline, three of whom had a worsening of grade.
 

 

Carfilzomib

Carfilzomib is a highly selective epoxyketone proteasome inhibitor with minimal affinity for nontarget proteases. In a recent phase II trial in patients with relapsed/refractory MM, reported at the 2010 American Society of Hematology (ASH) meeting, carfilzomib produced durable responses and was well tolerated.2 An ongoing phase I/II trial assessing carfilzomib, lenalidomide, and dexamethasone in newly diagnosed MM, also reported at the 2010 ASH meeting, has shown good activity and tolerability of the regimen.3 A phase III trial comparing carfilzomib plus lenalidomide and low-dose dexamethasone versus lenalidomide and low-dose dexamethasone in relapsed MM has been initiated.

Relapsed/refractory MM

In the trial in patients with relapsed/refractory MM, 266 patients with multiply relapsed MM who had disease refractory to their last treatment received carfilzomib (20 mg/m2 IV on days 1, 2, 8, 9, 15, and 16) every 28 days for the first cycle, with the dose then being escalated to 27 mg/m2 on the same schedule for up to 12 cycles.2 Prior therapies included bortezomib, either lenalidomide or thalidomide, and an alkylating agent. Patients had a median duration of MM of 5.4 years and had received a median of 5 prior lines of chemotherapy and a median of 13 antimyeloma treatments; prior treatments included bortezomib in 99.6% of patients (a median of two prior regimens containing bortezomib), lenalidomide in 94%, thalidomide in 74%, corticosteroids in 98%, alkylating agents in 91%, and stem cell transplantation in 74%. Overall, 65% of patients were refractory to bortezomib prior to study entry.

At the time of reporting, 79 patients (30%) had completed at least 6 cycles of study treatment, approximately 11% had completed 12 cycles (with most entering an extension phase of the study), and 15 patients remained on study (all with more than 10 cycles of study treatment). Among 257 patients evaluable for response, 0.4% (one patient) had a complete response, 4.7% had a very good partial response, and 19% had a partial response, for an overall response rate of 24%; an additional 12% of patients had a minimal response, yielding an overall clinical benefit rate of 36%. Stable disease for at least 6 weeks was achieved in 32%. Among patients with a partial response or better, the median duration of response was 7.4 months. Among patients with a minimal response, the median duration of response was 6.3 months, indicating durable minor responses.

Toxicity consisted mainly of myelosuppression. Grade 3/4 hematologic toxicities consisted of thrombocytopenia in 18% of patients, lymphopenia in 11%, neutropenia in 8%, and anemia in 7%.4 Grade 3/4 nonhematologic toxicities included fatigue in 6% of patients; pneumonia and congestive cardiac failure in 3% each; nausea, dyspnea, increased blood creatinine levels, and increased blood uric acid levels in 1% each; and diarrhea in 0.4%. Grade 1/2 peripheral neuropathy was present in 77% of patients at baseline; new-onset neuropathy was infrequent, with grade 3 or lower neuropathy occurring in less than 1% of patients.2

Newly diagnosed MM

In an ongoing phase I/II trial, patients with newly diagnosed MM are receiving carfilzomib, lenalidomide, and dexamethasone.3 Carfilzomib is started at 20 mg/m2 (dose level 1) and increased to 27 mg/m2 (dose level 2) and 36 mg/m2 (dose level 3) given IV on days 1, 2, 8, 9, 15, and 16 in 28-day cycles. Lenalidomide is given at 25 mg/d on days 1−21 in each cycle, and dexamethasone is given weekly at 40 mg during cycles 1−4 and at 20 mg during cycles 5−8. Patients with a partial response or better are eligible to proceed to stem cell collection and autologous stem cell transplantation after at least 4 cycles and can continue study treatment after transplantation. After completion of 8 cycles, patients are to receive maintenance cycles consisting of carfilzomib on days 1, 2, 15, and 16; lenalidomide on days 1−21; and weekly dexamethasone at doses tolerated at the end of 8 cycles. A planned 36 patients are to be treated at the carfilzomib maximum tolerated dose.

At the time of reporting, 24 patients had been enrolled, 4 at dose level 1, 14 at dose level 2, and 6 at dose level 3. Toxicity data were available for 21 patients, including 19 who completed at least 1 cycle of treatment. A single dose-limiting toxicity event was observed, consisting of nonfebrile neutropenia in a patient at dose level 2. The maximum tolerated dose had not yet been reached. Grade 3/4 hematologic toxicities consisted of neutropenia in three patients, thrombocytopenia in three patients, and anemia in one patient. Grade 3 nonhematologic toxicities included five cases of elevated blood glucose levels, deep vein thrombosis during aspirin prophylaxis in one patient, and fatigue in one patient. Emergent peripheral neuropathy was observed in two patients, who developed grade 1 neuropathy.
 

 

At the time of reporting, 23 patients continued on treatment, with 20 having no need for dose modifications. After a median of 4 months of treatment (range, 1−8 months), the preliminary response rate in 19 evaluable patients completing at least 1 cycle was 100% with at least a partial response, including 63% with a very good partial response and 37% with a complete response or near-complete response. Partial responses were observed in 17 of 19 patients after 1 cycle, with responses improving in all patients with continuing treatment. Seven patients had proceeded to stem cell collection using growth factors only after a median of 4 cycles, and all resumed study treatment after stem cell collection. No disease progression had been observed in any of the evaluable patients, and all remained alive.

References

1. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia 2010;24:1934−1939.

2. Siegel DSD, Martin T, Wang M, et al. Results of PX-171-003-A1, an open-label, single-arm, phase 2 study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). Blood 2010;116:985.

3. Jakubowiak AJ, Dytfeld D, Jagannath S, et al. Carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma: initial results of phase I/II MMRC trial. Blood 2010;116:862.

4. Singhal SB, Siegel DSD, Martin T, et al. Pooled safety analysis from phase 1 and 2 studies of carfilzomib (CFZ) in patients with relapsed and/or refractory multiple myeloma (MM). Blood 2010;116:1954.

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BEST PRACTICES IN: The Treatment of Heavy Menstrual Bleeding

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A supplement to Internal Medicine News®. This supplement was sponsored by Ferring Pharmaceuticals.

 


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  • Introduction
  • Definition & Diagnosis
  • Tranexamic Acid for the Treatment of HMB
  • Conclusion

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  • Definition & Diagnosis
  • Tranexamic Acid for the Treatment of HMB
  • Conclusion

Faculty/Faculty Disclosure

Lee Shulman, MD, FACOG, FACMG
The Anna Ross Lapham Professor in Obstetrics and Gynecology
Feinberg School of Medicine of Northwestern University
Chicago, Illinois

Dr Shulman is a consultant to Ferring Pharmaceuticals, Inc.  

Matt T. Rosenberg, MD
Family Physician
Mid-Michigan Health Centers
Jackson, Michigan

Dr Rosenberg

 

 

 

Copyright © 2011 Elsevier Inc.


A supplement to Internal Medicine News®. This supplement was sponsored by Ferring Pharmaceuticals.

 


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Topics

 

  • Introduction
  • Definition & Diagnosis
  • Tranexamic Acid for the Treatment of HMB
  • Conclusion

Faculty/Faculty Disclosure

Lee Shulman, MD, FACOG, FACMG
The Anna Ross Lapham Professor in Obstetrics and Gynecology
Feinberg School of Medicine of Northwestern University
Chicago, Illinois

Dr Shulman is a consultant to Ferring Pharmaceuticals, Inc.  

Matt T. Rosenberg, MD
Family Physician
Mid-Michigan Health Centers
Jackson, Michigan

Dr Rosenberg

 

 

 

Copyright © 2011 Elsevier Inc.

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BEST PRACTICES IN: Renal Impairment in Patients With Type 2 Diabetes: an Important Determinant of Treatment Selection

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A supplement to Family Practice News®. This supplement was sponsored by Boehringer Ingelheim Pharmaceuticals, Inc. and Eli Lilly and Company.

 



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  • Complications Associated With T2DM
  • Epidemiology of CKD/RI With DM
  • Risk Factors for CKD/RI in Patients With DM
  • Early Identification and Screening
  • Healthcare Providers Are Unaware of the Negative Effects of CKD on Cardiovascular Outcomes in Patients With T2DM
  • Awareness of CKD/RI: Clinicians
  • Awareness of CKD/RI: Patients
  • Awareness of CKD/RI: Glycemic Control
  • Prevention and Management

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Michael Kodack, PharmD
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Fernando Ovalle, MD, has disclosed no potential conflicts of interest. Michael Kodack, PharmD, is an employee of BlueSpark Healthcare Communications LLC.

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  • Epidemiology of CKD/RI With DM
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Fernando Ovalle, MD, has disclosed no potential conflicts of interest. Michael Kodack, PharmD, is an employee of BlueSpark Healthcare Communications LLC.

Copyright © 2011 Elsevier Inc.

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  • Complications Associated With T2DM
  • Epidemiology of CKD/RI With DM
  • Risk Factors for CKD/RI in Patients With DM
  • Early Identification and Screening
  • Healthcare Providers Are Unaware of the Negative Effects of CKD on Cardiovascular Outcomes in Patients With T2DM
  • Awareness of CKD/RI: Clinicians
  • Awareness of CKD/RI: Patients
  • Awareness of CKD/RI: Glycemic Control
  • Prevention and Management

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Director, Fellowship Training Program
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UAB School of Medicine
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Michael Kodack, PharmD
Vice President, Medical
BlueSpark Healthcare Communications LLC
Basking Ridge, NJ

Fernando Ovalle, MD, has disclosed no potential conflicts of interest. Michael Kodack, PharmD, is an employee of BlueSpark Healthcare Communications LLC.

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LAS VEGAS – The results from the National Lung Screening Trial constitute a "game changer" for lung cancer screening, Dr. James R. Jett said at the annual meeting of the National Association for Medical Direction of Respiratory Care.

The study results, reported in a press release by the National Cancer Institute last November, "changed the landscape" for screening by showing that lung imaging by low-dose helical CT done annually for 3 years in people with a smoking history of least 30 pack-years cut their mortality rate from lung cancer during follow-up by 20%, compared with people who underwent three annual chest x-rays. "This is the biggest advance in lung cancer in my career, an absolutely stunning result," said Dr. Jett, a pulmonologist and lung cancer specialist at National Jewish Health in Denver.

    Dr. James R. Jett

The researchers who ran the National Lung Screening Trial will likely publish their full results this spring, after which annual screening of people who match the profile of those in the study should become the standard of care, Dr. Jett predicted.

The screening trial enrolled 53,454 current or former cigarette smokers aged 55-74 years, who had each accumulated at least 30 pack-years of smoking history but had quit within the previous 15 years. The more than 75,000 total screening events by CT and more than 73,000 total screens by chest x-ray yielded 24% positive CT images and 7% positive x-ray images. During roughly 144,000 person-years of follow-up in each arm, the mortality due to lung cancer reached 246 deaths per 100,000 person-years in the CT group and 308 deaths per 100,000 person-years in the x-ray group, a 20% absolute mortality reduction with CT screening that was statistically significant, and which led the trial’s Data and Safety Monitoring Board to stop the study and release the results.

The people screened by CT also had a 7% reduction in all-cause mortality, compared with those screened by x-ray, also a statistically significant difference.

As about 160,000 Americans die from lung cancer annually, a 20% cut in mortality from low-dose helical CT screening could potentially save about 32,000 lives a year in the United States alone. "That’s almost like eliminating all 40,000 breast cancer deaths each year," Dr. Jett said.

The results did not directly address the question of how long annual screening should continue. In the trial, screening stopped after three annual examinations because of limited financial resources, although despite that the study cost about $200 million, he said. But his review of the results identified no suggestion that in routine practice screening should stop after 3 years. "There was no drop in the number of cancers" during each sequential year of screening. "I don’t see anything that tells me you can stop [screening] after 3 years," he said.

"The biggest question is, can we afford" to do annual CT screening on the scale needed to include all people who fit the profile included in the trial.

A second issue is the safety of annual CT imaging, but Dr. Jett presented a brief analysis suggesting that it is safe. A low-dose CT scan involves a radiation exposure of about 0.65 mSv, less than 10% of the dose of a conventional chest CT, Dr. Jett said. With that level of exposure, annual low-dose CT imaging of currently smoking women aged 50 might cause an excess of 5 cancer deaths for every 10,000 people screened, compared with a background lung cancer mortality of 100 for every 10,000 people with no screening. Because screening could prevent 20% of these 100 deaths, it would avert more deaths that it might cause. For men, the risk: benefit ratio runs even higher because currently smoking men undergoing annual CT screening would have about 2 extra lung cancer deaths per 10,000 people due to the radiation exposure, compared with 110 per 10,000 without screening. Women face a higher risk from the radiation of screening than men because of the impact of chest radiation on breast cancer, Dr. Jett said.

Dr. Jett said that he has been an adviser to Genentech, Pfizer, and Bristol-Myers Squibb, and that he has a research grant pending from Oncimmune.



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LAS VEGAS – The results from the National Lung Screening Trial constitute a "game changer" for lung cancer screening, Dr. James R. Jett said at the annual meeting of the National Association for Medical Direction of Respiratory Care.

The study results, reported in a press release by the National Cancer Institute last November, "changed the landscape" for screening by showing that lung imaging by low-dose helical CT done annually for 3 years in people with a smoking history of least 30 pack-years cut their mortality rate from lung cancer during follow-up by 20%, compared with people who underwent three annual chest x-rays. "This is the biggest advance in lung cancer in my career, an absolutely stunning result," said Dr. Jett, a pulmonologist and lung cancer specialist at National Jewish Health in Denver.

    Dr. James R. Jett

The researchers who ran the National Lung Screening Trial will likely publish their full results this spring, after which annual screening of people who match the profile of those in the study should become the standard of care, Dr. Jett predicted.

The screening trial enrolled 53,454 current or former cigarette smokers aged 55-74 years, who had each accumulated at least 30 pack-years of smoking history but had quit within the previous 15 years. The more than 75,000 total screening events by CT and more than 73,000 total screens by chest x-ray yielded 24% positive CT images and 7% positive x-ray images. During roughly 144,000 person-years of follow-up in each arm, the mortality due to lung cancer reached 246 deaths per 100,000 person-years in the CT group and 308 deaths per 100,000 person-years in the x-ray group, a 20% absolute mortality reduction with CT screening that was statistically significant, and which led the trial’s Data and Safety Monitoring Board to stop the study and release the results.

The people screened by CT also had a 7% reduction in all-cause mortality, compared with those screened by x-ray, also a statistically significant difference.

As about 160,000 Americans die from lung cancer annually, a 20% cut in mortality from low-dose helical CT screening could potentially save about 32,000 lives a year in the United States alone. "That’s almost like eliminating all 40,000 breast cancer deaths each year," Dr. Jett said.

The results did not directly address the question of how long annual screening should continue. In the trial, screening stopped after three annual examinations because of limited financial resources, although despite that the study cost about $200 million, he said. But his review of the results identified no suggestion that in routine practice screening should stop after 3 years. "There was no drop in the number of cancers" during each sequential year of screening. "I don’t see anything that tells me you can stop [screening] after 3 years," he said.

"The biggest question is, can we afford" to do annual CT screening on the scale needed to include all people who fit the profile included in the trial.

A second issue is the safety of annual CT imaging, but Dr. Jett presented a brief analysis suggesting that it is safe. A low-dose CT scan involves a radiation exposure of about 0.65 mSv, less than 10% of the dose of a conventional chest CT, Dr. Jett said. With that level of exposure, annual low-dose CT imaging of currently smoking women aged 50 might cause an excess of 5 cancer deaths for every 10,000 people screened, compared with a background lung cancer mortality of 100 for every 10,000 people with no screening. Because screening could prevent 20% of these 100 deaths, it would avert more deaths that it might cause. For men, the risk: benefit ratio runs even higher because currently smoking men undergoing annual CT screening would have about 2 extra lung cancer deaths per 10,000 people due to the radiation exposure, compared with 110 per 10,000 without screening. Women face a higher risk from the radiation of screening than men because of the impact of chest radiation on breast cancer, Dr. Jett said.

Dr. Jett said that he has been an adviser to Genentech, Pfizer, and Bristol-Myers Squibb, and that he has a research grant pending from Oncimmune.



LAS VEGAS – The results from the National Lung Screening Trial constitute a "game changer" for lung cancer screening, Dr. James R. Jett said at the annual meeting of the National Association for Medical Direction of Respiratory Care.

The study results, reported in a press release by the National Cancer Institute last November, "changed the landscape" for screening by showing that lung imaging by low-dose helical CT done annually for 3 years in people with a smoking history of least 30 pack-years cut their mortality rate from lung cancer during follow-up by 20%, compared with people who underwent three annual chest x-rays. "This is the biggest advance in lung cancer in my career, an absolutely stunning result," said Dr. Jett, a pulmonologist and lung cancer specialist at National Jewish Health in Denver.

    Dr. James R. Jett

The researchers who ran the National Lung Screening Trial will likely publish their full results this spring, after which annual screening of people who match the profile of those in the study should become the standard of care, Dr. Jett predicted.

The screening trial enrolled 53,454 current or former cigarette smokers aged 55-74 years, who had each accumulated at least 30 pack-years of smoking history but had quit within the previous 15 years. The more than 75,000 total screening events by CT and more than 73,000 total screens by chest x-ray yielded 24% positive CT images and 7% positive x-ray images. During roughly 144,000 person-years of follow-up in each arm, the mortality due to lung cancer reached 246 deaths per 100,000 person-years in the CT group and 308 deaths per 100,000 person-years in the x-ray group, a 20% absolute mortality reduction with CT screening that was statistically significant, and which led the trial’s Data and Safety Monitoring Board to stop the study and release the results.

The people screened by CT also had a 7% reduction in all-cause mortality, compared with those screened by x-ray, also a statistically significant difference.

As about 160,000 Americans die from lung cancer annually, a 20% cut in mortality from low-dose helical CT screening could potentially save about 32,000 lives a year in the United States alone. "That’s almost like eliminating all 40,000 breast cancer deaths each year," Dr. Jett said.

The results did not directly address the question of how long annual screening should continue. In the trial, screening stopped after three annual examinations because of limited financial resources, although despite that the study cost about $200 million, he said. But his review of the results identified no suggestion that in routine practice screening should stop after 3 years. "There was no drop in the number of cancers" during each sequential year of screening. "I don’t see anything that tells me you can stop [screening] after 3 years," he said.

"The biggest question is, can we afford" to do annual CT screening on the scale needed to include all people who fit the profile included in the trial.

A second issue is the safety of annual CT imaging, but Dr. Jett presented a brief analysis suggesting that it is safe. A low-dose CT scan involves a radiation exposure of about 0.65 mSv, less than 10% of the dose of a conventional chest CT, Dr. Jett said. With that level of exposure, annual low-dose CT imaging of currently smoking women aged 50 might cause an excess of 5 cancer deaths for every 10,000 people screened, compared with a background lung cancer mortality of 100 for every 10,000 people with no screening. Because screening could prevent 20% of these 100 deaths, it would avert more deaths that it might cause. For men, the risk: benefit ratio runs even higher because currently smoking men undergoing annual CT screening would have about 2 extra lung cancer deaths per 10,000 people due to the radiation exposure, compared with 110 per 10,000 without screening. Women face a higher risk from the radiation of screening than men because of the impact of chest radiation on breast cancer, Dr. Jett said.

Dr. Jett said that he has been an adviser to Genentech, Pfizer, and Bristol-Myers Squibb, and that he has a research grant pending from Oncimmune.



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EXPERT ANALYSIS FROM THE ANNUAL MEETING OF THE NATIONAL ASSOCIATION FOR MEDICAL DIRECTION OF RESPIRATORY CARE

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SHM Honors Four Hospitalists

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SHM will induct its second class of Masters in Hospital Medicine (MHM) at HM11 in May, and while each of the four honorees says the title is a personal honor, they all emphasize that it is a professional point of pride to see just how far HM has come in the past 15 years.

"For the specialty, it brings identity and awareness of all that we do," Erin Stucky, MD, MHM, a pediatric hospitalist at Rady Children's Hospital in San Diego, wrote in an email. "We are QI in mortal form, acting and pressing on to deliver excellence in healthcare within our systems. Each of us, members of the society, those with FHM, SFHM, and MHM—we each deliver on this promise every day."

The other MHMs, each of whom spoke to The Hospitalist via email, are:

Ron Greeno, MD, MHM, chief medical officer for Cogent Healthcare and a member of SHM's Public Policy Committee. "I've had the privilege of working in hospital medicine for 18 years and, along with my colleagues at Cogent, have helped shape the field," Dr. Greeno says. "To be one of a handful of hospitalists to be named a Master in Hospital Medicine is truly exciting, but equally exciting is to see the growing leadership capabilities of a number of our younger colleagues who will become the future leaders of our specialty."

Russell L. Holman, MD, MHM, Cogent's COO and past president of SHM. "Our specialty is constantly evolving; there is no paved road before us," Dr. Holman says. "We are cutting the path, and are part of an historical transformation of the way care is provided in this country. Twenty years from now we will reflect on an enduring legacy of dramatically improving the quality, safety, and sustainability of care for hospitalized patients. The privilege of being part of this movement is rewarding and inspirational for me."

Mary Jo Gorman, MD, MBA, MHM, former SHM president and CEO of St. Louis-based Advanced ICU Care. "It is a terrific honor to be recognized by SHM in this way," Dr. Gorman says. "The group that is included has accomplished many things and it's gratifying to be recognized with them. It’s hard to believe that SHM has come so far that we have fellows and masters in the society! Those early days seem a long way away!"

SHM has now recognized seven MHMs. Last year's class consisted of Winthrop F. Whitcomb, MD, MHM, Robert Wachter, MD, MHM, and John Nelson, MD, MHM. Each is recognized for what SHM says is the "utmost demonstration of dedication to the field of hospital medicine through significant contributions to the development and maturation of the profession."

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SHM will induct its second class of Masters in Hospital Medicine (MHM) at HM11 in May, and while each of the four honorees says the title is a personal honor, they all emphasize that it is a professional point of pride to see just how far HM has come in the past 15 years.

"For the specialty, it brings identity and awareness of all that we do," Erin Stucky, MD, MHM, a pediatric hospitalist at Rady Children's Hospital in San Diego, wrote in an email. "We are QI in mortal form, acting and pressing on to deliver excellence in healthcare within our systems. Each of us, members of the society, those with FHM, SFHM, and MHM—we each deliver on this promise every day."

The other MHMs, each of whom spoke to The Hospitalist via email, are:

Ron Greeno, MD, MHM, chief medical officer for Cogent Healthcare and a member of SHM's Public Policy Committee. "I've had the privilege of working in hospital medicine for 18 years and, along with my colleagues at Cogent, have helped shape the field," Dr. Greeno says. "To be one of a handful of hospitalists to be named a Master in Hospital Medicine is truly exciting, but equally exciting is to see the growing leadership capabilities of a number of our younger colleagues who will become the future leaders of our specialty."

Russell L. Holman, MD, MHM, Cogent's COO and past president of SHM. "Our specialty is constantly evolving; there is no paved road before us," Dr. Holman says. "We are cutting the path, and are part of an historical transformation of the way care is provided in this country. Twenty years from now we will reflect on an enduring legacy of dramatically improving the quality, safety, and sustainability of care for hospitalized patients. The privilege of being part of this movement is rewarding and inspirational for me."

Mary Jo Gorman, MD, MBA, MHM, former SHM president and CEO of St. Louis-based Advanced ICU Care. "It is a terrific honor to be recognized by SHM in this way," Dr. Gorman says. "The group that is included has accomplished many things and it's gratifying to be recognized with them. It’s hard to believe that SHM has come so far that we have fellows and masters in the society! Those early days seem a long way away!"

SHM has now recognized seven MHMs. Last year's class consisted of Winthrop F. Whitcomb, MD, MHM, Robert Wachter, MD, MHM, and John Nelson, MD, MHM. Each is recognized for what SHM says is the "utmost demonstration of dedication to the field of hospital medicine through significant contributions to the development and maturation of the profession."

SHM will induct its second class of Masters in Hospital Medicine (MHM) at HM11 in May, and while each of the four honorees says the title is a personal honor, they all emphasize that it is a professional point of pride to see just how far HM has come in the past 15 years.

"For the specialty, it brings identity and awareness of all that we do," Erin Stucky, MD, MHM, a pediatric hospitalist at Rady Children's Hospital in San Diego, wrote in an email. "We are QI in mortal form, acting and pressing on to deliver excellence in healthcare within our systems. Each of us, members of the society, those with FHM, SFHM, and MHM—we each deliver on this promise every day."

The other MHMs, each of whom spoke to The Hospitalist via email, are:

Ron Greeno, MD, MHM, chief medical officer for Cogent Healthcare and a member of SHM's Public Policy Committee. "I've had the privilege of working in hospital medicine for 18 years and, along with my colleagues at Cogent, have helped shape the field," Dr. Greeno says. "To be one of a handful of hospitalists to be named a Master in Hospital Medicine is truly exciting, but equally exciting is to see the growing leadership capabilities of a number of our younger colleagues who will become the future leaders of our specialty."

Russell L. Holman, MD, MHM, Cogent's COO and past president of SHM. "Our specialty is constantly evolving; there is no paved road before us," Dr. Holman says. "We are cutting the path, and are part of an historical transformation of the way care is provided in this country. Twenty years from now we will reflect on an enduring legacy of dramatically improving the quality, safety, and sustainability of care for hospitalized patients. The privilege of being part of this movement is rewarding and inspirational for me."

Mary Jo Gorman, MD, MBA, MHM, former SHM president and CEO of St. Louis-based Advanced ICU Care. "It is a terrific honor to be recognized by SHM in this way," Dr. Gorman says. "The group that is included has accomplished many things and it's gratifying to be recognized with them. It’s hard to believe that SHM has come so far that we have fellows and masters in the society! Those early days seem a long way away!"

SHM has now recognized seven MHMs. Last year's class consisted of Winthrop F. Whitcomb, MD, MHM, Robert Wachter, MD, MHM, and John Nelson, MD, MHM. Each is recognized for what SHM says is the "utmost demonstration of dedication to the field of hospital medicine through significant contributions to the development and maturation of the profession."

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In the Literature: Research You Need to Know

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Clinical question: Are such alternatives as tiotropium bromide, a long-acting anticholinergic agent, effective in improving symptoms and lung function in those patients who are inadequately controlled on a low-dose inhaled glucocorticoid?

Background: Many asthmatics remain uncontrolled on low doses of inhaled glucocorticoid therapy. Treatment options include increasing the dose or adding a long-acting beta-agonist (LABA). Safety concerns, however, have emerged recently regarding LABA use. It is unclear whether the use of alternatives, such as anticholinergics, is beneficial in managing symptoms.

Study design: Double-blind, three-way crossover trial.

Setting: Multicenter study.

Synopsis: Researchers studied a total of 210 patients with uncontrolled asthma. Three treatments were used with low-dose inhaled glucocorticoids (beclomethasone) as a baseline: adding tiotropium, doubling the dose of inhaled glucocorticoids, or adding an LABA (salmeterol). Patients were treated in all three groups, each lasting 14 weeks with a two-week washout period between treatments (when only the baseline medication was used). The primary outcome measure was the morning peak expiratory flow (PEF).

When compared to doubling the inhaled glucocorticoid dose, patients receiving tiotropium had a higher morning PEF (25.8 liters, 95% CI 14.4-37.1, P<0.001). Tiotropium use also showed statistically significant improvement in the evening PEF, pre-bronchodilator FEV1, proportion of asthma control days, and scores for daily symptoms.

Tiotropium was found to be noninferior to salmeterol, including no difference in morning PEF. Other measurements were similar, except that pre-bronchodilator FEV1 favored tiotropium (0.11 liter increase, 95% CI 0.04-0.18, P=0.003). Because treatments did not last for more than 14 weeks, long-term safety issues and exacerbation rates could not be determined.

Bottom line: When added to a low-dose inhaled glucocorticoid, tiotropium improves asthma symptoms and lung function compared with doubling the corticosteroid dose and is noninferior when compared to a LABA.

Citation: Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med. 2010;363(18):1715-1726.

Reviewed for TH eWire by Elizabeth Schulwolf, MD, MA, Sean Greenhalgh, MD, Aziz Ansari, DO, FHM, Nathan Derhammer, MD, FAAP, Paula Marfia, MD, Elizabeth Wantuch, MD, MS, Division of Hospital Medicine, Loyola University, Chicago.

For more physician reviews of HM-related research, visit our website.

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Clinical question: Are such alternatives as tiotropium bromide, a long-acting anticholinergic agent, effective in improving symptoms and lung function in those patients who are inadequately controlled on a low-dose inhaled glucocorticoid?

Background: Many asthmatics remain uncontrolled on low doses of inhaled glucocorticoid therapy. Treatment options include increasing the dose or adding a long-acting beta-agonist (LABA). Safety concerns, however, have emerged recently regarding LABA use. It is unclear whether the use of alternatives, such as anticholinergics, is beneficial in managing symptoms.

Study design: Double-blind, three-way crossover trial.

Setting: Multicenter study.

Synopsis: Researchers studied a total of 210 patients with uncontrolled asthma. Three treatments were used with low-dose inhaled glucocorticoids (beclomethasone) as a baseline: adding tiotropium, doubling the dose of inhaled glucocorticoids, or adding an LABA (salmeterol). Patients were treated in all three groups, each lasting 14 weeks with a two-week washout period between treatments (when only the baseline medication was used). The primary outcome measure was the morning peak expiratory flow (PEF).

When compared to doubling the inhaled glucocorticoid dose, patients receiving tiotropium had a higher morning PEF (25.8 liters, 95% CI 14.4-37.1, P<0.001). Tiotropium use also showed statistically significant improvement in the evening PEF, pre-bronchodilator FEV1, proportion of asthma control days, and scores for daily symptoms.

Tiotropium was found to be noninferior to salmeterol, including no difference in morning PEF. Other measurements were similar, except that pre-bronchodilator FEV1 favored tiotropium (0.11 liter increase, 95% CI 0.04-0.18, P=0.003). Because treatments did not last for more than 14 weeks, long-term safety issues and exacerbation rates could not be determined.

Bottom line: When added to a low-dose inhaled glucocorticoid, tiotropium improves asthma symptoms and lung function compared with doubling the corticosteroid dose and is noninferior when compared to a LABA.

Citation: Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med. 2010;363(18):1715-1726.

Reviewed for TH eWire by Elizabeth Schulwolf, MD, MA, Sean Greenhalgh, MD, Aziz Ansari, DO, FHM, Nathan Derhammer, MD, FAAP, Paula Marfia, MD, Elizabeth Wantuch, MD, MS, Division of Hospital Medicine, Loyola University, Chicago.

For more physician reviews of HM-related research, visit our website.

Clinical question: Are such alternatives as tiotropium bromide, a long-acting anticholinergic agent, effective in improving symptoms and lung function in those patients who are inadequately controlled on a low-dose inhaled glucocorticoid?

Background: Many asthmatics remain uncontrolled on low doses of inhaled glucocorticoid therapy. Treatment options include increasing the dose or adding a long-acting beta-agonist (LABA). Safety concerns, however, have emerged recently regarding LABA use. It is unclear whether the use of alternatives, such as anticholinergics, is beneficial in managing symptoms.

Study design: Double-blind, three-way crossover trial.

Setting: Multicenter study.

Synopsis: Researchers studied a total of 210 patients with uncontrolled asthma. Three treatments were used with low-dose inhaled glucocorticoids (beclomethasone) as a baseline: adding tiotropium, doubling the dose of inhaled glucocorticoids, or adding an LABA (salmeterol). Patients were treated in all three groups, each lasting 14 weeks with a two-week washout period between treatments (when only the baseline medication was used). The primary outcome measure was the morning peak expiratory flow (PEF).

When compared to doubling the inhaled glucocorticoid dose, patients receiving tiotropium had a higher morning PEF (25.8 liters, 95% CI 14.4-37.1, P<0.001). Tiotropium use also showed statistically significant improvement in the evening PEF, pre-bronchodilator FEV1, proportion of asthma control days, and scores for daily symptoms.

Tiotropium was found to be noninferior to salmeterol, including no difference in morning PEF. Other measurements were similar, except that pre-bronchodilator FEV1 favored tiotropium (0.11 liter increase, 95% CI 0.04-0.18, P=0.003). Because treatments did not last for more than 14 weeks, long-term safety issues and exacerbation rates could not be determined.

Bottom line: When added to a low-dose inhaled glucocorticoid, tiotropium improves asthma symptoms and lung function compared with doubling the corticosteroid dose and is noninferior when compared to a LABA.

Citation: Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med. 2010;363(18):1715-1726.

Reviewed for TH eWire by Elizabeth Schulwolf, MD, MA, Sean Greenhalgh, MD, Aziz Ansari, DO, FHM, Nathan Derhammer, MD, FAAP, Paula Marfia, MD, Elizabeth Wantuch, MD, MS, Division of Hospital Medicine, Loyola University, Chicago.

For more physician reviews of HM-related research, visit our website.

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NCCN Upgrades Rituximab Regimens for Follicular Lymphoma

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HOLLYWOOD, FLA. – New data have led to upgrades of two rituximab regimens and radioimmunotherapy for follicular lymphoma in the National Comprehensive Cancer Network’s clinical practice guidelines for non-Hodgkin’s lymphoma.

Other changes include a section that addresses the utility of positron emission tomography in the assessment of follicular lymphoma and the addition of recommendations for the evaluation and management of posttransplant lymphoproliferative disorder (PTLD), according to Dr. Andrew D. Zelenetz of Memorial Sloan-Kettering Cancer Center in New York.

At the National Comprehensive Cancer Network’s annual conference on clinical practice guidelines, he reported updates in the following areas on behalf of the NCCN’s 30-member panel on non-Hodgkin’s lymphoma:

Rituximab plus bendamustine. The combination of rituximab (Rituxan) plus bendamustine (Treanda) has been upgraded from a category 2A to a category 1 recommendation for first-line treatment of follicular lymphoma, a common form of NHL, Dr. Zelenetz announced.

The most widely used first-line regimen for follicular lymphoma has been R-CHOP (a combination of rituximab, cyclophosphamide, doxorubicin HCl, vincristine sulfate, and prednisone). In a study presented in 2009 at the American Society of Hematology (ASH) annual meeting comparing the efficacy of the R-CHOP protocol with that of the rituximab-bendamustine (RB) combination, the complete remission rate among patients randomized to RB treatment was 73% vs. 39.6% in the R-CHOP arm, Dr. Zelenetz said (Blood [ASH Annual Meeting Abstracts] 2009 Nov.;114:405).

"The median progression-free survival was also higher [in the RB group], at 54.9 months compared with 34.8 months [in the R-CHOP arm]," a finding that he described as unexpected. "This study was designed as an equivalency study, and it certainly surprised many of us that rituximab-bendamustine was significantly better in terms of progression-free survival," he said.

Although there was no difference in overall survival between the two groups, he noted, the RB protocol was better tolerated with less hematologic toxicity and no alopecia.

Rituximab maintenance and radioimmunotherapy. The panel also upgraded rituximab maintenance and chemotherapy followed by radioimmunotherapy from a category 2B to a category 1 recommendation for the treatment of follicular lymphoma after the first remission. The guideline change regarding postremission management was sparked by the results of two recent studies, Dr. Zelenetz said.

The first demonstrated a significant reduction in the risk of recurrence among patients who received rituximab maintenance after responding to induction with rituximab plus chemotherapy (Lancet 2011;377:42-51). The other, presented at the 2010 ASH meeting, showed that postremission radioimmunotherapy following chemotherapy significantly improved the complete response and progression-free survival rates relative to the experience in patients who received no additional treatment following remission (Blood [ASH Annual Meeting Abstracts] 2010 Nov.;116:594).

"Unfortunately, neither study was associated with improvement in overall survival," he said.

PET imaging. In the assessment of follicular lymphoma, "studies have shown that PET imaging can be used to distinguish between indolent and aggressive lymphoma and can help guide the site for optimal biopsy, "especially in patients in whom there is a concern about transformation from indolent to aggressive disease," Dr. Zelenetz said. While it cannot replace biopsy, "[PET imaging] can help identify the best vs. the most convenient lymph node to biopsy," he said(J. Clin. Oncol. 2005;23:4643-51; Ann. Oncol. 2009; 20:508-12).

In addition, PET–computed tomography (PET-CT) has a role in the assessment of treatment response because "the predictive power of posttreatment PET-CT is stronger than other prognostic factors," Dr. Zelenetz explained.

Posttransplant lymphoproliferative disorder. PTLD "has emerged as a significant complication of solid organ and allogeneic bone marrow transplantation," according to Dr. Zelenetz.

The revised guidelines recommend outlining the procedure for establishing a diagnosis based on histology and immunophenotype, and categorizes relevant tests as essential or useful under certain circumstances. Among information deemed "essential," he said, is the determination of patients’ Epstein Barr virus (EBV) status, as well as their histopathology (polymorphic or monomorphic cells) and immunophenotype.

NCCN recommendations include reducing immunosuppression for patients with early lesions, which are usually associated with Epstein-Barr virus, and for those with polymorphic systemic and monomorphic disease. Treatment may include antiviral prophylaxis with gancyclovir (Cytovene), rituximab, or chemoimmunotherapy, depending on PTLD subtype, said Dr. Zelenetz, noting that "stem cell transplantation is usually reserved for relapse or refractory situations, as we would manage other aggressive lymphomas."

Dr. Zelenetz disclosed receiving grant and research support from companies including Amgen Inc., Celgene Corp., Cell Therapeutics Inc., Cephalon Inc., Genentech Inc., GlaxoSmithKline, and Sanofi-Aventis US.

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HOLLYWOOD, FLA. – New data have led to upgrades of two rituximab regimens and radioimmunotherapy for follicular lymphoma in the National Comprehensive Cancer Network’s clinical practice guidelines for non-Hodgkin’s lymphoma.

Other changes include a section that addresses the utility of positron emission tomography in the assessment of follicular lymphoma and the addition of recommendations for the evaluation and management of posttransplant lymphoproliferative disorder (PTLD), according to Dr. Andrew D. Zelenetz of Memorial Sloan-Kettering Cancer Center in New York.

At the National Comprehensive Cancer Network’s annual conference on clinical practice guidelines, he reported updates in the following areas on behalf of the NCCN’s 30-member panel on non-Hodgkin’s lymphoma:

Rituximab plus bendamustine. The combination of rituximab (Rituxan) plus bendamustine (Treanda) has been upgraded from a category 2A to a category 1 recommendation for first-line treatment of follicular lymphoma, a common form of NHL, Dr. Zelenetz announced.

The most widely used first-line regimen for follicular lymphoma has been R-CHOP (a combination of rituximab, cyclophosphamide, doxorubicin HCl, vincristine sulfate, and prednisone). In a study presented in 2009 at the American Society of Hematology (ASH) annual meeting comparing the efficacy of the R-CHOP protocol with that of the rituximab-bendamustine (RB) combination, the complete remission rate among patients randomized to RB treatment was 73% vs. 39.6% in the R-CHOP arm, Dr. Zelenetz said (Blood [ASH Annual Meeting Abstracts] 2009 Nov.;114:405).

"The median progression-free survival was also higher [in the RB group], at 54.9 months compared with 34.8 months [in the R-CHOP arm]," a finding that he described as unexpected. "This study was designed as an equivalency study, and it certainly surprised many of us that rituximab-bendamustine was significantly better in terms of progression-free survival," he said.

Although there was no difference in overall survival between the two groups, he noted, the RB protocol was better tolerated with less hematologic toxicity and no alopecia.

Rituximab maintenance and radioimmunotherapy. The panel also upgraded rituximab maintenance and chemotherapy followed by radioimmunotherapy from a category 2B to a category 1 recommendation for the treatment of follicular lymphoma after the first remission. The guideline change regarding postremission management was sparked by the results of two recent studies, Dr. Zelenetz said.

The first demonstrated a significant reduction in the risk of recurrence among patients who received rituximab maintenance after responding to induction with rituximab plus chemotherapy (Lancet 2011;377:42-51). The other, presented at the 2010 ASH meeting, showed that postremission radioimmunotherapy following chemotherapy significantly improved the complete response and progression-free survival rates relative to the experience in patients who received no additional treatment following remission (Blood [ASH Annual Meeting Abstracts] 2010 Nov.;116:594).

"Unfortunately, neither study was associated with improvement in overall survival," he said.

PET imaging. In the assessment of follicular lymphoma, "studies have shown that PET imaging can be used to distinguish between indolent and aggressive lymphoma and can help guide the site for optimal biopsy, "especially in patients in whom there is a concern about transformation from indolent to aggressive disease," Dr. Zelenetz said. While it cannot replace biopsy, "[PET imaging] can help identify the best vs. the most convenient lymph node to biopsy," he said(J. Clin. Oncol. 2005;23:4643-51; Ann. Oncol. 2009; 20:508-12).

In addition, PET–computed tomography (PET-CT) has a role in the assessment of treatment response because "the predictive power of posttreatment PET-CT is stronger than other prognostic factors," Dr. Zelenetz explained.

Posttransplant lymphoproliferative disorder. PTLD "has emerged as a significant complication of solid organ and allogeneic bone marrow transplantation," according to Dr. Zelenetz.

The revised guidelines recommend outlining the procedure for establishing a diagnosis based on histology and immunophenotype, and categorizes relevant tests as essential or useful under certain circumstances. Among information deemed "essential," he said, is the determination of patients’ Epstein Barr virus (EBV) status, as well as their histopathology (polymorphic or monomorphic cells) and immunophenotype.

NCCN recommendations include reducing immunosuppression for patients with early lesions, which are usually associated with Epstein-Barr virus, and for those with polymorphic systemic and monomorphic disease. Treatment may include antiviral prophylaxis with gancyclovir (Cytovene), rituximab, or chemoimmunotherapy, depending on PTLD subtype, said Dr. Zelenetz, noting that "stem cell transplantation is usually reserved for relapse or refractory situations, as we would manage other aggressive lymphomas."

Dr. Zelenetz disclosed receiving grant and research support from companies including Amgen Inc., Celgene Corp., Cell Therapeutics Inc., Cephalon Inc., Genentech Inc., GlaxoSmithKline, and Sanofi-Aventis US.

HOLLYWOOD, FLA. – New data have led to upgrades of two rituximab regimens and radioimmunotherapy for follicular lymphoma in the National Comprehensive Cancer Network’s clinical practice guidelines for non-Hodgkin’s lymphoma.

Other changes include a section that addresses the utility of positron emission tomography in the assessment of follicular lymphoma and the addition of recommendations for the evaluation and management of posttransplant lymphoproliferative disorder (PTLD), according to Dr. Andrew D. Zelenetz of Memorial Sloan-Kettering Cancer Center in New York.

At the National Comprehensive Cancer Network’s annual conference on clinical practice guidelines, he reported updates in the following areas on behalf of the NCCN’s 30-member panel on non-Hodgkin’s lymphoma:

Rituximab plus bendamustine. The combination of rituximab (Rituxan) plus bendamustine (Treanda) has been upgraded from a category 2A to a category 1 recommendation for first-line treatment of follicular lymphoma, a common form of NHL, Dr. Zelenetz announced.

The most widely used first-line regimen for follicular lymphoma has been R-CHOP (a combination of rituximab, cyclophosphamide, doxorubicin HCl, vincristine sulfate, and prednisone). In a study presented in 2009 at the American Society of Hematology (ASH) annual meeting comparing the efficacy of the R-CHOP protocol with that of the rituximab-bendamustine (RB) combination, the complete remission rate among patients randomized to RB treatment was 73% vs. 39.6% in the R-CHOP arm, Dr. Zelenetz said (Blood [ASH Annual Meeting Abstracts] 2009 Nov.;114:405).

"The median progression-free survival was also higher [in the RB group], at 54.9 months compared with 34.8 months [in the R-CHOP arm]," a finding that he described as unexpected. "This study was designed as an equivalency study, and it certainly surprised many of us that rituximab-bendamustine was significantly better in terms of progression-free survival," he said.

Although there was no difference in overall survival between the two groups, he noted, the RB protocol was better tolerated with less hematologic toxicity and no alopecia.

Rituximab maintenance and radioimmunotherapy. The panel also upgraded rituximab maintenance and chemotherapy followed by radioimmunotherapy from a category 2B to a category 1 recommendation for the treatment of follicular lymphoma after the first remission. The guideline change regarding postremission management was sparked by the results of two recent studies, Dr. Zelenetz said.

The first demonstrated a significant reduction in the risk of recurrence among patients who received rituximab maintenance after responding to induction with rituximab plus chemotherapy (Lancet 2011;377:42-51). The other, presented at the 2010 ASH meeting, showed that postremission radioimmunotherapy following chemotherapy significantly improved the complete response and progression-free survival rates relative to the experience in patients who received no additional treatment following remission (Blood [ASH Annual Meeting Abstracts] 2010 Nov.;116:594).

"Unfortunately, neither study was associated with improvement in overall survival," he said.

PET imaging. In the assessment of follicular lymphoma, "studies have shown that PET imaging can be used to distinguish between indolent and aggressive lymphoma and can help guide the site for optimal biopsy, "especially in patients in whom there is a concern about transformation from indolent to aggressive disease," Dr. Zelenetz said. While it cannot replace biopsy, "[PET imaging] can help identify the best vs. the most convenient lymph node to biopsy," he said(J. Clin. Oncol. 2005;23:4643-51; Ann. Oncol. 2009; 20:508-12).

In addition, PET–computed tomography (PET-CT) has a role in the assessment of treatment response because "the predictive power of posttreatment PET-CT is stronger than other prognostic factors," Dr. Zelenetz explained.

Posttransplant lymphoproliferative disorder. PTLD "has emerged as a significant complication of solid organ and allogeneic bone marrow transplantation," according to Dr. Zelenetz.

The revised guidelines recommend outlining the procedure for establishing a diagnosis based on histology and immunophenotype, and categorizes relevant tests as essential or useful under certain circumstances. Among information deemed "essential," he said, is the determination of patients’ Epstein Barr virus (EBV) status, as well as their histopathology (polymorphic or monomorphic cells) and immunophenotype.

NCCN recommendations include reducing immunosuppression for patients with early lesions, which are usually associated with Epstein-Barr virus, and for those with polymorphic systemic and monomorphic disease. Treatment may include antiviral prophylaxis with gancyclovir (Cytovene), rituximab, or chemoimmunotherapy, depending on PTLD subtype, said Dr. Zelenetz, noting that "stem cell transplantation is usually reserved for relapse or refractory situations, as we would manage other aggressive lymphomas."

Dr. Zelenetz disclosed receiving grant and research support from companies including Amgen Inc., Celgene Corp., Cell Therapeutics Inc., Cephalon Inc., Genentech Inc., GlaxoSmithKline, and Sanofi-Aventis US.

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FROM THE ANNUAL CONFERENCE OF THE NATIONAL COMPREHENSIVE CANCER NETWORK

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Mobile technology, such as tablet computers, Internet-enabled smartphones, and the applications both devices use, will change the face of HM and other physician specialties, one medical software executive says.

"Mobile technology will improve efficiency and reduce costs," Mark Cain, chief technology officer of MIM Software Inc., writes in an e-mail to The Hospitalist. "Compare the cost of an iPad to that of an exam room PC. If I was making the decision, I'd find a way to remove every exam room PC [with their keyboards, CPUs, mice, monitors, and network cables] and instead supply iPads to be carried by the staff. With a good Wi-Fi network and iPads, every room is digitally equipped as soon as the doctor walks in."

Cain has seen the paradigm shift of touchscreen technology firsthand: The FDA recently approved an application from Cleveland-based MIM to let doctors make medical diagnoses based on computed tomography (CT) and magnetic resonance imaging (MRI) via an application available for the iPhone and iPad. The application, the first with the FDA's imprimatur for diagnostic radiology, allows hospitalists and other physicians to access data via a secure network transfer.

The app for that is just the latest sign that the growing prevalence of touchscreen technology is changing the face of HM.

The evolution has its pitfalls, though. Patient privacy, wireless security, and the hesitancy of physicians to adopt change will likely slow the adoption of technology, but "the integration of interactive devices into a physician's daily workflow could become as commonplace in 10 years as the presence of hospitalists is today," Cain says.

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Mobile technology, such as tablet computers, Internet-enabled smartphones, and the applications both devices use, will change the face of HM and other physician specialties, one medical software executive says.

"Mobile technology will improve efficiency and reduce costs," Mark Cain, chief technology officer of MIM Software Inc., writes in an e-mail to The Hospitalist. "Compare the cost of an iPad to that of an exam room PC. If I was making the decision, I'd find a way to remove every exam room PC [with their keyboards, CPUs, mice, monitors, and network cables] and instead supply iPads to be carried by the staff. With a good Wi-Fi network and iPads, every room is digitally equipped as soon as the doctor walks in."

Cain has seen the paradigm shift of touchscreen technology firsthand: The FDA recently approved an application from Cleveland-based MIM to let doctors make medical diagnoses based on computed tomography (CT) and magnetic resonance imaging (MRI) via an application available for the iPhone and iPad. The application, the first with the FDA's imprimatur for diagnostic radiology, allows hospitalists and other physicians to access data via a secure network transfer.

The app for that is just the latest sign that the growing prevalence of touchscreen technology is changing the face of HM.

The evolution has its pitfalls, though. Patient privacy, wireless security, and the hesitancy of physicians to adopt change will likely slow the adoption of technology, but "the integration of interactive devices into a physician's daily workflow could become as commonplace in 10 years as the presence of hospitalists is today," Cain says.

Mobile technology, such as tablet computers, Internet-enabled smartphones, and the applications both devices use, will change the face of HM and other physician specialties, one medical software executive says.

"Mobile technology will improve efficiency and reduce costs," Mark Cain, chief technology officer of MIM Software Inc., writes in an e-mail to The Hospitalist. "Compare the cost of an iPad to that of an exam room PC. If I was making the decision, I'd find a way to remove every exam room PC [with their keyboards, CPUs, mice, monitors, and network cables] and instead supply iPads to be carried by the staff. With a good Wi-Fi network and iPads, every room is digitally equipped as soon as the doctor walks in."

Cain has seen the paradigm shift of touchscreen technology firsthand: The FDA recently approved an application from Cleveland-based MIM to let doctors make medical diagnoses based on computed tomography (CT) and magnetic resonance imaging (MRI) via an application available for the iPhone and iPad. The application, the first with the FDA's imprimatur for diagnostic radiology, allows hospitalists and other physicians to access data via a secure network transfer.

The app for that is just the latest sign that the growing prevalence of touchscreen technology is changing the face of HM.

The evolution has its pitfalls, though. Patient privacy, wireless security, and the hesitancy of physicians to adopt change will likely slow the adoption of technology, but "the integration of interactive devices into a physician's daily workflow could become as commonplace in 10 years as the presence of hospitalists is today," Cain says.

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C. Diff Rates Rise for Hospitalized Children

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An article in the upcoming May issue of Archives of Pediatrics and Adolescent Medicine tracks the growing incidence of Clostridium difficile bacterial infections in hospitalized children.

Cade M. Nylund, MD, assistant professor of pediatrics at the Uniformed Services University of the Health Sciences in Bethesda, Md., and colleagues analyzed a national database of children discharged from hospitals in 1997, 2000, 2003, and 2006. Of 10.5 million total cases, only 0.2% had C. diff infections, but the number of cases increased by about 15% per year.

Incidence, severity, and deaths from C. diff in adults have also been increasing. Unlike adults, however, the authors did not observe an increase in severity of the disease for children over this time period. Infection, however, was associated with increased risk of death, higher colectomy rates, longer hospital stays, and higher costs.

Dr. Nylund says it is difficult to explain why is increasing in hospitalized children, but it might reflect antibiotic treatment practices, since prior antibiotic exposure is considered a risk factor. It also could be due to a more virulent strain of C. diff commonly found in hospitals, or the fact that healthcare providers are more aware of the need to test symptomatic patients for this infection.

According to Dr. Nylund, pediatric hospitalists should be aware of the significant impact of C. diff. "These children are more likely to stay in the hospital or die," he says. He suggests paying attention to such risk factors as antibiotic use, immune system suppression, and persistent diarrhea, as well as the need for a differential diagnosis. Appropriate and early isolation is important, as is hand-washing with soap and water, not using just alcohol-based hand gels, he adds.

"A lot of antibiotics are used to treat C. diff, some of them off-label," Dr. Nylund says. "I get phone consults, typically for difficult, recurring, and chronic cases. It seems like I'm receiving those calls more frequently."

For more information on treatment of C. diff, check out the Key Clinical Question in the March 2009 issue of The Hospitalist.

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An article in the upcoming May issue of Archives of Pediatrics and Adolescent Medicine tracks the growing incidence of Clostridium difficile bacterial infections in hospitalized children.

Cade M. Nylund, MD, assistant professor of pediatrics at the Uniformed Services University of the Health Sciences in Bethesda, Md., and colleagues analyzed a national database of children discharged from hospitals in 1997, 2000, 2003, and 2006. Of 10.5 million total cases, only 0.2% had C. diff infections, but the number of cases increased by about 15% per year.

Incidence, severity, and deaths from C. diff in adults have also been increasing. Unlike adults, however, the authors did not observe an increase in severity of the disease for children over this time period. Infection, however, was associated with increased risk of death, higher colectomy rates, longer hospital stays, and higher costs.

Dr. Nylund says it is difficult to explain why is increasing in hospitalized children, but it might reflect antibiotic treatment practices, since prior antibiotic exposure is considered a risk factor. It also could be due to a more virulent strain of C. diff commonly found in hospitals, or the fact that healthcare providers are more aware of the need to test symptomatic patients for this infection.

According to Dr. Nylund, pediatric hospitalists should be aware of the significant impact of C. diff. "These children are more likely to stay in the hospital or die," he says. He suggests paying attention to such risk factors as antibiotic use, immune system suppression, and persistent diarrhea, as well as the need for a differential diagnosis. Appropriate and early isolation is important, as is hand-washing with soap and water, not using just alcohol-based hand gels, he adds.

"A lot of antibiotics are used to treat C. diff, some of them off-label," Dr. Nylund says. "I get phone consults, typically for difficult, recurring, and chronic cases. It seems like I'm receiving those calls more frequently."

For more information on treatment of C. diff, check out the Key Clinical Question in the March 2009 issue of The Hospitalist.

An article in the upcoming May issue of Archives of Pediatrics and Adolescent Medicine tracks the growing incidence of Clostridium difficile bacterial infections in hospitalized children.

Cade M. Nylund, MD, assistant professor of pediatrics at the Uniformed Services University of the Health Sciences in Bethesda, Md., and colleagues analyzed a national database of children discharged from hospitals in 1997, 2000, 2003, and 2006. Of 10.5 million total cases, only 0.2% had C. diff infections, but the number of cases increased by about 15% per year.

Incidence, severity, and deaths from C. diff in adults have also been increasing. Unlike adults, however, the authors did not observe an increase in severity of the disease for children over this time period. Infection, however, was associated with increased risk of death, higher colectomy rates, longer hospital stays, and higher costs.

Dr. Nylund says it is difficult to explain why is increasing in hospitalized children, but it might reflect antibiotic treatment practices, since prior antibiotic exposure is considered a risk factor. It also could be due to a more virulent strain of C. diff commonly found in hospitals, or the fact that healthcare providers are more aware of the need to test symptomatic patients for this infection.

According to Dr. Nylund, pediatric hospitalists should be aware of the significant impact of C. diff. "These children are more likely to stay in the hospital or die," he says. He suggests paying attention to such risk factors as antibiotic use, immune system suppression, and persistent diarrhea, as well as the need for a differential diagnosis. Appropriate and early isolation is important, as is hand-washing with soap and water, not using just alcohol-based hand gels, he adds.

"A lot of antibiotics are used to treat C. diff, some of them off-label," Dr. Nylund says. "I get phone consults, typically for difficult, recurring, and chronic cases. It seems like I'm receiving those calls more frequently."

For more information on treatment of C. diff, check out the Key Clinical Question in the March 2009 issue of The Hospitalist.

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