Hematologic Malignancies

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Myelodysplastic syndromes (MDS) represent a related group of bone marrow disorders that share features of bone marrow failure and, to a variable degree, a predisposition toward progression to acute myelogenous leukemia (AML). Reflective of these dual manifestations, goals of treatment for MDS include both the amelioration of cytopenias and delaying the progression to acute leukemia. In addition to disease-focused treatment measures, supportive care remains an important component in the management of patients with MDS. Allogeneic stem cell transplantation, the only potentially

curative treatment option for MDS, should be considered for younger patients with available donors, however, appropriate timing of transplant is important to minimize exposing patients with low risk disease to unnecessary risk early in the course of their disease. This overview of the management of MDS will attempt to address and provide our institutional perspectives on these current issues in the management of MDS. Treatment of MDS

Until the last decade, supportive measures represented the standard of care for patients with MDS. Numerous studies of chemotherapy regimens developed for treating AML have failed to show convincing evidence of benefit in MDS patients, due in part to suboptimal complete response rates and poor tolerance by typically older MDS patient populations. Within the past 10 years, however, three drugs have been approved by the FDA for the treatment of MDS. Two of these agents, azacytidine and

decitabine, are structurally similar and are believed to function by inhibiting the enzyme DNA methyltransferase, responsible for silencing the expression of tumor suppressor genes that are postulated to play a role the pathogenesis of MDS.

Both azacytidine and decitabine produce complete or near-complete response rates of approximately 20-25%, and overall response rates of ~50% (including hematologic improvement). In addition, both agents have been shown in randomized trials to delay the progression to AML, and azacytidine has resulted

in prolonged overall survival compared with supportive care alone, low dose cytarabine, or standard anti-leukemic induction chemotherapy. Although originally approved based on a three-times-daily dosing regimen (15 mg/ m2 q8 hours for 3 days), decitabine is more commonly administered as a daily regimen associated with less myelosupression and better suited to outpatient administration (20 mg/m2 daily for 5 days). Based on their acceptably modest toxicities (primarily mild myelosuppression), outside of a clinical trial it is reasonable to offer a trial of a hypomethylating agent to most patients with higher risk (as defined by IPSS score) or transfusion-dependent MDS. The optimal duration of therapy for responding patients is not well-defined. In published studies utilizing these agents, responding patients continued therapy until progression, although there is no evidence that observation after a prolonged course of therapy, for example in patients achieving a complete response, might not result in equivalent outcomes. The benefit of treating

Myelodysplastic Syndromes

Peter Westervelt, M.D., Ph.D., Associate Professor of Medicine

Chief, Section of Bone Marrow Transplantation, Washington University School of Medicine

Issue Number 7 — Spring 2010 C O N N E C T I N G L I F E A N D S C I E N C E

Leukemia, Lymphoma, Myeloma and Stem Cell Transplantation

Hematologic Malignancies

To refer a patient, please call: 877-251-6485 Call Monday-Friday 8:30 a.m. to 4:30 p.m.

central time.

Within 24 hours (excluding weekend and holidays) a new patient coordinator will contact your office to

facilitate the referral process. If a patient requires direct admission or emergent transfer, please call 800-252-3627.

Available 24 hours a day, seven days a week.

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Hematologic Malignancies

asymptomatic, non-transfusion-dependent patients with low risk disease has not been established and these patients should generally be

observed without treatment until symptomatic disease progression. Lenalidomide, an orally bioavailable thalidomide analog

originally developed and approved as a treatment for multiple myeloma, is highly active in treating the subset of MDS patients with 5Q minus syndrome. Treatment of red blood cell transfusion-dependent 5Q minus syndrome patients with lenalidomide has been shown to eliminate the need for

transfusional support in 76% of patients, usually within a few weeks of initiating treatment, with most responses persisting

for over two years. Although responses were seen across a spectrum of additional karyotypic abnormalities seen

in conjunction with the 5Q minus deletion, responses in the absence of a 5Q deletion have been relatively

modest (25% hematologic improvement). Hence, a trial of lenalidomide should be considered frontline therapy only for those patients with a 5Q deletion.

We are currently investigating the use of decitabine in combination with an investigational oral histone deacetylase inhibitor (LBH589). Eligibility requirements

for this study include age greater than 60, advanced MDS with an IPSS score 1.5 or greater, and no prior

treatment with azacytidine or decitabine. This study is also open to patients over age 60 with AML.

Allogeneic stem cell transplantation Whereas stem cell transplantation was once reserved for the relatively small subset of MDS patients under age 60 in good overall health, it is no longer unusual for selected patients well into their 60’s (or older) to undergo allogeneic stem cell transplantation utilizing reduced intensity conditioning regimens.

Determining the optimal timing of stem cell transplantation for MDS can challenging, balancing its substantial treatment-related toxicity with better transplant outcomes when deployed earlier in the course of the disease. In general, however, it is reasonable to delay transplant in low risk patients until progression (transfusion dependence, increasing blasts, eg), and to transplant upfront in patients with more advanced disease. This approach has been validated by a study based on retrospective outcomes analysis of three large registries of MDS patients. The role of induction therapy prior to transplant is poorly defined. Most studies have demonstrated minimal benefit for AML induction chemotherapy prior to transplant for MDS, despite evidence that patients in remission at transplant fare better overall. There is, moreover, no clear evidence that less aggressive treatment with a hypomethylating agent prior to transplant improves transplant outcome, albeit based only on retrospective analysis of a small series of patients. Decisions regarding treatment of MDS patients where the goal is to establish a bridge to transplant are individualized, and typically influenced by factors such as donor availability and the pace of disease progression. Recommendations

1. Observation alone in low risk, transfusion-independent MDS patients

2. Therapeutic trial of azacytidine or decitabine higher risk (IPSS > 1.5) or transfusion dependent patients 3. Therapeutic trial of lenalidomide for patients with

5Q minus syndrome

4. Early referral for consideration of allogeneic stem cell transplant

5. Enrollment in well-designed clinical trials whenever possible

Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine is hosting an educational symposium entitled “Advances in Diagnosis and Treatment of Hematologic Malignancies”. The symposium will take place on Saturday, August 28 at the Four Seasons Hotel in St. Louis, Missouri.

The annual symposium provides the audience with updated information on cancer treatment and diagnosis through discussions on hematological malignancies. In addition to the conference, we are hosting our 17th

Annual Bone Marrow Transplant Patient Celebration on Saturday, August 28, in the ballroom of the St. Louis Four Seasons Hotel. You and a guest are invited to attend this event in honor of our survivors. Please join us for a private physician reception an hour prior to the patient celebration.

If you are interested in attending the symposium, physician reception or the patient celebration, please call the CME office at Washington University School of Medicine at 314-362-6891 or 1-800-325-9862.

Save the Date

Continuing Medical Education: Advances in Diagnosis and Treatment of Hematologic Malignancies August 28, 2010 at the Four Seasons Hotel in St. Louis, Missouri

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Clinical Trials

To LEARn MoRE AbouT THE CLiniCAL TRiALS, oR To EnRoLL A pATiEnT,

pLEASE ConTACT THE LiSTED STuDy CooRDinAToR AT 314-454-8377.

Hematological Malignancies is published by The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. The Siteman Cancer Center is designated as a Comprehensive Cancer Center by the National Cancer Institute (NCI) and is a member of the National Comprehensive Cancer Center Network (NCCN).

Editors: Geoffrey Uy, M.D. and Ryan Monahan | Article Contributors: Peter Westervelt M.D., Ph.D. Production Manager: Angela Benassi

(continued on page 4)

CALGB 10603 PI: Geoffrey Uy Study Coordinator: Kris McDonald

A Phase III Randomized, double-blind Study of

Induction (Daunorubicin/ Cytarabine and Consolidation (High-dose Cytarabine) Chemotherapy + Midostaurin (PKC412) (IND#101261) or Placebo in Newly Diagnosed Patients < 60 Years of Age with FLT3 Mutated Acute Myeloid Leukemia

Notes: Newly dx de novo AML age 18-59, decitabine maintenance after induction and risk adapted consolidation based on cytogenetics to either HiDAC or auto

transplant-CALGB 10503 PI: Geoffrey Uy Study Coordinator: Kris McDonald

Phase II Study of Maintenance Therapy With

Decitabine Following Standard Induction and Cytogenetic Risk-Adapted Intensification in Previously Untreated Patients With AML ≤ 60 Years.

Notes: Newly dx de novo AML age 18-59, decitabine maintenance after induction and risk adapted consolidation based on cytogenetics to either HiDAC or auto transplant

09-1171 PI: Geoffrey Uy Study Coordinator: Liz Procknow

A Phase I, Dose Escalation Study of Plerixafor in

Combination with Cytarabine and Daunorubicin in Patients with De Novo Acute Myeloid Leukemia

Notes: Newly dx de novo AML age 18-70.

09-1126 PI: John DiPersio Study Coordinator: Liz Procknow

Maintenance Therapy with Decitabine after Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndrome

08-0126 PI: Geoffrey Uy Study Coordinator: Kris McDonald

SWOG S0521— A Randomized Trial of Maintenance Versus Observation for Patients with Previously Untreated Low and Intermediate Risk Acute Promyelocytic Leukemia (APL), Phase III.

Notes: Low or intermediate risk APL 18 years and older with no prior systemic therapy or recurrent disease.

ACuTE LEukEMiA /MDS

AML, relapsed refractory

MDS/AML, other

Phase I Study of Oral Clofarabine Consolidation in Adults Aged 60 and Older with Acute Myeloid Leukemia

Notes AML in CR1, ≥ 60 years old,up to one cycle of HiDAC allowed.

08-0853 PI: Camille Abboud Study Coordinator: Sarah Witowski

A Phase I Study of Intravenous Plerixafor in Combination with Mitoxantrone Etoposide and Cytarabine for Relapsed or Refractory Acute Myeloid Leukemia

Notes: Age 18-70 with either primary refractory AML, relapsed AML

09-1825 PI: Geoffrey Uy Study Coordinator: Jeff Demland

A Phase I/II Study of LBH589 plus Decitabine for Patients Age > 60 Years with High Risk MDS or AML

Notes: Age > 60 with MDS (IPSS≥1.5) or AML with no prior treatment with a hypomethylating agent

AML, newly diagnosed

A Phase I/II Study of LBH589 plus Decitabine for Patients Age > 60 Years with High Risk MDS or AML

Notes: Age > 60 with MDS (IPSS≥1.5) or AML with no prior treatment with a hypomethylating agent

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Clinical Trials

To LEARn MoRE AbouT THE CLiniCAL TRiALS, oR To EnRoLL A pATiEnT, pLEASE ConTACT THE LiSTED STuDy CooRDinAToR AT 314-454-8377.

Hematologic Malignancies

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A Phase 2 Study of Inotuzumab Ozogamicin (CMC-544) in Subjects with Indolent Non-Hodgkin’s Lymphoma (NHL) that is Refractory to or has Relapsed after Rituximab and Chemotherapy or Radioimmunotherapy

Notes: Patients with Follicular, Marginal Zone, or SLL are eligible; must have progressed after at least 2 prior therapies; Patients must have had no response or have progressed within 6 months from the completion of Rituxan or Rituxan containing therapy or within 12 months of completion of RIT.

09-1125 PI: Nina

Wagner-Johnston Study Coordinator: Rachael Keeley

ALL

A Randomized Phase II trial of Rituximab vs. Lenalidomide (RevlimidTM, CC-5013) (IND # 73034) vs. Rituximab +

Lenalidomide in Recurrent Follicular Non-Hodgkin Lymphoma (NHL) That Is Not Rituximab-Refractory (Arm A, Rituximab Alone, was permanently closed effective 9/15/2007)

Notes: Patients must have been treated with rituximab either alone or in combination with chemotherapy. The last prior treatment regimen need not include rituximab but must have progressed >6 months from their last rituximab dose.

CALGB 50401 PI: Nancy L.

Bartlett Study Coordinator: Rachael Keeley

A Phase I/II Study of Eltrombopag in Thrombocytopenic Subjects with Advanced Myelodysplastic Syndrome (MDS) or secondary Acute Myeloid Leukemia after MDS

(sAML/MDS

09-1264 PI: Camille Abboud

Maintenance Therapy with Decitabine after Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndrome

indolent

CALGB 10403 PI: Geoffrey Uy Study Coordinator: Kris McDonald

An Intergroup Phase II Clinical Trial for Adolescents and Young adults with Untreated Acute Lymphoblastic Leukemia.

Notes: Newly diagnosed and untreated ALL between the age of 16 and 40

non-HoDGkin LyMpHoMA (nHL)

A Phase I/II Dose Escalation Study of the Pan-Histone Deacetylase (HDAC) Inhibitor PCI-24781 in Lymphoma

Notes: Patients must have had no more than 4 prior therapies; prior allogeneic transplant not allowed. Only open for Follicular NHL and Mantle Cell Lymphoma

08-0494 PI: Nancy L.

Bartlett Study Coordinator: Justina First

Phase III Randomized Study of R-CHOP vs. Dose-Adjusted EPOCH-R with Molecular Profiling in Untreated De Novo Diffuse Large B-Cell Lymphomas

Notes: Patients must have a new biopsy if fresh/frozen tissue was not available from their first biopsy, unless contraindicated

Bartlett Study Coordinator: Sarah Larson

Large Cell

An Open-label, Single-Arm, Phase 2 Study of Inotuzumab Ozogamicin Plus Rituximab in Subjects With Relapsed/ Refractory CD22-Positive Diffuse Large B-Cell Lymphoma, Eligible for Autologous Stem Cell Transplantation

09-0890 PI: Nina

Wagner-Johnston Study Coordinator: Rachael Keeley

A randomized, double-blind, placebo-controlled, multi-center phase III study of RAD001 adjuvant therapy in poor risk patients with Diffuse Large B-Cell Lymphoma (DLBCL) of RAD001 versus matching placebo after patients have achieved complete response with first-line rituximab-chemotherapy

09-0839 PI: Nina

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AiDS/HTLV

Mantle Cell

An open-label, Single Arm Phase II Study of RAD001 in Patients with Refractory Mantle Cell Lymphoma

Notes: Patients must have been refractory to Bortezomib and to their last line of therapy (if other than Bortezomib).

A Randomized Phase II Trial of Maintenance vs.

Consolidation Bortezomib Therapy Following Aggressive Chemo-Immunotherapy and Autologous Stem Cell Transplant for Previously Untreated Mantle Cell Lymphoma

Notes: Patients must be between the ages of 18 and 69 years with any stage (I-IV).

A Phase II Trial of Bortezomib (NSC #681239) + Lenalidomide (RevlimidTM_{, CC-5013) (NSC#703813) For}

Relapsed/Refractory Mantle Cell Lymphoma

Notes: Patients may not have received prior bortezomib or lenalidomide therapy.

A Phase 2, Multicenter, Single-Arm, Open-Label Study to Determine the Efficacy and Safety of Single-Agent Lenalidomide (Revlimid) in Patients With Mantle Cell NHL Who Have Relapsed or Progressed After Treatment With Bortezomib or Are Refractory to Bortezomib.

Prospective Phase II Study of a High Dose, Short Course Regimen (R-CODOX-M/IVAC) Including Central Nervous System (CNS) Penetration and Intensive Intrathecal (IT) Prophylaxis in HIV-Associated Burkitt’s and Atypical Burkitt’s Lymphoma.

AMC 048 _{PI: Lee Ratner} Study Coordinator: Lee Ratner

Phase I/II Study of Pre-Irradiation Chemotherapy with Methotrexate, Rituximab, and Temozolomide and Post-Irradiation Temozolomide for Primary Central Nervous System Lymphoma

RTOG 0227 _{PI: David Mansur} Study Coordinator: Shannon Rickey

primary CnS

A Phase I Sequential Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of CAL-101 in Patients with Select, Relapsed or Refractory Hematologic Malignancies.

Notes: open to patients with Indolent B-Cell, Mantle Cell, and CLL. 08-1270 PI: Nina

Wagner-Johnston Study Coordinator: Justina First

All Lymphoma Histologies

Pivotal Study of SGN-35 in Treatment of Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma (ALCL).

T-Cell

Retreatment with SGN-35 in Patients with CD30-positive Hematologic Malignancies

Notes: For patients who experienced either a complete or partial remission with known SGN-35 treatment, and had relapse after discontinuing treatment in the prior SGN-35 study.

Treatment of Peripheral T-Cell Lymphoma with Aggressive Induction Chemotherapy Followed by Autologous Stem Cell Transplant using Denileukin Diftitox (Ontak) for in-vivo Purging and Post-Transplant Therapy: A Multicenter Phase II Clinical Trial

Notes: For patients with previously untreated T-Cell Lymphoma or could have received up to 1 prior cycle of chemotherapy.

A Phase I/II Dose Escalation Study of the Pan-Histone Deacetylase (HDAC) Inhibitor PCI-24781 in Lymphoma

Notes: Patients must have had no more than 4 prior therapies; prior allogeneic transplant not allowed. Only open for Follicular NHL and Mantle Cell Lymphoma

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Hematologic Malignancies

Clinical Trials (continued)

6

A Phase II Trial of Response-Adapted Therapy of Stage III-IV Hodgkin Lymphoma using Early Interim FDG-PET Imaging

SWOG S0816 PI: Nancy L.

HoDGkin LyMpHoMA (HL)

Retreatment with SGN-35 in Patients with CD30-positive Hematologic Malignancies

Notes: For patients who experienced either a complete or partial remission with known SGN-35 treatment, and had relapse after discontinuing treatment in the prior SGN-35 study.

A Phase II Multicenter Study of Lenalidomide in Relapsed or Refractory Classical Hodgkin Lymphoma

Notes: Patients must have recurred after at least 1 prior therapy. Patients with any stage and who have had prior autologous or allogeneic stem cell transplant are eligible. 07-0233 PI: Nancy L.

A Randomized Phase II study of Rituximab with ABVD vs. Standard ABVD for Patients with Advanced-Stage Classical Hodgkin Lymphoma with Poor Risk Features

Notes: IPS Score >2.

A Phase I/II an Open-Label Study of Pralatrexate and Gemcitabine with Vitamin B12 and Folic Acid

Supplementation in Patients with Relapsed or Refractory Lymphoproliferative Malignancies

Notes: Patients must have at least 1 prior treatment; no prior allogeneic transplant; patients must have relapsed > 100 days from autologous transplant.

CHRoniC LyMpHoCyTiC LEukEMiA (CLL)

Bartlett Study Coordinator: Kris McDonald

A Randomized Phase II Study of Three Fludarabine/ antibody Combinations for Patients with Symptomatic, Previously Untreated Chronic Lymphocytic Leukemia

Notes: For previously untreated CLL patients requiring therapy (symptomatic, intermediate or high-risk by Rai staging system).

MuLTipLE MyELoMA

08-0705 PI: Ravi Vij Study Coordinator: Mark Fiala

A Phase 1b, Multicenter, Open-label, Dose-escalation Study of HuLuc63 (Humanized Anti-CS1 Monoclonal IgG1 Antibody) in Combination with Lenalidomide and Dexamethasone in Subjects with Relapsed Multiple Myeloma

Notes: Ages 18 and older Lenalidomide naïve with measurable disease and disease progression on their prior line of therapy. 09-0462 PI: Ravi Vij Study Coordinator:

Mark Fiala

A Phase 1/2 Multi-Center, Randomized, Open Label Dose Escalation Study to Determine the Maximum Tolerated Dose, Safety, and Efficacy of CC-4047 Alone or in Combination with Dexamethasone in Patients with Relapsed and Refractory Multiple Myeloma Who Have Received Prior Treatment that Included Lenalidomide and Bortezomib

Notes: Relapsed or relapsed/refractory Multiple Myeloma patients 18 years old or greater with measurable disease and at least 2 prior lines of therapy.

09-1749 PI: Ravi Vij Study Coordinator: Mark Fiala

Multicenter, Open-label, Single-arm, Phase 1b/2 Study of the Safety and Efficacy of Combination Treatment with Carfilzomib, Lenalidomide and Dexamethasone (CRD) in Subjects with Newly Diagnosed, Previously Untreated Multiple Myeloma Requiring Systemic Chemotherapy (MMRC\University of Michigan)

Notes: Newly diagnosed stage I, II, or III ages 18 and older with measurable disease.

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TRAnSpLAnT

08-0897 PI: Amanda Cashen Study Coordinator: Stefanie Goran

A Phase I/II Study of Intravenous AMD3100 Added to a Mobilization Regimen of G-CSF to Increase the Number of Peripheral Blood Stem Cells Collected From Patients with Lymphoma.

Notes: Any patient aged 18-75 with hodgkins or non-hodgkins lymphoma and eligible for autologous transplant.

General

A Multicenter, Prospective Trial to Evaluate the Role of NK Cell Kir Epitope Mismatch on Mortality and Disease Relapse in T-Cell Depleted Hematopoietic Stem Cell Transplantation from HLA-C Mismatched, Unrelated Donors for Myeloid Malignancies (MT2004-04).

CTN 0603 PI: Peter

Westervelt Study Coordinator: Jeremy Gabriel

A Multicenter, Phase II Trial of Nonmyeloblative Conditioning (NST)and Transplantation of Partially HLA-Mismatched Bone Marrow for Patients with Hematologic Malignancies (BMT CTN 0603).

Notes: Open to AML in 2nd or subsequent CR or AML in high risk CR1, ALL in high risk CR1, Burkitt’s Lymphoma in 2nd or subsequent CR, Lymphoma (large cell, Mantle cell and Hodgkin’s in CR or PR and marginal and B-cell lymphoma progressed after 2 or more therapies).

09-0744 PI: John DiPersio Study Coordinator: Jeremy Gabriel

Infusion of Genetically Modified T cells: A Phase I Study of Tracking and Toxicity

Notes: Ages > 18, prior recipients of allogeneic BMT for any hematologic malignancy. Eligible patients would include those with leukemia, non Hodgkins Lymphoma, Hodgkins Disease, myelodysplastic syndrome and multiple myeloma.

09-0042 PI:Keith

Stockerl-Goldstein Study Coordinator: Liz Procknow

Autologous Followed by Non-myeloablative Allogeneic Transplantation for Non-Hodgkin’s Lymphoma

Notes: Ages 18-70, must have relapse or persistent disease following allogeneic transplant.

GVHD

08-1093 PI: John DiPersio Study Coordinator: Stefanie Goran

A Phase 2, Open-Label, Single Arm, Pilot Study of Safety and Efficacy of CC-4047 (Pomalidomide) in Patients with Advanced Chronic Graft-Versus-Host Disease.

09-0713 PI: John DiPersio Study Coordinator: Sandra Lopez

A Phase II Study Evaluating the Safety and Efficacy of Intravenous AMD3100 for the Mobilization and

Transplantation of HLA-Matched Sibling Donor Hematopoietic Stem Cells in Patients with Advanced Hematological

Malignancies

Notes: Any patient aged 18-65 with (matched donor 18-70) in first or greater remission with a dx of AML, ALL, high grade MDS, CML in accelerated phase or > 2 remission, Myeloma stage 2-3, NHL or HD in > 2 remission, and CLL Rai Stage 2-4 failing at least 2 prior therapies.