THE MORTIMER J. LACHER, MD HEMATOLOGY/ONCOLOGY AND RADIATION THERAPY FELLOWSHIP CONFERENCES
of the MEMORIAL SLOAN KETTERING CANCER CENTER 

2009 THE LACHER FELLOWS RESEARCH CONFERENCE OF THE MEMORIAL SLOAN KETTERING CANCER CENTER WAS HELD ON WEDNESDAY MORNING, JUNE 10, 2009 – IN THE ZUCKERMAN RESEARCH BUILDING

Introduction:
Craig Moskowitz, M.D.
Clinical Director, Division of Hematologic Oncology, Associate Member, Lymphoma Service
Memorial Sloan Kettering Cancer Center
PRESENTATIONS:
James Hoffman, M.D.
Mentor: Hani Hassoun, M.D.
Light Chain Amyloidosis: Diagnostic Pitfalls and Therapeutic Progress
Todd Rosenblatt, M.D.
Mentor: Joseph Jurcic, M.D.
Alpha Particle Radioimmunotherapy of AML
Jonathan Schatz, M.D.
Mentors: Dr. Hans-Guido Wendel, M.D. & Dr. Andrew Zelenetz, M.D., Ph.D.
Emerging Targets: The PIM Family Kinases in Lymphomagenesis and Resistance to Therapy
Marco Davila, M.D.
Mentor: Michael Sadelain, M.D., Ph.D.
Development of a Cell Therapy for B cell Malignancies in Immunocompetent Mice
Stephanie Terezakis, M.D.
Mentor: Joachim Yahalom, M.D.
18FDG-PET with CT Scan Co-Registration for Radiation Treatment Planning of Lymphoma Patients

Concluding Remarks:
Mortimer J. Lacher, M.D., F.A.C.P.
President, the Lymphoma Foundation
Consultant, Department of Medicine
Memorial Sloan Kettering Cancer Center

2008 THE LACHER FELLOWS RESEARCH CONFERENCE OF THE MEMORIAL SLOAN KETTERING CANCER CENTER WAS HELD ON WEDNESDAY MORNING, JUNE 11, 2008 – IN THE ROCKEFELLER RESEARCH BUILDING

The following Fellows and their mentors presented the results of their research of the past year:
James Hoffman, M.D.  Mentor: Raymond Comenzo, M.D.
 CD32B in Plasma Cell Diseases
Bradford Hoppe, M.D.  Mentor: Joachim Yahalom, M.D.
 The Role of PET Imaging & Involved-Field Radiotherapy in Relapsed or Refractory Diffuse Large B cell Lymphoma
Matthew Matasar, M.D.  Mentor: Andrew D. Zelenetz, M.D., PhD
  Late Morbidity in Survivors of Hodgkin’s Lymphoma
Alison Moskowitz, M.D.  Mentor:  Craig Moskowitz, M.D.
  Improving Outcomes for Relapsed & Refractory Hodgkin’s Lymphoma
Todd Rosenblatt, M.D.  Mentor: Joseph Jurcic, M.D.
  Alpha-Particle Immunotherapy for Acute Myeloid Leukemia (AML) With Bismuth-213 and Actinium 225

The Conference was chaired by Dr. Craig Moskowitz, Clinical Director, Division of Hematologic Oncology and Dr. Mortimer J. Lacher provided concluding remarks

2007 - THE LACHER FELLOWS RESEARCH CONFERENCE WAS HELD AT THE MEMORIAL SLOAN KETTERING CANCER CENTER - THE ROCKEFELLER RESEARCH LABORATORY BUILDING on WEDNESDAY, JUNE 13, 2007 - 8:30AM to 11:30AM

Introduction: Tarun Kewalramani, M.D.
Presentations:

Justin Bekelman, M.D. Mentor: Joachim Yahalom, M.D. and Deborah Schrag, M.D.
Radiotherapy Quality: Perspectives from Randomized Trials and Practice
David Chung, M.D., Ph.D. Mentor: James Young, M.D.
Regulatory T cells Induced by Human Dendritic Cells Expressing Indoleamine 2, 3-Dioxygenase Suppress Antitumor Immunity

Robert Jenq, M.D. Mentor: Miguel Perales, M.D.
Combining DNA Tumor Vaccines with Vaccine Adjuvants and Immune Reconstituting Agents to Enhance Graft versus Tumor Responses after Allogeneic Bone Marrow Transplantation

Alexander Lesokhin, M.D. Mentor: Alan Houghton, M.D.
Immunosuppressive Elements in the Tumor Microenvironment

Matt Matasar, M.D., M.S. Mentor: Andrew Zelenetz, M.D.
Clinical and Pathologic Collaboration between Public Hospitals and MSKCC in the Management of Lymphoma

Concluding Remarks: Mortimer J. Lacher, M.D.

2006 - THE LACHER FELLOWS RESEARCH CONFERENCE WAS HELD AT THE MEMORIAL SLOAN KETTERING CANCER CENTER - THE ROCKEFELLER RESEARCH LABORATORY BUILDING on WEDNESDAY, JUNE 7, 2006

Introduction: Tarun Kewalramani, M.D.
     Michelle Klem, M.D. - Mentor – Dr. Joachim Yahalom -- Breast Cancer in Patients Irradiated for Hodgkin Lymphoma: A Review of 92 Cancers in 77 Patients   
    John Gerecitano, M.D., Ph.D. – Mentor – Dr. Owen O’Connor -- Proteasome Inhibition and the Treatment of Non-Hodgkin's Lymphomas
    Carlos Ramos, M.D. - Mentors – Dr. Shahin Rafii/ Dr. Mark Heaney -- Accerlerating Hematopoietic Recovery with Chemokines  
    Daniel Persky, M.D. – Mentor - Dr. Craig Moskowitz -- High dose chemoradiotherapy and ASCT may overcome the prognostic importance of bcl-2, bim, and p53 overexpression in relapsed/refractory Hodgkin’s Lymphoma
Conference Summation: Mortimer J. Lacher, M.D.
In his summation, in part,  Dr. Lacher noted the special importance of seeking means to avoid the radiation induced late onset breast cancers as reported by Dr. Klem, et al.. In a concise presentation he emphasized the role of reducing the size and amount of radiation and the controversy surrounding the concept of completely eliminating radiation therapy in favor of chemotherapy.

(For more detailed information regarding the reports by Dr. Klem, Dr. Ramos, Dr. Gerecitano and Dr. Persky  GO TO: EVENTS and SCIENTIFIC MEETINGS)

THE MORTIMER J. LACHER, MD HEMATOLOGY/ONCOLOGY AND RADIATION THERAPY FELLOWSHIP RECIPIENTS
of the MEMORIAL SLOAN KETTERING CANCER CENTER 
2003-2004
presented the results of their research of the past year at a Special Hematology Oncology Seminar on June 16, 2004 in the Memorial Sloan Kettering Cancer Center Rockefeller Research Laboratory Building. The following are abstracts of the presentations:
 

Dr. Jeffrey Halaas (Mentor - Dr. Andrew Zelenetz)

Feasibility and preliminary efficacy of R-CHOP-14 in patients with diffuse large B-Cell lymphoma (DLBCL)  Jeffrey L. Halaas, Craig H. Moskowitz, Steve Horowitz, Carol Portlock, Ariela Noy, David Straus, Owen O’Connor, Joachim Yahalom, Andrew D. Zelenetz

BACKGROUND Standard therapy for newly diagnosed DLBCL is CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone).  Recent studies have shown that either the addition of rituximab (R) or shortening the interval between cycles to two weeks can improve survival. This retrospective review analyses our early experience with this regimen. METHODS We retrospectively identified patients with newly diagnosed DLBCL (Diffuse Lowgrade B-cell Lymphoma) with normal cardiac, pulmonary, hepatic and CNS function treated at MSKCC with R-CHOP-14.  All patients received filgrastim and prophylactic sulfamethoxazole/trimethoprim, fluconazole and acyclovir.  Erythropoietin was given per institutional guidelines. Patients received involved field radiation therapy to early stage sites of disease or bulky or symptomatic sites of disease and intrathecal prophylaxis if indicated.

RESULTS In total, 49 patients were included for analysis.  Prognostic factors are as follows: median age is 52 (14/49 > 60); 20/49 with KPS < 70%; 26/49 with elevated LDH; 18/49 ≥2 extranodal sites and 71% with advanced stage. According to the International Prognostic Index (IPI) 30.6% patients had low risk disease, 22.4% had low-intermediate risk, 28.6% had high-intermediate risk, and 18.4% had high risk disease.  Ninety-two percent of patients received 6 cycles of R-CHOP-14.  Seventy-three percent of courses were delivered within 14 days and the planned dose given was greater than 96% for R, cyclophosphamide and doxorubicin but 67.5% for vincristine (VCR). Ten patients were hospitalized a total of 21 times; neutropenic fever was uncommon and occurred in 3.6% (9/252) of cycles given. Among evaluable patients 37/45 (82.2%) achieved a CR/CRu and 1 patient had refractory disease.  Of 7 patients with refractory or relapsed disease, 4 are currently alive.  Progression free survival at 18 months is 89%.

CONCLUSIONS: Administration of R-CHOP-14 is feasible and early results show favorable efficacy. Most cycles can be delivered on time and at full dose except for VCR which was dose-reduced in one third of patients.  Early results are encouraging and warrant comparison to R-CHOP-21. 
 

Dr. Nicole Lamanna (Mentor- Dr. Mark Weiss)

Chronic Lymphocytic Leukemia: The MSKCC Program Upfront treatment, salvage therapy, future directions

Sequential therapy with fludarabine, high dose cyclophosphamide, and rituximab induces a high incidence of complete response in patients with chronic lymphocytic leukemia (CLL).  Previously, combinations of purine analogs and alkylating agents have been limited by severe combined myelosuppression and immunosuppression.  In order to take advantage of the activity of these agents without sacrificing dose intensity, we have studied a sequential treatment program. We have previously reported that sequential fludarabine followed by high-dose cyclophosphamide (HDC) markedly improves the frequency of complete response compared to treatment with fludarabine alone.  Based on those encouraging results we now report a three-stage sequential treatment program with fludarabine as induction, HDC as first consolidation, and rituximab as a second non-cross-resistant consolidation. To date 30 previously untreated patients with intermediate (13pts) or high-risk (17 pts) CLL  HIGH RISK CLL have been included in this study.   Fludarabine was administered at 25mg/m²/d x5d q 4 weeks x 6 cycles. Consolidation #1 was HDC 3g/m² (administered with G-CSF support) q 3weeks for 3 cycles.   Consolidation #2 was rituximab 375mg/m² weekly x 4 doses.

In this comparison we were unable to demonstrate an improvement in response frequency with the 3 drug regimen but we believe confounding variables such as overlapping confidence intervals and potential differences in patient mix may obscure an improved anti-leukemic response.  We plan to further study this regimen in patients with untreated CLL.

Dr. Deborah Mulford (Mentor- Dr. Joseph Jurcic)

Antibody-based Therapy for Elimination of Minimal Residual Disease in Acute Myeloid Leukemia Deborah A. Mulford, Memorial Sloan-Kettering Cancer Center, New York, NY 10021

HuM195, a humanized monoclonal antibody against CD33, targets myeloid leukemia cells without immunogenicity.  It can produce occasional CRs in patients with relapsed acute myeloid leukemia (AML).  Two approaches to the use of this antibody for elimination of minimal residual disease (MRD) in AML have been studied:  (1) native antibody therapy in acute promyelocytic leukemia (APL) and (2) alpha particle immunotherapy. In a previous study, we found that HuM195 can eliminate MRD detectable by RT-PCR for PML-RARa mRNA in approximately 50% of patients with newly diagnosed APL.  When combined with all-trans retinoic acid (ATRA) and consolidation chemotherapy, 5-year remissions were seen in 93% on patients.  Arsenic trioxide (ATO) produces CRs in 85-90% of patients with relapsed APL. 

We studied postremission therapy with HuM195 and ATO using a risk-adapted approach based on RT-PCR monitoring of MRD.  Patients with newly diagnosed APL who achieved a clinical CR after ATRA-based induction were treated with HuM195 followed by ATO.  Patients in molecular remission after ATO received one course of idarubicin.  If patients remained RT-PCR-positive after ATO, up to 3 cycles of idarubicin could be administered.  Patients then received maintenance therapy with ATRA.  To date, 13 patients (median age, 48 years) have been treated.  All remain in a clinical CR with median follow-up of 19 months.  Following induction, MRD was detectable in 6 patients.  Three became RT-PCR-negative after HuM195, and the remaining 3 achieved molecular remission after ATO.  No patient required more than one cycle of idarubicin.  Thirteen patients (100%) remain in molecular remission; one became RT-PCR-positive after 8 months and has been in a second molecular remission for 8 months following a HLA-matched related allogeneic transplant. This risk-adapted approach significantly reduced the number of hospital days compared with standard consolidation therapy given in a previous study (p < 0.0001).  Postremission therapy based on RT-PCR monitoring of MRD and the use of newer agents such as HuM195 and ATO can reduce, and potentially eliminate, the need for standard anthracycline-based consolidation in APL.

 Unlike beta-emitting isotopes, alpha-emitters can selectively kill individual cancer cells with a single atomic decay, making them ideally suited for the treatment of minimal residual disease.  To enhance the potency of native HuM195 yet avoid the nonspecific cytotoxicity of beta-emitters, the alpha-emitting radiometal bismuth-213 (²¹³Bi) was conjugated to HuM195.  Eighteen patients with advanced myeloid leukemia were treated with ²¹³Bi-HuM195 (0.28-1 mCi/kg) in an initial phase I trial.  Fourteen of the 18 patients (78%) had reductions in the percentage of bone marrow blasts.  The use of ²¹³Bi-HuM195 for elimination of residual disease after partial cytoreduction with the chemotherapeutic agent cytarabine is currently under study.  In an ongoing phase I/II study, 6 of the 18 patients with AML who received 1 or 1.25 mCi/kg of ²¹³Bi-HuM195 after cytarabine responded (2 CR, 3 CRp [CR with incomplete platelet recovery], 2 PR).  Actinium-225 (²²⁵Ac) immunoconjugates, which produce a cascade of four alpha particles, were found to be 1000 times more potent than ²¹³Bi analogs.  In xenograft models of prostate carcinoma and disseminated lymphoma, tumor specific ²²⁵Ac constructs prolonged survival and cured a substantial fraction of animal without toxicity.  A phase I trial of ²²⁵Ac-HuM195 in advanced myeloid leukemia is planned. 
 

 Dr. Kathryn P. Beal (Mentor - Dr. Joachim Yahalom)

Excellent long term experience with primary bone lymphoma: Analysis of prognostic factors Kathryn P. Beal, M.D., Joachim Yahalom, M.D.  Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: There is limited information on the preferred treatment and long term prognosis of primary bone lymphomas (PBL).  We analyzed all PBL cases treated at Memorial Sloan Kettering Cancer Center (MSKCC) between 1963 and 2003 to determine patient, disease, and treatment factors that could affect outcome measured by overall survival (OS), cause specific survival (CSS), and freedom-from-treatment failure (FFTF).  Materials and Methods:  101 patients with primary bone lymphoma diagnosed at our institution were identified.  19 patients were excluded as they transferred their treatment or follow-up to another center.  82 patients were analyzed for prognostic factors by performing a univariate analysis and subjecting the significant factors to a Cox regression multivariate analysis.  Results:  Median age was 48 years (range 11:83);  the M:F ratio was 1:1;  80% presented with DLCL;  81% presented with stage I or II disease;  57% were treated with combined modality therapy (CMT), 14% were treated with radiation therapy alone, 30% were treated with chemotherapy alone.  The median follow-up was 67 months (range 2:280).  For the whole group, the 5-year OS, CSS, and FFTF was 88%, 96% and 81% respectively.  The 5 year OS for patients treated with CMT was 95% vs. 78% (p=0.013) for patients treated with single modality therapy, and the 5 year FFTF for patients treated with CMT was 90% vs. 67% (p=.025).  The 5 year CSS for patients treated with CMT was 95% vs. 83% (p=.065).  On univariate analysis age <40, use of CMT, lack of B symptoms, normal LDH level, and female gender were favorable prognostic factors for OS;  KPS>=70%, use of CMT, normal LDH level, and female gender were favorable for FFTF;  and only female gender was favorable for CSS.  IPI was not significant for OS, CSS, or FFTF.  On multivariate analysis, age <40, use of CMT, and normal level LDH were favorable prognostic factors for OS; age <40, use of CMT, normal LDH level, and lack of B symptoms were prognostic for CSS; and age <40 and use of CMT were prognostic for FFTF.

Conclusion:  This largest published modern series of Primary Bone Lymphoma (PBL) demonstrates that primary lymphoma involving the bone has an excellent prognosis.  Patients with PBL treated with Combined Modality Therapy (CMT) versus single modality therapy had a superior outcome with a significantly better survival.

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