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LYMPHOMA FOUNDATION NEWSLETTERS

SEEKING SOLUTIONS TO SERIOUS  LATE OCCURRING COMPLICATIONS OF RADIATION THERAPY

Use of the radiation therapy to a 'mantle field' was responsible for effectively limiting the chances of early relapses and helped introduce long survival in many patients with Hodgkin's disease. Now it is understood that this treatment has its own unique limitations.


THE PROBLEM: In Hodgkin’s patients treated with radiation therapy to the chest and neck areas a shortened life expectancy is caused by an increased late occurring incidence of coronary heart disease and stroke.
THE POSSIBLE SOLUTIONS: Consider stopping the routine use of Radiation Therapy for patients with Hodgkin’s disease and treat primarily with chemotherapy [**Reference a research study supported in part with Lymphoma Foundation grants by Dr. D. J. Straus, et al at Memorial Sloan Kettering Cancer Center published in Blood, 1 December 2004, Vol. 104, No. 12, pp. 3483-3489 with a supporting commentary by Dr. D. L. Longo of the National Institute of Aging p. 3418:

 ”ABVD chemotherapy alone is as effective as ABVD plus radiation therapy in early-stage Hodgkin disease; thus, the majority of patients are curable without being exposed to the life-long, life-threatening risks of therapeutic radiation.”

¨ Because the use of Radiation therapy may not be stopped but only modified it will continue to be a significant risk factor for the development of coronary heart disease. Therefore cardiologists and oncologists should unite to consider and initiate a study of the value of adding long term use of a statin to the radiation treatment.

¨ Advise the American College of Cardiology (ACC) and the American Heart Association (AHA)  that radiation therapy to the chest and neck in lymphoma patients should be added as a serious risk factor for the development of acute coronary syndromes and stroke and the already treated surviving patients post-radiation should consider starting statin medication and be sure to lower the LDL cholesterol levels to the lowest levels now expected to achieve the best results.

    In this regard an Editorial appeared in the Journal of the American Medical Association entitled

The IDEAL Cholesterol

Lower Is Better

by Christopher P. Cannon, MD

JAMA. November 16, 2005;Volume 294:page 2492

“… patients should know their cholesterol numbers, for both LDL-C and HDL-C, to enable them to see how much lowering is needed to reach targets of an LDL-C level of less than 100 mg/dL for patients with risk factors or less than 70 mg/dL for patients with heart disease  … any drug treatment should be taken together with an appropriate diet and exercise program to lower cholesterol and overall vascular risk. … The amount of LDL-C lowering with diet is only in the range of 7% to 12%. Clearly, diet is a central part of the treatment, but to get the benefits of very low cholesterol levels, drug treatment is often necessary. ...Optimal use of diet and appropriate use of medications will dramatically reduce the risk of MI, stroke, and death from heart disease. These new data should help motivate any patients who have been hesitating about treating their cholesterol to talk with their physician to get the benefits of intensive cholesterol lowering”

 And... in the August 2, 2005 issue of the Annals of Internal Medicine of the American College of Physicians Dr. John V.L. Sheffield and Dr. Eric B. Larson reviewed data regarding Cardiovascular Disease and Statin Use and they noted the following:

“This year's trial results [2004] indicate a real change in our understanding of indications for the use of statins.

In type 2 diabetic patients with at least 1 additional risk factor for coronary heart disease, lipid-lowering treatment with statins is effective for primary prevention of cardiovascular disease (CVD). In patients with acute coronary syndromes, early initiation of intensive lipid-lowering treatment to achieve serum low-density lipoprotein (LDL) cholesterol levels below 1.80 mmol/L (<70 mg/dL) prevents major cardiovascular events more effectively than moderate lipid lowering.

Intensive lipid lowering is also beneficial for patients with stable coronary disease.

These results indicate that statin treatment could benefit a greater number of patients and that target LDL cholesterol levels for treatment of patients at highest risk should be lower than previously recommended. 

Because these findings indicate that patients are now more likely to be using statins for many years, we are reassured to learn that treatment for as long as 10 years appears to be safe.”

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ATTENTION  ALL  LYMPHOMA PATIENTS AND ALL PERSONS  —- BE INFORMED AND INFORM YOUR PHYSICIANS AND YOUR FRIENDS ABOUT THE DATA REGARDING ‘STATIN’ ANTI-CHOLESTEROL MEDICATION and THE ROLE OF MAMMOGRAPHY TO ACHIEVE AN EARLY DIAGNOSIS OF BREAST CANCER —-

GO TO THE ‘HEART' AND ‘BREAST CANCER’ PAGES OF THE LYMPHOMA FOUNDATION WEBSITE TO REVIEW THIS INFORMATION

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 THE LYMPHOMA FOUNDATION CONTINUES TO DISTRIBUTE ITS GRANT SUPPORT FOR A BROAD SPECTRUM OF BASIC AND CLINICAL RESEARCH OF THE LYMPHOMAS AND ALLIED DISEASES

UNIVERSITY OF UTAH — HEMATOLOGY DIVISION — SCHOOL OF MEDICINE—
SALT LAKE CITY, UTAH
Studies of the early stages of lymphoid development, using a novel culture model that provides a differentiation signal crucial to specification of the T lymphocyte lineage at the stage of the lymphoid progenitor.

DUKE UNIVERSITY MEDICAL CENTER — DURHAM, NORTH CAROLINA
Studies in aging regarding the relationship of hPot1 and cellular senescence, a biomarker of aging. The objective will be to determine which proteins hPot1 interacts with to keep the telomere in a closed state, and hence protect telomeres from eliciting a senescence signal.

YALE UNIVERSITY CANCER CENTER — NEW HAVEN, CONNECTICUT
Clinical management of patients with Hodgkin’s disease and the non-Hodgkin’s lymphomas

CORNELL NEW YORK-PRESBYTERIAN HOSPITALS — NEW YORK, NEW YORK
▪ Further assessment of the anti-CD22 antibody epratuzumab and other antibodies in B-cell malignancies. 
▪ Evaluation of combination regimens with rituximab and biologic agents (including IL-2, anti-CD80, revlimid and CpG immunostimulatory oligonucleotides).

MEMORIAL SLOAN KETTERING CANCER CENTER —NEW YORK, NEW YORK
▪ Targeting the ubiquitin proteasome pathway  in indolent and mantle cell lymphoma.
▪ Alpha-particle immunotherapy by targeted Alpha-emitters or Alpha-emitting isotope generators.
▪ Seeking genetic modifiers that are protective against cancer in a subset of elderly individuals.
▪ Analysis of cancer prevention data in children of families affected by hereditary cancer syndromes.
▪ Intensity-modulated radiotherapy for lymphoma involving the mediastinum.
▪ Methods to overcome platinum resistance, consolidation strategies in patients with ovarian cancer and immune directed strategies directed towards CA-125.
▪ New approaches to the treatment of multiple myeloma.
▪ Treatment of patients with low grade lymphoma and chronic lymphocytic leukemia.
▪ Analysis of Schwann cell origin: the role of tumor environment of Neurofibromas in NF1.
▪ High-dose chemotherapy and stem cell transplantation for Large Cell Lymphoma and relapsed and refractory Hodgkin’s disease.
▪ Continuing development of DNA vaccines against CD20 antigen expressed by lymphoma cells.

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SUMMARIES OF RESEARCH IN PROGRESS

Monoclonal antibody, Anti-sense BC-2 and Bortezomib therapy JOHN P. LEONARD, M.D.,  Joan and Sanford Weill Medical College of Cornell University “The assistance of the Lymphoma Foundation [will] be used to support the following efforts at our center in very meaningful ways…”  “Novel initial therapies for aggressive lymphoma.  We continue to explore ways to improve outcomes with chemotherapy, particularly combinations of CHOP chemotherapy and rituximab along with agents such as Bcl-2 antisense, idiotype vaccines, and bortezomib (Velcade).  Trials with these are ongoing, and initial phase I results of the CHOP-R-Velcade study have been submitted to ASH.  We are excited about these preliminary findings, and the support from the Lymphoma Foundation will help us to continue this trial as well as to conduct correlative studies on tumor tissue that will allow us to characterize tumors from the molecular standpoint in the patients on the study.  We also plan additional future trials with other novel agents.” “Further assessment of the anti-CD22 antibody epratuzumab and other antibodies in B-cell malignancies.  We continue to study this agent, with which we have demonstrated evidence of clinical activity and manageable toxicity.  We are evaluating patients treated with single-agent epratuzumab, repeated courses (at relapse) as well as in combination with rituximab.  Substantial numbers of these patients remain in remission years later (initial results from one study recently reported in the JCO).  Our initial efforts are encouraging in this regard, and we are currently conducting a pilot study in lymphoplasmacytic lymphoma (which highly expresses CD22).  We are also attempting to identify clinical, laboratory, and pathologic parameters, which may correlate with response and therefore allow us to better target appropriate patient populations.  Further trials in combination with CHOP-R and with rituximab are being planned.  Additionally, we are currently conducting phase I studies with anti-CD40 and anti-interleukin 6 monoclonal antibodies.”

Is there a genetic (inherited) component that protects against the development of cancer? KENNETH OFFIT, M.D., MPH, Memorial Sloan Kettering Cancer Center: As a result of the “genetic revolution” it is now possible to look for genetic variations between individuals and to learn if these are associated with disease.  The goal of one aspect of our genetic research  at the Memorial Sloan Kettering Cancer Center has been to use “whole genome” technologies to look for genetic markers that will predict resistance to disease in the elderly.  Our initial research paper soon to be published demonstrated that it is possible to do “whole genome” analysis to “rediscover” known genes.  As preliminary data we performed low density genomic scans and we have been able to resolve two significant regions: one on chromosome 12 and one on chromosome 22 that may be associated with the resistance to breast cancer in this elderly population.  As we continue our research we hope to better map these regions and to discover other genetic regions that confer cancer resistance in the elderly.

How is cell senescence (aging) controlled
CHRISTOPHER M. COUNTER, PhD, Duke University Medical School Human cells can continue to divide up to a time when they stop growing and enter a period termed senescence.  It is thought that this hard-wiring of cell lifespan may be related to the process of aging.  One of the 'clocks' that keeps track of how long a cell can continue to divide is the end of the chromosomes, or telomeres.  Telomeres shorten every round of cell division, ticking off the number of divisions a cell has left.  When telomeres reach a short length associated with senescence it is proposed that they signal the cell to stop dividing, perhaps because the telomeres become recognized as damaged DNA.  We have shown that reducing the amount of the telomere-binding protein, hPot1, achieves the same fate, namely that cells stop dividing and enter what appears to be senescence.  We are now very interested in determining how this occurs, and are currently testing what functions of hPot1 can stop this senescence.  Understanding how loss of hPot1 function induces senescence may shed light on this process, and aging.

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THE DILEMMA POSED IN CHOOSING TREATMENT OF ‘LOW GRADE’ FOLLICULAR LYMPHOMAS
The ‘indolent’ follicular lymphomas are not usually aggressive early in their course and may be ‘observed’ for many years without any  treatment as noted in a COMMENTARY by Craig H. Moskowitz, M.D. (in BLOOD February 15, 2005, Vol.105, Number 4)
“Follicular lymphoma is a chronic disease with a variable course; many patients can be monitored for years without therapy yet others need to be treated aggressively at the onset. Median survival in 2004 approaches 14 years…”  

New approaches to treatment are being studied in order to secure the much needed improved longer-term survival. 
1) Human clinical trials are underway with an ‘auto’ vaccine (a vaccine developed from the patients’ own lymph node cells) added to primary forms of chemotherapy with or without monoclonal antibody treatments. Uniquely different trials are outlined on the National Cancer Institute Clinical Trials website. There are no conclusions yet and much time will have to pass before it is determined whether or not this approach improves survival. [GO TO HOME PAGE TO REVIEW HOW TO LOG ON TO THE CLINICAL TRIALS SITE AND ACCESS THE LYMPHOMA VACCINE TRIALS]

2) Some of the latest clinical human research implies that the best current approach to treatment for Follicular Lymphoma is a combination of chemotherapy plus the monoclonal antibody rituximab in sequence… and possibly with long term intermittent maintenance treatment with rituximab

“Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group” Hindemann, et al in BLOOD December 1, 2005 Vol.106, Number 12, pp 3725-3732: 

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