Departmental Presentation

1. RECENT ADVANCES IN TREATMENT OF LYMPHOMA Presenter: Tanoy Bose Post graduate student Moderator: Dr. B.C.Kalita Assistant Professor The Department of Medicine Assam Medical College, Dibrugarh The 29th of October 2008

2. WHAT ARE LYMPHOMAS? They are cancers arising from the cells of the immune system at different stages of differentiation, resulting in a wide range of morphologic, immunologic, and clinical findings Some almost always present as leukemia (i.e. primary involvement of bone marrow & blood), while others almost always present as lymphomas (i.e. solid tumors of the immune system) Clinical pattern can change over course of illness: more often in patients suffering from lymphoma and then develop the manifestations of leukemia over the course of the illness.

3. BACKGROUND: Represent 4% to 5% of all new cancer cases. The fifth leading cause of cancer death in the United States and the second fastest growing cancer in terms of mortality. The highest reported incidence rates are in the United States, and also Europe and Australia; the lowest rates have generally been reported in Asia Seow A, Lee J, Sng I, et al. Non-Hodgkin's lymphoma in an Asian population: 1968–1992 time trends and ethnic differences in Singapore. Cancer 1996;77(9):1899.

4. THE INDIAN SCENARIO

5. Distribution of various subtypes of non-Hodgkin's lymphoma in India: A study of 2773 lymphomas using R.E.A.L. and WHO Classifications.Annals of Oncology. 11 Supplement 1:S63-S67, 2000.Naresh, K. N.; Srinivas, V.; Soman, C. S.

6. The distribution of NHL subtypes in India shows important differences with those from the rest of the world. Follicular lymphoma and mantle-cell lymphoma are less common in India compared to Europe and the USA. Peripheral T-cell lymphomas and T/NK-cell lymphomas of nasal and nasal types, which are common in many other Asian countries, are also less prevalent. T-cell lymphoblastic lymphoma and anaplastic large T/null cell lymphoma are more prevalent in India.

7. Clinical characteristics

8. The Lymphoma staging:HL

9. RECENT ADVANCES IN TREATMENT OF NON HODGKIN’S LYMPHOMA

10. The therapeutic options till date & the Problem Statement Therapeutic options till date included systemic chemotherapy either single drug or combination, radiation and bone marrow transplantation. The most common NHL , DLBCL responds well to combination chemotherapeutic regimen like CHOP or CVP. The problem in treating lymphomas are Indolent lymphoma Poor response to first line therapy Lyphomas which are refractory to standard therapeutic regimen.

11. Multiple agents are now under clinical investigation as a therapeutic alternative for these patients. One of these, the immunomodulatory drug lenalidomide, has shown promising activity in both phase I and II clinical trials. Other agents currently under development for NHL include the alkylating agent bendamustine, the proteasome inhibitor bortezomib, and the radioimmunotherapeutic drug 90Y-ibritumomab tiuxetan. The results of several of these studies are summarized in the following abstract reviews.

15. Three factors: Tumor burden, Time since last Rituximab dose, and Absolute lymphocyte count were predictive of patient response to lenalidomidemonotherapy.

16. Low disease burden, estimated by tumor size, was associated with a superior benefit from lenalidomide treatment

17. Significantly, patients with favorable values for both disease burden (<50 cm2 tumor) and time since last rituximab dose (≥230 days) had a statistically higher objective response rate compared to patients with unfavorable values for both

19. The duration of response ranged from 2+ to 8+ months.

20. Importantly, in the 2 patients with previously documented refractory disease, 1 patient had a PR that lasted 6 months and the second patient exhibited SD

23. The therapeutic options till date & the Problem Statement The use of extended field radiotherapy and/or alkylating agent-based chemotherapy, e.g. MOPP (mustine, vincristineprocarbazine, prednisone), has resulted in high long- term disease free – and overall – survival rates for patients with Hodgkin’s lymphoma. However, it is now recognised that each of these treatments is associated with significant long-term toxicity – of major importance in a disease which mainly affects young adults. The use of radiotherapy, particularly to the mediastinum, produces an increased risk of second malignancies such as lung and breast cancer, pulmonary fibrosis, and coronary heart disease. The use of alkylating agent-based chemotherapy increases the risks of secondary leukaemia, non-Hodgkin lymphoma, infertility, and premature ovarian failure. A major emphasis of recent trials in Hodgkin’s lymphoma has therefore been to reduce radiation fields, and to introduce alternative chemotherapy regimens containing fewer alkylating agents

27. Therapy for NHL has significantly evolved over the last decade. While systemic treatments consisted primarily of cytotoxic chemotherapy for many years, the development of the anti-CD20 antibody rituximab has ushered in the era of targeted therapy. Since about 90% of NHL cases are of B-cell origin and therefore express the CD20 antigen, use of this agent is applicable across a broad array of lymphoma subtypes

28. While targeting CD20 with unlabeled antibodies does show activity, it is clear that radiolabeled antibodies offer the potential for augmented activity through targeted radiation. Two such agents, 90Y ibritumomabtiuxetanand 131 I-tositumomab, are approved for use in patients with recurrent indolent lymphoma An additional strategy beyond single-agent use is to employ radiolabeled antibodies after chemotherapy in an attempt to extend remission and enhance survival

29. The approach presented at ASH included CHOP-R treatment followed by 90Y ibritumomabtiuxetan in initial treatment of MCL. Therapy was well tolerated and response rates were high, but additional follow-up will be needed to determine whether long-term outcomes are enhanced by the consolidative therapy

30. Recently, bortezomib was FDA approved for the treatment of recurrent MCL and recent data demonstrated that remission duration can be substantial in a subset of patients. Ongoing studies, including those that combine bortezomib with rituximab in recurrent indolent lymphoma and with CHOP-R in upfront DLBCL and MCL, as well as other trials evaluating bortezomib maintenance, seek to define the best setting for its use

31. Recent trials have shown that lenalidomide is well tolerated as therapy in both indolent and aggressive lymphoma, with overall response rates as high as 53% in the latter subtype. Notable activity has been noted in patients with recurrent DLBCL, MCL and T-cell histologies. One can anticipate an extensive evaluation of lenalidomide in lymphoid malignancies in the near future, and it appears that this agent may have a potentially significant impact in these settings

32. Various data suggest that bendamustineoffers a potentially useful new option for patients with disease that has become resistant to other cytotoxics and rituximab This study warrants close attention, and if efficacy data hold up in the longer term, one can envision that this may be a very useful option for the initial treatment of indolent lymphoma, in particular with respect to the favorable safety profile and allowance to defer anthracycline treatment (and its associated toxicity).

33. CONCLUSION

34. While we continue to explore treatment options that appear to have targeted or specific mechanisms of action, it is clear that some agents with generalized effects will continue to have important therapeutic roles. Considerable challenges remain in determining the optimal setting for the use of novel agents, including their combination and sequence with standard therapies. Accrual to ongoing and future clinical trials should remain a priority so that we may rapidly sort out the best use of these new strategies

35. THANK YOU