Lenalidomide has shown promising activity against various types of lymphoma in clinical trials. It achieved objective response rates of 44% in relapsed/refractory peripheral T-cell lymphoma and 53% in mantle cell lymphoma. Bortezomib also achieved durable responses as a single agent in relapsed/refractory mantle cell lymphoma. The addition of rituximab to standard chemotherapy such as CHOP has improved outcomes in diseases like DLBCL and increased 5-year survival rates. Combining epratuzumab with rituximab has also shown high response rates in recurrent indolent lymphomas. Radioimmunotherapy with 90Y-ibritumomab tiuxetan following R-

1. RECENT ADVANCES IN TREATMENT OF LYMPHOMAPresenter: Tanoy BosePost graduate studentModerator:Dr. B.C.KalitaAssistant ProfessorThe Department of MedicineAssam Medical College, DibrugarhThe 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 findingsSome 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 AsiaSeow 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 StatementTherapeutic 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 lymphomaPoor response to first line therapyLyphomas 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.

12. Rituximab + Combination chemotherapy : in DLBCL35% of the patients with a low IPI score of 0-1, the 5 year survival is 70% with CHOP and 85% with Rituximab,while for 20% of patients with high IPI score of 4-5, the 5 year survival is increased upto 35% from 20% with addition of Rituximab.When compared with standard CHOP alone, the addition of Rituximab to standard CHOP regimen reduces the risk of treatment failure in patients with diffuse large B-cell NHL, and doesn't increase the occurrence of chemotherapy-related adverse events.May also be added to CVP regimen.Currently R-CHOP is the GOLD standard treatment in advanced stage DLBCL.Ai Zheng. 2005 Dec;24(12):1421-6. Links[Comparison between R-CHOP regimen and CHOP regimen in treating naive diffuse large B-cell lymphoma in China--a multi-center randomized trail]

13. www.clinicaladvances.comFebruary 2008 Volume 6, Issue 2, Supplement 4Recent Advances in the Treatment of LymphomaA Review of Selected PresentationsFrom the 49th American Society of Hematology Annual Meeting and ExpositionDecember 8–11, 2007Epratuzumab Plus Rituximab: in Recurrent Indolent Non-Hodgkin’s LymphomaEpratuzumab is a novel monoclonal antibody directed against CD22, a molecule commonly expressed on the surface of NHL cells Phase I and II clinical studies in NHL patients have shown that epratuzumab is active both as a single agent and in combination with rituximabThe results of a pilot study evaluating the addition of epratuzumab and rituximab to CHOP therapy were recently published, showing an overall response (OR) rate of 87%Numerous studies have shown effective durable response to Epratuzumab +/- Rituximab in pretreated aggressive and refractory or recurrent NHL which includes DLBCL, FL & SLL suggesting it’s activity against different histologies.Preteatment with Rituximab did not affect the outcomeFuture studies to evaluate this combination as first-line therapy for indolent NHL are both ongoing and planned. Leonard JP, Schuster SJ, Emmanouilides C, et al. Presentation at the 49th American Society of Hematology Annual Meeting and Exposition; Atlanta, GA. December 8-11, 2007:

14. Monoclonal Antibody Therapy and Combination Chemotherapy in Treating Patients With Stage II, Stage III, or Stage IV Diffuse Large B-Cell Lymphoma. www.clinicaltrials.gov Lenalidomide: Relapsed/Refractory Aggressive Non-Hodgkin’s Lymphoma The NHL-002 study: a phase II trial designed to evaluate the safety and efficacy of single-agent lenalidomide in patients with relapsed or refractory aggressive NHL

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

18. Czuczman M, Reeder CB, Polikoff J, et alPresentation at the 49th American Society of Hematology Annual Meeting and Exposition; Atlanta, GA. December 8-11, 2007Lenalidomide Oral Therapy for Peripheral T-Cell LymphomaAll patients (N=10) had either relapsed or refractory disease (n=8) or were untreated because of a comorbid illness that prevented standard chemotherapyThe OR rate to lenalidomidemonotherapy in this first set of PTCL patients was 44%. All of these patients had a PR; an additional patient exhibited SD.

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

21. Reiman T, Finch D, Chua N, et al. Presentation at the 49th American Society of Hematology Annual Meeting and Exposition; Atlanta, GA. December 8-11, 2007:Bortezomib in Patients With Relapsed or Refractory Mantle Cell Lymphoma: The PINNACLE trialThe proteasome inhibitor bortezomibhas shown promise as a novel therapy for NHL, and it is currently approved for patients with relapsed or refractory MCLIn the initial evaluation, 33% of relapsed or refractory MCL patients responded to bortezomibmonotherapy, including a CR in 8% of patientsUpdated results of the PINNACLE trial confirmed the efficacy of single-agent bortezomib for patients with relapsed or refractory MCL. A predictable and manageable safety profile, combined with durable responses, has led to the continued approval of bortezomib for these patients. Future studies of bortezomib-based regimens are underway to study its activity as a first-line therapy Goy A, Bernstein S, Kahl B, et al. Durable responses with bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter PINNACLE studyLenalidomide in Relapsed/Refractory Aggressive Non-Hodgkin’s Lymphoma with Prior Stem Cell TransplantThe NHL-002 study is an ongoing, multicenter, single-arm, open-label phase II trial designed to assess the safety and efficacy of lenalidomidemonotherapy in patients with relapsed or refractory aggressive NHLIn the first report, presented by Tuscano and colleagues The objective response rate in the MCL subset was 53%.The second report, by Vose and colleagues, sought to determine the efficacy of lenalidomidemonotherapy following stem cell transplant using a subset of NHL patients who had received a stem cell transplant prior to initiating the study treatment.The objective response rate in this subset of patients was 50%Importantly, all of these responses occurred in patients with favorable prognostic factors, including a low tumor burden (<50 cm2) and having 230 or more days since the time of their last rituximab doseVose JM, Tuscano JM, Justice G, et al. Presentation at the 49th American Society of Hematology Annual Meeting and Exposition; Atlanta, GA. December 8-11, 2007R-CHOP Followed by 90Y-Ibritumomab Tiuxetan in Untreated Mantle Cell Lymphoma90Y-ibritumomab tiuxetan is a novel radioimmunotherapeutic comprised of the anti-CD20 monoclonal antibody ibritumomab connected to the radioactive isotope yttrium-90 with the linker tiuxetanSeveral phase I and II clinical trials have established the efficacy of 90Y-ibritumomab tiuxetan in NHL patients, with OR rates of 74–83% 90Y-ibritumomab tiuxetan following R-CHOP had a relatively safe toxicity profile. Although 55% of patients experienced grade 3 or 4 neutropenia and 45% had grade 3 or 4 thrombocytopenia, all but 1 patient with thrombocytopenia recovered by 12 weeks following treatment. The study authors suggested that because the addition of 90Y-ibritumomab tiuxetan to R-CHOP produces prolonged FFS over that expected with R-CHOP alone, this is a potentially efficacious strategy for MCL patients with an otherwise poor prognosis Smith MR, Zhang L, Gordon LI, et al. Eastern Cooperative Oncology Group study E1499. Presentation at the 49th American Society of Hematology Annual Meeting and Exposition; Atlanta, GA. December 8-11, 2007Lenalidomide in Combination With Rituximab: in Relapsed/Refractory Mantle Cell LymphomaBecause both lenalidomide and rituximab have activity in MCL, Wang and colleagues examined the efficacy of combining the two agents in a phase I/II clinical trial. The phase I portion of the study evaluated the safety of this combination, and further determined the maximal tolerated dose (MTD) of lenalidomide when combined with rituximab. In the initial phase I portion of the trial, an OR rate of 67% was achieved in the 6 patients who were administered the MTD .This early report reveals promising efficacy of the combination of lenalidomide with rituximab, and a further analysis of the ongoing phase II portion of this study will be used to confirm these results in a larger population of MCL patients Wang M, Fayad L, Hagemeister F, et al. Presentation at the 49th American Society of Hematology Annual Meeting and Exposition; Atlanta, GA. December 8-11, 2007Bendamustine Plus Rituximab :in the First-line Treatment of Patients With Indolent and Mantle Cell LymphomasBendamustine is an alkylating agent with established activity in several malignancies. Single-agent bendamustine produced OR rates of 73% and 82.5% in two clinical studies of relapsed or refractory NHL patients Between Benzamustine +Rituximab Vs R-CHOP,both treatment combinations had similar activity, with a 93% OR rate in each treatment group.Bendamustine combination proved to be less toxic than the CHOP combination, with lower incidences of alopecia (0% vs 94%, respectively), grade 3 or 4 leucocytopenia (16% vs 41%), and infectious complications (23% vs 41%). Taken together, these trials show that bendamustine is a safe and effective therapy for NHL patients. Future studies are planned to determine the efficacy of bendamustine as long-term maintenance therapy for patients with FL and other NHL malignancies

22. Rummel MJ, von Gruenhagen U, Niederle N, et al. Presentation at the 49th American Society of Hematology Annual Meeting and Exposition; Atlanta, GA. December 8-11, 2007Salvage induction therapy for Relapsed NHLAutologous stem cell transplantation (ASCT) is the most effective treatment for patients with NHL who have failed primary therapy. However, many patients are not considered candidates due to age or significant co-morbid conditions. The usual regimens for such re-induction attempts prior to ASCT include DHAP (dexamethasone, cytarabine, and cisplatin), ESHAP (etoposide, solumedrol, cytarabine, cisplatin), and RICE (rituximab, ifosfamide, carboplatin, etoposide). The addition of rituximab to these regimens appears to improve outcomes ASCO 2008: Advances in Treatment of Lymphoma and Chronic Lymphocytic LeukemiaSalvage induction therapy for Relapsed NHL: continued …At ASCO 2008 researchers from M.D. Anderson Cancer Center presented data on 37 patients with relapsed aggressive NHL treated with gemcitabine, rituximab, oxaliplatin (GROC) and pegfilgrastimgiven every 14 daysIt was concluded that GROC was as effective as the other commonly used salvage therapies with less toxicities. ASCO 2008: Advances in Treatment of Lymphoma and Chronic Lymphocytic LeukemiaAdvances in management of Cutaneous T cell LymphomaDenileukindiftitoxis a fusion protein targeting the IL-2 receptor in malignant cells. Denileukindiftitox has been approved by the FDA since 1999 for the treatment of persistent and recurring CTCL. Denileukindiftitox had significant activity in patients with CTCL regardless of CD25 statusVorinostat is a histonedeacetylase (HDAC) inhibitor, which was approved by the FDA in 2006 for treatment of CTCL. The HDAC inhibitors act by modulating both histone and non–histone targets. A number of non–histone proteins such as heat shock protein 90, HIF-1 alpha, and tubulin are acetylated by HDAC inhibitors. Authors suggest that vorinostat can be administered safely for prolonged periods ASCO 2008: Advances in Treatment of Lymphoma and Chronic Lymphocytic LeukemiaReduced-Intensity Allogeneic Stem Cell Transplants (SCT) for Relapsed Follicular LymphomaPatients with low-grade lymphoma, including CLL and follicular lymphoma, have many palliative treatment options, but ultimately virtually all patients become refractory to treatmentThe consensus of data suggests that survival is related to complete eradication of molecular evidence of diseaseResearchers from Italy have previously reported that allogeneic SCT using a reduced intensity regimen of thiotepa, fludarabine, and cyclophosphamide results in high rate of complete clinical and molecular remissions in patients with relapsed or refractory chronic lymphocytic leukemia and follicular lymphoma. In this study the two-year disease-free survival was 100% for patients in molecular remission and 57% for those not in molecular remission. ASCO 2008: Advances in Treatment of Lymphoma and Chronic Lymphocytic LeukemiaBortezomib for the Treatment of Refractory Gastric MALT LymphomasAt ASCO 2008 researchers from Italy presented the results of treatment of patients with refractory gastric marginal zone MALT with bortezomib.After three cycles of therapy, 87.5% of patients showed OR. Two patients with partial remissions converted to complete remissions with further therapy. Responses appeared to be durable.Treatment of Extranodal Malt Lymphoma: At ASCO 2008 researchers presented the results of treating 22 newly diagnosed patients with extranodal MALT lymphoma with the combination of rituximab and fludarabine. Seventeen patients in this trial were evaluable for response, and 94% achieved a CR and the remainder a PR. ASCO 2008: Advances in Treatment of Lymphoma and Chronic Lymphocytic LeukemiaRECENT ADVANCES IN TREATMENT OFHODGKIN’S LYMPHOMA

23. The therapeutic options till date & the Problem StatementThe 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

24. Treatment of early stage Hodgkin's lymphomaCombined modality treatment with short duration chemotherapy followed by involved field radiotherapy is the approach taken for most patients.Evidence from clinical trials shows that the use of brief duration combination chemotherapy such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), with limited (involved field) radiotherapy produces good long-term overall Hodgkin's Lymphoma survival rates of 70% and 90%, with less potential for long-term toxicity than the previous approach using extended field radiotherapy alone.The emphasis for current clinical trials is to determine whether therapy may be reduced further without compromising Hodgkin's lymphoma cure rates, perhaps using newer imaging techniques such as Positron-Emission Tomography (PET) scanning to determine responses at an early stageSevcikova, E.L., et al., Neoplasma, 2000. 47(4): p. 253-6.

25. Bjorkholm, M., et al., Ann Oncol, 1995Treatment of advanced stage Hodgkin's lymphomaABVD is now recognised as the standard regimen for advanced Hodgkin’s lymphoma, producing five-year failure free survival rates of 65-80 %, depending on the selection of patients. More dose intensive regimens such as BEACOPP used in conjunction with involved field radiotherapy, have produced five-year overall Hodgkin's Lymphoma survival rates of up to 90%, albeit with a high risk of permanent infertility and some risk of secondary acute leukaemia . These regimens are now being compared with standard therapy in randomized clinical trials.High dose chemotherapy with autologous stem cell transplantation : relapsed or refractory disease. Recent advances : new antibody-based approaches being developed, including the use of immunotoxins. These are mostly directed at the CD30 antigen, expressed on RS cells. Clinical trials are in progress to test the efficacy of such antibodies against recurrent disease.Sweetenham JW, Taghipour G, Milligan D, et al. Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 1997

26. Borchmann P, Treml JF, Hansen H, et al.. Blood 2003The Lymphoma VaccineLymphomas express a tumor-specific antigen which can be targeted by cancer vaccinationThe ability of a new idiotype protein vaccine formulation to eradicate residual t(14;18)+ lymphoma cells in 20 patients in a homogeneous, chemotherapy-induced first clinical complete remission was evaluated.8 of 11 patients converted to lacking cells in their blood from the malignant clone detectable by PCR after vaccination and sustained their molecular remissionsThe demonstration of molecular remissions, analysis of cytotoxic T lymphocytes against autologous tumor targets, and addition of granulocyte-monocyte colony-stimulating factor to the vaccine formulation provide principles relevant to the design of future clinical trials of other cancer vaccines administered in a minimal residual disease setting Nat Med. 1999 Oct;5(10):1171-7.SUMMARY

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 ibritumomabtiuxetanand131 I-tositumomab, are approved for use in patients with recurrent indolent lymphomaAn 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 rituximabThis 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