Fatal Pneumonitis Related to Rituximab Based Regimen

1. Fatal Pneumonitis Related to Rituximab Based Regimen Yair Herishanu M.D. Department of Hematology

2. Case presentation • An 80 years old man, generally healthy • On October 2004 he noticed an enlarged right sub-mandibular mass. • On physical examination and CT there were both supra and infra-diaphragmatic enlarged lymph nodes.

3. Lymph node biopsy: Follicular grade 3 non-Hodgkin's lymphoma

4. Treatment • Rituximab+CHOP Cyclophosphamide Doxorubicin Vincristine Prednisone • Every 21 days

5. A mid-treatment PET-CT

6. A mid-treatment PET-CT

7. Clinical course after 3rd cycle of therapy • The patient complained of mild effort dyspnea • On physical examination - bilateral basilar crepitations were evident. • Pulse oximetry was normal • Chest X-ray was normal

8. Treatment was continued as scheduled • 2 days after starting the 5th cycle, he complained of dry cough and worsening dyspnea. • On examination he was afebrile, tachypneic, hypoxemic and had bilateral basal inspiratory crepitiations

11. Bronchoscopy • Was grossly normal • Staining of the BAL fluid for: Bacteria Acid-fast bacilli PCP • Cultures for cytomegalovirus Were all negative

12. Trans-bronchial Biopsy

13. Treatment • IV methylprednisolone (1mg/Kg) • Broad spectrum antibiotics • The patient developed rapidly progressive respiratory insufficiency requiring mechanical ventilation • Died 10 days after admission.

14. Rituximab (Mabthera)

15. Rituximab: A Mouse/Human Chimeric MoAb Murine variable regions bind specifically to CD20 on B cells Human kappa constant region Human IgG1 Chimeric IgG1 Rybak et al. Proc Natl Acad Sci USA. 1992;89:3165.

16. Rituximab: Mechanism of Action

17. Complement-mediated cell lysis C1r CD20 Fc region C1 C1s C1q Rituximab B cell H20/ Ions Lysis Pores (8-18 C9s)

18. Antibody-dependent cellular cytotoxicity(ADCC) Granules CD20 Fc receptor (FcγRIII) Fc region NK Cell Rituximab B cell Granules release perforins and granzymes; cytokines secreted (eg, IFN- ) Lysis H20, ions, granzymes Pores (perforin)

19. Apoptosis CD20 Rituximab B cell

20. Rituximab - Clinical Data

21. Indolent Non-Hodgkin’s Lymphoma

22. Monotherapy: Relapsed low grade / follicular lymphoma • ORR-50%, median time to progression -12 months. • 62% bcl-2 PCR-negative in PB and/or BM Re-treatment • ORR-40% and median time to progression-18 months

23. Monotherapy: Previously untreated follicular lymphoma • ORR-73%, CR-20% • Median time to progression-18 months • 30% bcl-2 PCR-negative in PB and BM • Molecular response is associated with a lower rate of disease progression

24. Rituximab Pre-treatment Sensitizes Cells to Cytotoxic Agents % Cytotoxicity + rituximab – rituximab P Value Cytotoxic Agent DTX 50 36 0.0001 Ricin 40 5 0.004 TNF alpha 43 7 0.0015 ADR 53 28 0.0027 CDDP 27 4 0.0456 VP16 8.5 0.6 0.0263 Demidem et al. Cancer Biother Radiopharm. 1997;12:177.

25. CVP ± Rituximab in previously untreated follicular NHL: response rates Marcus R, et al. Blood 2003;102:28a (Abstract 87)

26. CVP ± Rituximab in previously untreated follicular NHL Duration of response Time to next antilymphoma treatment 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 MabThera + CVP: median not reached MabThera + CVP: median not reached Probability Probability CVP: median 12 months CVP: median 10 months p<0.0001 p<0.0001 0 3 6 9 12 15 18 21 24 27 30 33 0 3 6 9 12 15 18 21 24 27 30 33 Months Months Marcus R, et al. Blood 2003;102:28a (Abstract 87)

27. Aggressive Non-Hodgkin’s Lymphoma

28. CHOP vs 2nd and 3rdgeneration regimens in aggressive NHL Overall Survival Fisher et al. NEJM 328 (1993)

29. R±CHOP inelderly patients with DLCL 399 patients aged 60–80 years Stage II–IV ECOG 3 excluded R CHOP21 x 8 R-CHOP21 x 8 Coiffier et al 2002. N Engl J Med;346:235–42

30. Results of the GELA study *Unconfirmed CR Coiffier et al 2002. N Engl J Med;346:235–42

31. GELA-LNH 98.5: 5-year PFS 100 80 60 40 20 0 R-CHOP 54% Progression-free survival (%) CHOP 30% p<0.00001 0 1 2 3 4 5 6 7 Years Feugier P, et al. J Clin Oncol 2005;23:Epub

32. GELA-LNH 98.5: 5-year OS 100 80 60 40 20 0 R-CHOP 58% Overall survival (%) CHOP 45% p<0.007 0 1 2 3 4 5 6 7 Years Feugier P, et al. J Clin Oncol 2005;23:Epub

33. MInT – Design 6 x CHOP-like + 30–40 Gy (Bulk, E) CD20+ DLBCL 18–60 years IPI 0,1 Stages II–IV, I with bulk Randomisation 6 x MabThera + CHOP-like + 30–40 Gy (Bulk, E) Pfreundshuh et al. 2004. Blood;104(Suppl. 1):Abst. 157.

34. Early results of MInT trial R-Chemo Chemo CR 81% 67% TTF @ 2 yrs 80% 61% OS @ 2 yrs 95% 86% (Benefit seen in IPI 0 and 1) Pfreundshuh et al. 2004. Blood;104(Suppl. 1):Abst. 157.

35. MInT full analysis - TTF Median observation time: 22 months 1.0 79.9% R-CHEMO 0.9 0.8 0.7 0.6 60.8% CHEMO Probability 0.5 0.4 0.3 0.2 p<0.0001 0.1 0.0 0 5 10 15 20 25 30 35 40 45 50 Months Pfreundshuh et al. 2004. Blood;104(Suppl. 1):Abst. 157.

36. MInT full analysis - OS Median observation time: 23 months 94.6% R-CHEMO 1.0 0.9 0.8 0.7 86.2% CHEMO 0.6 Probability 0.5 0.4 0.3 0.2 p=0.0002 0.1 0.0 0 5 10 15 20 25 30 35 40 45 50 Months Pfreundshuh et al. 2004. Blood;104(Suppl. 1):Abst. 157.

37. Rituximab in NHL • Maintenance • BMT • In vivo purging agent • Combination with conditioning therapy • Post-transplant adjuvant immunotherapy • GVHD

38. Rituximab in other lymphoproliferative disorders • Post-transplant lymphoproliferative disorder (PTLD) • Waldenström’s macroglobulinemia • Chronic lymphocytic leukemia • B-cell (CD20+) acute lymphoblastic leukemia

39. Rituximab in autoimmune disorders • Warm and cold autoimmune hemolytic anemia (AIHA) • Idiopathic thrombocytopenic purpura (ITP) • Trombotic trombocytopenic purpura (TTP) • Acquired FVIII inhibitors and alloimmunization in hemophilia A+B

40. Rituximab in autoimmune disorders • Rheumatoid arthritis (RA) • Lupus (SLE) • Mixed cryoglobulinemia-type II • IgM polyneuropathies

41. Rituximab - Adverse Effects

42. Generally well tolerated • Infusion-related reactions: usually during the first infusion, fevers, chills, hypotension and dyspnea • Anaphylactic and other hypersensitivity reactions • Cytokine-release syndrome or tumor lysis syndrome associated with high number of circulating malignant cells (>25,000)

43. Rare side effects • Delayed neutropenia • HBV reactivation and fulminant hepatitis • Serum sickness • Interstitial pneumonitis

44. Differential Diagnosis • Infection • Drug induced • Rituximab • Cyclophosphamide • GCSF • Lymphoma

45. Rituximab-infectious complications

46. 100 10 0 Median absolute CD19 count in peripheral blood (/µl) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Base- Pre- Pre- 3 months 6 months 9 months 12 months line dose dose post TX post TX post TX post TX #2 #4 Rituximab Rapidly Depletes B-cells: n=166 McLaughlin et al. J Clin Oncol. 1998;16:2825.

47. Serum Ig Concentrations in Patients Receiving Rituximab 1200 (N=235) 1000 800 IgG (mg/dL) 600 400 200 1 2 3 4 5 6 7 8 9 10 11 12 13 Months 220 180 IgA (mg/dL) 140 100 60 1 2 3 4 5 6 7 8 9 10 11 12 13 Months 700 600 500 IgM (mg/dL) 400 300 200 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Months

48. Infections following rituximab • 30.3 % of 356 treated patients suffered from infectious events • Bacterial infections - 18.8% • Viral infections - 10.4% • Fungal infections - 1.4% • Severe infectious events (grade 3 or 4) occurred in 3.9 % of patients

49. Despite B-cell depletion, the incidence of infection did not appear to be greater than observed in chemotherapy trials • Majority were typical of those common in normal hosts

50. Lung Toxicity Related to Rituximab