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Fatal Pneumonitis Related to Rituximab Based Regimen

Fatal Pneumonitis Related to Rituximab Based Regimen. Yair Herishanu M.D. Department of Hematology. Case presentation. An 80 years old man, generally healthy On October 2004 he noticed an enlarged right sub-mandibular mass.

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Fatal Pneumonitis Related to Rituximab Based Regimen

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  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

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

  10. Trans-bronchial Biopsy

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

  12. Rituximab (Mabthera)

  13. 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.

  14. Rituximab: Mechanism of Action

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

  16. 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)

  17. Apoptosis CD20 Rituximab B cell

  18. Rituximab - Clinical Data

  19. Indolent Non-Hodgkin’s Lymphoma

  20. 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

  21. 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

  22. 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.

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

  24. 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)

  25. Aggressive Non-Hodgkin’s Lymphoma

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

  27. 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

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

  29. 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

  30. 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

  31. 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.

  32. 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.

  33. 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.

  34. 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.

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

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

  37. 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

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

  39. Rituximab - Adverse Effects

  40. 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)

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

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

  43. Rituximab-infectious complications

  44. 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.

  45. 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

  46. 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

  47. 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

  48. Lung Toxicity Related to Rituximab

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