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Journal of Clinical Oncology, Vol 23, No 1 (January 1), 2005: pp. 247-248 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.282
Persistent Panhypogammaglobulinemia After CHOP-Rituximab for HIV-Related LymphomaUniversity of California, Los Angeles Men's Health Program, Los Angeles, CA, for the AIDS Malignancy Consortium 010 Team To the Editor: Treatment with rituximab and combination chemotherapy for CD20+ lymphomas has become commonplace.1 Monoclonal antibody therapy that targets CD20 depletes malignant cells bearing this antigen, along with CD20 positive B cells.2 These cells are important in antibody production. We are reporting a case of severe persistent panhypogammaglobulinemia after treatment of a CD20+ HIV-related diffuse large cell lymphoma with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and rituximab. The patient is a 48-year-old male with stable, well-controlled HIV infection on multiagent antiretroviral therapy. At initiation of therapy, his CD4 cell number was 237/µL (normal range, 355 to 1,426/µL), HIV RNA was not detected, circulating CD19+ B cells were 20% (normal range, 7% to 25%), and serum immunoglobulins (Igs) were IgG, 747 mg/dL; IgM, 46 mg/dL; and IgA, 50 mg/dL. Only the serum IgA level was low (normal range, 81 to 23 mg/dL). Treatment consisted of rituximab (375 mg/m2) given 2 days before each cycle of standard dose CHOP chemotherapy for two cycles after a complete response. Two additional doses of rituximab were given after completion of the four cycles of chemotherapy. As shown (Fig 1), treatment with rituximab and CHOP chemotherapy resulted in the prompt disappearance of CD19+ B cells as well as circulating Igs that persisted for over 2 years. IgM, IgG, and IgA levels have been undetectable or below the lower limit of normal for over 3 years. One year after combined chemotherapy and immunotherapy, it was decided to supplement his immune system with Igs at a dose of 1 g/kg every 4 to 6 weeks (arrows in Fig 1). Despite supplementation, the levels of Ig only briefly increased above the lower limits of normal and promptly fell after supplementation was discontinued. CD19+ cells did not reappear in the peripheral circulation in normal numbers until after 2.5 years after the discontinuation of all therapy.
CD20+ B cells are needed for Ig homeostasis. It is not surprising that Ig levels fall to some extent after depletion of the circulating compartment with monoclonal antibody therapy.3 What is unusual is the severity of B-cell depletion and the failure to recover antibody production after such a protracted period of time. Low Ig levels have been reported after rituximab therapy in other settings, but this is a rare finding4-9 and usually lasts only 6 to 9 months after therapy. Whether the profound nature of the depletion experienced in this patient is idiosyncratic, a reflection of the unusual dosing schedule1 or an underlying disorder of Ig production in HIV infection remains to be seen. However, it is important to note that neutropenic sepsis and death were seen with a marked increase in other patients in this AIDS Malignancy Consortium (AMC) 010 trial.10 In particular, grade 3 or 4 neutropenia was reported in 37 (39%) of 95 patients treated with CHOP and rituximab versus only eight (17%) of 47 (P = .012). Documented infection in the setting of neutropenia occurred in 10 patients in the combined therapy group but not in the CHOP alone arm. Death due to infection occurred in seven patients treated with combined therapy but only once in patients treated with CHOP alone.10 Neutropenia alone may be the culprit,11 but if hypogammaglobulinemia were to simultaneously occur it would increase the risk for sepsis and death. Ig levels were measured on the AMC 010 trial, but only after most of the patients had experienced their clinical events, so their analysis will likely be of little value. However, there is an ongoing AMC trial 034 where sequential versus concurrent rituximab is evaluated in the context of EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) for AIDS-related lymphomas. It will be interesting to examine the Ig levels of patients who developed infectious complications and compare them to those who received similar therapy but did not develop infectious complications. This analysis may assist in better understanding the serious and unexpected toxicity of rituximab in this patient population. Until such an analysis is completed, oncologists treating HIV-related lymphomas with rituximab should be aware of this potential complication. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES 1. Coiffier B: Monoclonal antibodies in the management of newly diagnosed, aggressive B-cell lymphoma. Curr Hematol Rep 2:23-29, 2003[Medline]
2. Maloney DG, Grillo-Lopez AJ, White CA, et al: IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood 90:2188-2195, 1997 3. McLaughlin P, Grillo-Lopez A, Link B, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825-2833, 1998[Abstract]
4. Czuczman M, Grillo-Lopez A, White C, et al: Treatment of patients with low-grade B-cell lymphoma with combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 17:268-276, 1999 5. Bermudez A, Marco F, Conde E, et al: Fatal visceral varicella-zoster infection following rituximab and chemotherapy treatment in a patient with follicular lymphoma. Haematologica 85:894-895, 2000[Medline] 6. Quartier P, Brethon B, Philippet P, et al: Treatment of childhood autoimmune haemolytic anaemia with rituximab. Lancet 358:1511-1513, 2001[CrossRef][Medline] 7. Verschuuren EA, Stevens SJ, van Imhoff GW, et al: Treatment of posttransplant lymphoproliferative disease with rituximab: The remission, the relapse, and the complication. Transplantation 73:100-104, 2002[CrossRef][Medline] 8. Castagnola E, Dallorso S, Faraci M, et al: Long-lasting hypogammaglobulinemia following rituximab administration for Epstein-Barr virus-related post-transplant lymphoproliferative disease preemptive therapy. J Hematother Stem Cell Res 12:9-10, 2003[CrossRef][Medline] 9. Shimoni A, Hardan I, Avigdor A, et al: Rituximab reduces relapse risk after allogeneic and autologous stem cell transplantation in patients with high-risk aggressive non-Hodgkin's lymphoma. Br J Haematol 122:457-464, 2003[CrossRef][Medline] 10. Kaplan LD, Scadden DT, for the AIDS Malignancies Consortium: No benefit from rituximab in a randomized phase III trial of CHOP with or without rituximab for patients with HIV-associated non-Hodgkin's lymphoma: AIDS malignancies consortium study 010. Proc Am Soc Clin Oncol 22:564, 2003 (abstr 2268)
11. Voog E, Morschhauser F, Solal-Celigny P: Neutropenia in patients treated with rituximab. N Engl J Med 348:2691-2694, 2003
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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