Blood, 15 May 2003, Vol. 101, No. 10, pp. 4225-4225
CORRESPONDENCE
To the editor:
Agranulocytosis unresponsive to growth factors following
rituximab in vivo purging
Rituximab, a chimeric monoclonal anti-CD20 antibody, has been
successfully used to in vivo purge CD20+ tumor cells during
mobilization for high-dose therapy with autologous stem cell
transplantation.1-6 Posttransplantation neutropenia has
been observed in as many as 25% of patients, although, to date, all
reported patients have responded to growth-factor administration. In
this report, we describe a case of agranulocytosis refractory to
high-dose stem cell growth factors and ultimately responsive to
cyclosporine following autologous stem cell transplantation for
non-Hodgkin lymphoma (NHL) purged in vivo with rituximab.
A 46-year-old man who presented with stage IV
lymphocyte-predominant Hodgkin disease was treated with
standard chemotherapy and achieved a brief partial response. Review of
the pathology resulted in modification of the diagnosis to diffuse
large B-cell lymphoma, T cell and histiocyte rich. Standard CHOP
chemotherapy resulted in another brief partial response. At the time of
disease progression, in preparation for an autologous stem cell
transplantation, the patient received and responded to 2 cycles of
ifosphamide, mesna, carboplatin, and etoposide (Figure
1)
. He underwent successful chemomobilization therapy that included 2 doses of 375 mg/m2 rituximab, 7 days apart. He
received 3.3 × 106 CD34 cells/kg following a
myeloablative conditioning regimen. Trilineage engraftment occurred by
day 9 after transplantation. Rituximab was administered on
days 30 and 37 without complication. On day 77, his total white blood
cell (WBC) count was 5000 mm3 with 86% neutrophils,
hemoglobin level 12.0 g/dL, platelet count 132 mm3. On day 122, the patient had a WBC of
1000/mm3 with 0.0% neutrophils, hemoglobin level 13.0 g/dL, platelet count 185 000 mm3. A bone marrow biopsy
performed on day 128 showed hypocellular bone marrow with little
maturation of the myeloid series and no evidence of disease relapse.
Dysplastic features were not observed despite a new cytogenetic
abnormality, del(20)(q11.2). An extensive evaluation for an infectious
etiology was negative. Autoantibodies against granulocytes were
not detected.
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| Figure 1.
Absolute neutrophil count during the course of
treatment.
(1) The patient received chemomobilization therapy with rituximab 375 mg/m2, days  54 and 47, cyclophosphamide 4 g/m2 intravenously, day 52, mesna 1.33 g/m2, thrice a day on day 52, etoposide 200 mg/m2 intravenously on days 52 to 50, and
dexa-methasone 10 mg orally four times a day, day 52 to 49. (2)
Peripheral blood stem cell collection. (3) Autologous transplant
following 12 Gy of linear accelerator radiation, etoposide 60 mg/kg,
and cyclophosphamide 100 mg/kg. (4) Posttransplantation rituximab (375 mg/m2 ) was given on days +30 and +37. (5) GCSF 480 µg/day beginning on day +130 and doubled on day +134. (6)
Two doses of intravenous immunoglobulin (IVIG). (7) GM-CSF,
250 µg/m2/day. (8) Cyclosporine 200 mg orally
twice a day, tapered ultimately to 50 mg orally twice a
day.
|
|
Possible offending agents were discontinued. Granulocyte
colony-stimulating factor (GCSF) began followed by
2 doses of intravenous immunoglobulin and granulocyte-macrophage
colony-stimulating factor (GM-CSF). Despite these maneuvers, absolute
neutropenia persisted for longer than 65 days. Within 5 days
of initiating therapy with cyclosporine (200 mg orally twice a day),
the neutrophil count returned to normal levels. GM-CSF and
GCSF were tapered with no decrement in neutrophil count. The patient
continues on cyclosporine with stable neutrophil counts 14 months
later. Attempts at dose reduction to 25 mg orally twice a day
have persistently resulted in relapsed neutropenia suggesting ongoing
autoimmune destruction of myeloid precursor cells.
This is the first reported case of agranulocytosis associated with
rituximab therapy that was refractory to growth-factor support but
responsive to cyclosporine. The efficacy of cyclosporine suggests a
T-lymphocyte-specific cellular response against autologous myeloid
precursors. Although cyclosporine has been used in the post-autologous
stem cell transplantation setting to induce autologous graft-versus-host disease (GVHD), there are no reports of its use in the post-autologous transplantation setting for the treatment of cytopenias. Del(20)(q11.2) has been reported with myelodysplastic syndromes (MDSs) related to high-dose therapy and autologous
transplantation for patients with non-Hodgkin lymphoma, and successful
immunosuppressive therapy with cyclosporine for MDS has been
reported.7-9 This patient, however, had no other
features suggestive of MDS. This single case experience suggests that
cyclosporine be considered in patients with rituximab-associated
neutropenia not responsive to GCSF.
Andrea L. Rose, Alice M. Forsythe, and David G. Maloney
Correspondence: Andrea L. Rose, Fred Hutchinson
Cancer Research Center, Clinical, Seattle, WA; e-mail:
arose{at}fhcrc.org
References
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