Blood, 15 September 2002, Vol. 100, No. 6, pp. 2260-2262
BRIEF REPORT
Rituximab treatment of refractory fludarabine-associated immune
thrombocytopenia in chronic lymphocytic leukemia
Upendra P. Hegde,
Wyndham
H. Wilson,
Therese White, and
Bruce D. Cheson
From the Center for Cancer Research, National Cancer
Institute, National Institutes of Health, Bethesda, MD.
 |
Abstract |
Fludarabine can exacerbate idiopathic thrombocytopenia (ITP) in
chronic lymphocytic leukemia (CLL). We report 3 CLL patients with
refractory fludarabine-associated ITP who responded to rituximab. The
patients had Rai stages III, III, and IV disease. Before
fludarabine treatment, the platelet counts were 141 000/µL,
118 000/µL, and 70 000/µL. ITP developed within week 1 of cycle 3 in 2 patients and within week 2 of cycle 1 in 1 patient. Platelet count
nadirs were 4000/µL, 1000/µL, and 2000/µL, respectively, and did
not respond to treatment with steroids or intravenous
immunoglobulin. Rituximab therapy (375 mg/m2 per week for 4 weeks) was begun on days 18, 23, and 20 of ITP. Patient 1 achieved a platelet count of more than 50 000/µL at day 21 and more
than 133 000/µL at day 28, patient 2 achieved a platelet count of
more than 50 000/µL at day 4 and more than 150 000/µL at day 10, and patient 3 achieved a platelet count of more than 50 000/µL at
day 5 and 72 000/µL at day 28 of rituximab therapy, with platelet
response durations of 17+, 6+, and 6 months. These results suggest
rituximab can rapidly reverse refractory fludarabine-associated ITP.
(Blood. 2002;100:2260-2262)
© 2002 by The American Society of Hematology.
| |
Introduction |
Patients with chronic lymphocytic leukemia (CLL)
are at increased risk for autoimmune complications. Autoimmune
hemolytic anemia (AIHA) and idiopathic thrombocytopenia (ITP) are
observed in approximately 20% to 35% and 2% of patients,
respectively.1,2 Despite the change in the standard
initial treatment from alkylating agents to
fludarabine.3,4 it is unclear whether the incidence of
severe and refractory AIHA has increased.5-8
Fludarabine-associated ITP in CLL is uncommon; only 6 cases have been
reported.9-13
Rituximab is a chimeric anti-CD20 monoclonal antibody with activity in
indolent lymphomas14 but with less efficacy in
CLL.15 Several reports have suggested rituximab may also
be effective in immune-mediated pure red cell aplasia, AIHA, and
ITP.15-18 In the present report, we describe the
successful use of rituximab in 3 CLL patients with severe
fludarabine-associated ITP.
| |
Study design |
Between 1998 and 2001, 3 of 21 patients with B-cell CLL treated
at the National Cancer Institute developed severe ITP while receiving
treatment on a fludarabine-containing protocol. The protocols were
approved by the institutional review board and informed consent was
provided according to the Declaration of Helsinki. All patients
required treatment for disease progression, and their clinical
characteristics and treatment histories are shown in Table
1. The diagnosis of B-CLL was confirmed
by peripheral blood flow cytometry, with CD19+, dim
CD20+, CD22+, CD23+,
CD5+, and CD10
small lymphocytes; bone marrow
biopsies showed diffuse infiltration by small lymphocytes.
Patients 1 and 2 received 25 mg/m2 fludarabine daily for 5 days every 4 weeks, and patient 3 received 25 mg/m2
fludarabine daily for 5 days with UCN-01, an investigational staurosporine analog, every 4 weeks. Patient 1, with a remote history
of posttraumatic splenectomy, developed a transient decrease in
platelets to 89 000/µL on day 5 of cycle 1 and to 37 000/µL on
day 24 of cycle 2 with recovery. However, during cycle 3 his platelet
count precipitously fell to 4000/µL on day 8. Epistaxis, buccal
hematoma, palatal petechiae, and ecchymoses in the scrotal area
developed, and he did not respond to multiple platelet transfusions. Patient 2 had a decrease in the platelet count to 67 000/µL by day 9 of cycle 1 and to less than 1000/µL on day 25, accompanied by palatal
petechiae and epistaxis refractory to platelet transfusions. Patient 3 had a decrease in platelet count to 10 000/µL on day 12 of cycle 3 with extremity and pharyngeal petechiae, which was refractory to
platelet transfusions with a platelet nadir of 4000/µL.
Bone marrow aspirations and biopsy specimens showed adequate
megakaryocytes without evidence of microangiopathic hemolysis in all 3 patients. Antiplatelet antibodies were detected in 2 patients (Table
1). Standard treatment with 1 mg/kg oral prednisone per day and 1 g/kg
per day intravenous immunoglobulin (IVIG) for 2 days (Gammar P,
Sandoglobulin, and Polygam SD, respectively) was begun in all 3 patients. Patient 1 also received 250 IU/kg RhoGam I (WinRho) on day
14, and patient 2 was switched to 150 mg/d intravenous methyl
prednisone for 5 days. Because no patient had a significant platelet
response and all continued with evidence of petechiae or mucosal
bleeding, 375 mg/m2 rituximab per week for 4 weeks was begun.
| |
Results and discussion |
All 3 patients in this series responded to fludarabine but had to
discontinue treatment because of severe refractory ITP. Rituximab
treatment was begun on days 18, 7, and 6 of platelet nadirs in patients
1, 2 and 3, respectively, because of refractory ITP. In each patient,
there was a prompt response to rituximab with a rise in platelet count
and a resolution of bleeding as shown for patient 1 in Figure
1. In patients 1 and 2, the platelet counts achieved normal levels within 4 weeks and lasted for 17+ and 6+
months. Patient 3 had a slow, incomplete treatment
response, possibly related to massive splenomegaly, but did achieve a
platelet count of 72 000/µL that persisted for 6 months. This
patient eventually died of progressive disease with a WBC count of
504 000/µL and development of disease-related thrombocytopenia.
We reviewed the literature and identified 6 previous cases of
fludarabine-associated ITP in CLL (3 ITP and 3 Evans
syndrome).9-13 All patients acquired severe
thrombocytopenia following fludarabine treatment and variable responses
to standard interventions. One patient was refractory to treatment and
died of a hemorrhage. In 5 patients, responses were ultimately achieved
with cyclosporine in 2 patients, splenectomy in 1 patient, and
prednisone/IVIG in 1 patient. Of note, there was also a report of 1 patient with Evans syndrome who responded to rituximab.
Although ITP is relatively uncommon, like AIHA and pure red cell
aplasia, there is an overall increased risk in CLL, suggesting that
immune dysregulation plays an important role. Of note is a report
showing platelet membrane-bound IgG in 8 of 9 patients with advanced
CLL, determined by an antiglobulin consumption assay, suggesting an
immune mechanism.19 It has also been suggested that the
immune suppression from fludarabine may derepress an antibody response
against hematopoietic antigens. Such observations form the basis for
the hypothesis that an imbalance in CD4-helper and CD8-suppressor cells
may produce immune dysregulation and autoimmune complications in
CLL.20 Various other theories have also been
suggested.21,22 Caligaria-Cappio and
Hamblin23 hypothesized that profound suppression of CD4
cells by fludarabine may cause aberrations of the immunoregulatory
circuits involving malignant B-cells. CLL and normal B cells can
coexpress CD40, which, when stimulated by CD40 ligand on T cells, may
up-regulate CD80 and CD86 costimulatory molecules and acquire the
ability to present hematopoietic antigens to normal bystander B cells and invoke an immune response.
In the present report, we describe the successful use of rituximab in 3 patients with advanced CLL and refractory, life-threatening, fludarabine-associated ITP. In all patients, the platelet counts showed
a rapid and unexpected decline during fludarabine treatment that were
not explained by the cytotoxic effects of fludarabine. Bone marrow
biopsy findings showed adequate megakaryocytes, confirming fludarabine-associated ITP. Patients were begun on steroids and IVIG,
and fludarabine treatment was discontinued. Although the patients
received steroids and IVIG for 8, 7, and 6 days, respectively, they
continued to have bleeding complications without platelet recovery and
were begun on rituximab because of reports of its efficacy in ITP and
other autoimmune diseases.16-18,24,25 Two patients
experienced a rapid and durable improvement in platelet count that
became evident on the first day of therapy. In the third patient, a
major improvement in platelet count was achieved but never reached
normal values, possibly because of massive splenomegaly.
These rapid increases in platelet count were most likely attributable
to rituximab and not to delayed effects of steroids and IVIG. First,
all patients showed a significant increase within 24 hours of rituximab
therapy; second, the platelet counts continued to rise despite steroid
discontinuation. A rapid response to rituximab has been reported by
other investigators in refractory ITP, suggesting that depletion of
antiplatelet antibodies is not the mechanism of rituximab
action.16,18 This observation has led to speculation that
rituximab causes opsonization of B cells that inhibit macrophage Fc
receptor function and clearance of IgG-coated platelets. This action
may lead to the eventual suppression of autoreactive B cells and the
sustained remissions observed in some patients.
Successful treatment of refractory ITP with rituximab has also been
reported in other settings. Perotta et al17 reported 10 patients with refractory ITP treated with 375 mg/m2
rituximab per week for 4 weeks. Of these, 5 patients achieved complete
responses and 1 achieved a partial response, lasting from 1 to 14 months. In another report, Stasi et al18 used the same
rituximab dose in 25 patients with chronic refractory ITP, and by 4 weeks, 20% of the patients achieved complete or partial responses, and 12% had minor responses. Most responding patients showed rapid platelet count increases within the first week of rituximab treatment.
Our results, in concert with previous reports, suggest that
rituximab is effective for the treatment of fludarabine-associated ITP.
Indeed, its efficacy in steroid-refractory disease and its low
incidence of long-term toxicity suggest it may be preferable to
standard treatments of ITP. Of note is that strategies that combine
rituximab and fludarabine may not only improve CLL response rates but
may decrease the incidence of autoimmune phenomenon.
| |
Footnotes |
Submitted November 16, 2001; accepted May 14, 2002.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Bruce Cheson, Georgetown University Hospital,
Lombardi Cancer Center, 3800 Reservoir Road, NW, Washington, DC 20007.
| |
References |
1.
Hamblin TJ, Oscier DG, Young BJ.
Autoimmunity in chronic lymphocytic leukemia.
J Clin Pathol.
1986;39:713-716[Abstract/Free Full Text].
2.
Rozman C, Montserrat E.
Chronic lymphocytic leukemia.
N Engl J Med.
1995;333:1052-1057[Free Full Text].
3.
Rai KR, Peterson BL, Appelbaum FR, et al.
Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia.
N Engl J Med.
2000;343:1750-1757[Abstract/Free Full Text].
4.
Johnson S, Smith AG, Loffler H, et al.
Multicenter prospective randomized trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukemia: the French Cooperative Group on CLL.
Lancet.
1996;347:1432-1438[Medline]
[Order article via Infotrieve].
5.
Myint H, Copplestone JA, Orchard J, et al.
Fludarabine-related autoimmune haemolytic anemia in patients with chronic lymphocytic leukemia.
Br J Haematol.
1995;91:341-344[Medline]
[Order article via Infotrieve].
6.
Gonzalez H.
Leblond V, Azar N, et al. Severe autoimmune hemolytic anemia in eight patients treated with fludarabine.
Hematol Cell Ther.
1998;40:113-118[Medline]
[Order article via Infotrieve].
7.
Weiss RB, Freiman J, Kweder SL, Diehl L, Byrd C.
Hemolytic anemia after fludarabine therapy for chronic lymphocytic leukemia.
J Clin Oncol.
1998;16:1885-1889[Abstract].
8.
Mauro FR, Foa R, Cerretti R, et al.
Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features.
Blood.
2000;95:2786-2792[Abstract/Free Full Text].
9.
Montillo M, Tedeschi A, Leoni P.
Recurrence of autoimmune thrombocytopenia after treatment with fludarabine in a patient with chronic lymphocytic leukemia.
Leuk Lymphoma.
1994;15:187-188[Medline]
[Order article via Infotrieve].
10.
Shivdel L, Mordechia S, Abraham K, et al.
Evans syndrome complicating fludarabine treatment for advanced B-CLL.
Br J Haematol.
1997;99:706-713[CrossRef][Medline]
[Order article via Infotrieve].
11.
Sen K, Kalayco M.
Evan's syndrome precipitated by fludarabine therapy in a case of CLL [abstract].
Am J Hematol.
1999;61:219[CrossRef][Medline]
[Order article via Infotrieve].
12.
Leach M, Parsons RM, Reilly JT, et al.
Autoimmune thrombocytopenia: a complication of fludarabine therapy in lymphoproliferative disorders.
Clin Lab Haematol.
2000;22:175-178[CrossRef][Medline]
[Order article via Infotrieve].
13.
Seipelt G, Bohme A.
Koschmieder S, Hoelzer D. Effective treatment with rituximab in a patient with refractory prolymphocytoid transformed B-chronic lymphocytic leukemia and Evans syndrome.
Ann Hematol.
2001;80:170-173[CrossRef][Medline]
[Order article via Infotrieve].
14.
Maloney DG, Grillo-Lopez AJ, White CA, et al.
IDEC-C2B8 (Rituximab) anti-CD20 antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma.
Blood.
1997;90:2188-2195[Abstract/Free Full Text].
15.
Huhn D, von Schilling C, Wilhelm M, et al.
Rituximab therapy of patients with B-cell chronic lymphocytic leukemia.
Blood.
2001;98:1326-1331[Abstract/Free Full Text].
16.
Zecca M, De Stefano P, Nobili B, Locatelli F.
Anti-CD20 monoclonal antibody for the treatment of severe, immune-mediated, pure red cell aplasia and hemolytic anemia.
Blood.
2001;97:3995-3997[Abstract/Free Full Text].
17.
Perotta A, Sunneberg TA, Scott J, et al.
Rituximab in the treatment of chronic idiopathic thrombocytopenia purpura (ITP) [abstract].
Blood.
1999;94:14.
18.
Stasi R, Pagano A, Stipa E, Amadori S.
Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenia purpura.
Blood.
2001;98:952-957[Abstract/Free Full Text].
19.
Kaden BR, Rosse WF, Hauch TW.
Immune thrombocytopenia in lymphoproliferative diseases.
Blood.
1979;53:545-551[Abstract/Free Full Text].
20.
Lewis FB, Schwarz RS, Dameshek W.
X-radiation and alkylating agents as possible "trigger" mechanisms in the autoimmune complications of malignant lymphoproliferative disease.
Clin Exp Immunol.
1966;1:3-11[Medline]
[Order article via Infotrieve].
21.
Dighiero G.
An attempt to explain disordered immunity and hypogammaglobulinemia in B-CLL.
Nouv Rev Fr Hematol.
1988;30:283-288[Medline]
[Order article via Infotrieve].
22.
Kipps TJ, Carson DA.
Auto-antibodies in chronic lymphocytic leukemia and related systemic autoimmune disease.
Blood.
1993;81:2475-2487[Free Full Text].
23.
Caligaria-Cappio F, Hamblin TJ.
B-Chronic lymphocytic leukemia: a bird of a different feather.
J Clin Oncol.
1999;17:399-408[Abstract/Free Full Text].
24.
Perotta AL, Abuel C.
Response of chronic relapsing ITP of 10 years duration to rituximab [abstract].
Blood.
1998;92:88.
25.
Zaja F, Russo D, Fuga G, et al.
Rituximab for myasthenia gravis developing after bone marrow transplant.
Neurology.
2000;55:1062-1063[Free Full Text].
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Abstract
Introduction
