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Ann Hematol (2007) 86:711–717DOI 10.1007/s00277-007-0335-1 Low rate of long-lasting remissions after successful treatmentof immune thrombocytopenic purpura with rituximab Christof Schweizer & Frederic J. Reu & Anthony D. Ho &Manfred Hensel Received: 27 October 2006 / Accepted: 19 March 2007 / Published online: 11 July 2007 Abstract Idiopathic thrombocytopenic purpura (ITP), also confirm that rituximab is well tolerated and effective in known as immune thrombocytopenic purpura, is thought to refractory and relapsed immune thrombocytopenias; how- be caused primarily by the production of autoantibodies ever, response duration was short, and only about one fifth directed against platelet surface glycoproteins. Treatment of of our patients enjoyed a long-lasting remission.
an acute ITP episode can be difficult, and relapses arecommon. Recent studies have shown that the anti-CD20 Keywords ITP. Idiopathic thrombocytopenic purpura .
antibody rituximab is effective in the treatment of relapsed and refractory patients. We report the results of a retro-spective analysis of rituximab treatment in 14 patients withimmune thrombocytopenic purpura. Nine of these patients had a refractory disease, and five patients had a relapse ofthe thrombocytopenia. The median time since last treatment Idiopathic thrombocytopenic purpura (ITP) or immune was 10 days (range 1–470 days). All patients were previ- thrombocytopenic purpura is an autoantibody-mediated ously treated with one to seven different regimens, and four disease defined by platelet counts <150×109/l in the periph- had undergone splenectomy. Rituximab was administered eral blood and exclusion of other causes of thrombocytope- at the standard dose of 375 mg/m2 once per week with a nia. Although standardized tests have yet to be developed, median of 4 infusions (range 2–4). The overall response the production of autoantibodies against glycoproteins rate was 64%; 7 of 14 patients (50%) achieved a complete exposed to the platelet surface membrane leading to destruc- remission (platelet levels>100×109/l), 2 of 14 patients tion of thrombocytes by the reticuloendothelial system, (14%) had a partial remission (platelets>50×109/l), and 5 especially in the spleen ], is felt to the major underlying patients did not respond. The median time to response was pathophysiological mechanism. A similar mechanism may 2 weeks (range 1–4) after the first infusion. Responding cause platelet destruction in patients who experience au- patients stayed in remission for a median period of 8 weeks toimmune hemolysis or autoimmune neutropenia in com- (range 10 days–36 months). Three patients (21%) remained bination with not otherwise explained thrombocytopenia.
in remission after 26 to 156 weeks of follow-up. All of the Secondary immune thrombocytopenias in patients with four splenectomized patients achieved a complete remission underlying hematologic or autoimmune diseases [] may after rituximab therapy, and two of them are still in re- also be caused by autoantibodies. Recent findings suggest mission after 26 and 156 weeks observation. Our data that not only platelet destruction but also suppressedplatelet production by disturbed megakaryopoiesis play arole in the pathogenesis of ITP ].
C. Schweizer F. J. Reu A. D. Ho M. Hensel (*) Immune thrombocytopenia most commonly presents as Department of Internal Medicine V, Haematology, Oncology and an ITP. Its estimated incidence is about 50–100 new cases per million inhabitants per year []. Treatment indication depends on the absolute platelet counts and the actual 69120 Heidelberg, Germanye-mail: manfred.hensel@med.uni-heidelberg.de bleeding risk of the individual patient. Standard first-line treatment comprises corticosteroids and intravenous immu- noglobulins (IVIG) ]. Sixty to 90% of adult patients respond to corticosteroids, but only 15–40% achieve along-lasting remission [Patients not responding to the initial treatment or with a relapse after tapering of steroids will need second-line therapy. Approximately two thirds of such patients respond to splenectomy [For patients refractory to or relapsing after splenectomy, there is no standard care. It has recently been reported that the anti- CD20 antibody rituximab might be an option to treat patients with an otherwise poor prognosis ].
The exact mechanism of rituximab action in ITP therapy still remains to be clarified. An overview about the different theories is given by Introna et al. [It is known that the anti-CD20 antibodies bind to the surface of B cells. This leads to complement activation and to complement-dependent cellular cytotoxicity. Additionally, B cells are also lysed by antibody-dependent cellular cytotoxicity via Fc receptor binding. The decrease in the B cell count might reduce the Time from diagnosis to rituximab (months) production of new autoreactive antibodies directed against platelet surface proteins. Apart from the depletion of the B cell compartment, additional mechanisms of action have been suggested because this depletion occurs in all patients irrespectively of their clinical course. One possibility is that rituximab or rituximab-coated B cells bind to Fc receptors of the reticuloendothelial system and thereby prevent platelet phagocytosis. Therefore, functional polymorphisms in the receptor for the Fc tail of IgG may be responsible for the different response to rituximab []. Another possible mech- anism is that activation of autoreactive T cells, which might be involved in the pathogenesis of ITP, is terminated by the B cell depletion in most but not all patients The encouraging results obtained with rituximab in ITP treatment led to use in other autoimmune cytopenias like Evans syndrome or autoimmune hemolytic anemia In this paper, we report our results of a retrospective analysis of 14 patients with chronic refractory immune thrombocytopenic purpura treated with standard doses ofrituximab focusing on response duration and rate of long-lasting response.
was inactive at the time of clinical presentation withautoimmune thrombocytopenia: One patient was in remis- sion from hairy cell leukemia; another patient was offimmunosuppression and in complete response (CR) 6 years after allogeneic stem cell transplantation for acute myeloidleukemia (AML). All patients were previously treated with We retrospectively analyzed 14 patients with autoimmune other ITP regimens (median 3, range 1–7). These regimens thrombocytopenia (5 men, 9 women) that were treated at the consisted either of steroids (prednisone and dexamethasone) Department of Haematology, Oncology and Rheumatology or other immunosuppressive agents (vincristine, cyclophos- of the University of Heidelberg since March 2002 (Table ).
phamide, cyclosporine A, azathioprine). Nine patients had The median age was 67 years (range 16–84 years). Two of received IVIG before rituximab therapy. Four patients had these patients had a secondary autoimmune thrombocyto- undergone splenectomy (Table The median time since penia because of the history of a hematological disorder that last treatment was 10 days (range 1–470 days).
dexamethasone,vincristine, IVIG,splenectomy,azathioprine, CsA splenectomy,azathioprine,cyclophosphamide n Number of cycles, TTR time to response, DOR duration of response, IVIG intravenous immunoglobulines, PBSCT peripheral blood stem cell transplantation, CR complete remission, PR partial remission, NC no change partial response (PR) as the rise in the platelet count to>50×109/l. A rise of the platelet count to 20–50×109/l was Rituximab was administered at 375 mg/m2 intravenously defined minimal response (MR). No response (NR) was once per week for 2–4 weeks. The median number of defined as an increase in platelet counts below 20×109/l or infusions was 4. All patients received standard premed- ication, with an antihistamine (i.e., 2-mg clemastil i.v.) andan antipyretic agent (i.e., 500-mg paracetamol p.o.).
The indication to start rituximab therapy was autoimmune We retrospectively analyzed the elevation of platelet counts.
thrombocytopenia refractory to other therapy with platelet The response criteria were defined as follows: A CR was counts below 40×109/l or severe bleeding, side effects from defined as the rise in platelet counts to >100×109/l and a glucocorticoids, evidence of rapid relapse after response to previous therapy, or history of refractory disease during the (50%) and partial remission in 2 of 14 patients (14%), for an overall response rate of 64%. Within the group of Eight patients completed the scheduled regimen of four responders, there were heavily pretreated patients as well as rituximab cycles, two patients received three cycles. Four patients receiving rituximab as a second-line therapy. Nine patients had only two infusions of the monoclonal antibody.
of the 14 patients were previously treated with IVIG, and 4 In patient 1 and 13, treatment was stopped because of lack had undergone splenectomy. Since the first report on of response and disease requiring alternative treatment im- rituximab treatment of refractory ITP in 1998 ], several mediately. In two cases, the treatment was stopped because case reports and results in small cohorts have been of a complete remission after two antibody infusions (pts. 4 published. In Table , reports available to date describing and 10). No patient experienced major treatment-related five or more adult patients treated with rituximab for toxic side effects. Altogether, we achieved an overall re- ITP and discriminating between splenectomized and non- sponse rate (CR+PR) of 64% (9 of 14 patients). Seven splenectomized patients are listed. Taken together, the patients had a complete remission (50%) and two had a outcome of about 229 adult patients is documented. The partial remission (14%). Patients 6, 7, and 14 remained in overall response rate was about 62% (44% complete complete remission without additional treatment and 26 and response, 16% partial response, and 2% minimal response).
156 weeks of our follow-up. On the other hand, there were Lately, a review of 19 reports (313 patients) on ITP four patients (pts. 4, 9, 10, and 12) with an increase in treatment with rituximab was published []. The authors platelet counts after the first rituximab infusion, but this found a weighted mean of complete response of 43.6% and response lasted only for 1 to 3 weeks. The treatment of of overall response of 62.5%. The results of our study are patients 4, 9, and 10 was therefore stopped after course 2 or thus in line with published data. Apart from this, there are 3. Patient 3 died from an unknown cause about 2 months only few reports on the therapy for ITP in childhood with after the start of the rituximab therapy. The last count rituximab , So far, the role of rituximab in showed platelets above 100×109/l about 2 weeks before his pediatric ITP remains to be clarified ]. Rituximab has death. One patient (number 2) was lost to follow-up about also been used for the treatment of autoimmune thrombo- 5 months after the end of treatment. Patients 13 and 14 had cytopenias in the setting of hematologic and autoimmune a secondary autoimmune thrombocytopenia due to a histo- diseases [, , , ]. Several case reports were ry of a hematological disease. Patient 13 had undergone published on patients suffering from chronic lymphatic allogeneic stem cell transplantation for an AML 6 years leukemia (CLL) and either CLL-associated or fludarabine- before ITP was diagnosed. The patient was off immuno- or pentostatin-induced autoimmune thrombocytopenias suppressive therapy, and a relapse of the AML was excluded by bone marrow aspiration. The patient exhibited no clinical Unfortunately, the effect of rituximab treatment is not signs or laboratory findings indicating a chronic graft-vs- always of long duration. As listed in Table , about two host disease. Administration of two cycles of rituximab had thirds of our patients achieved a remission, lasting for a no effect on platelet counts; treatment was therefore stopped median period of 8 weeks (range 1–156 weeks). The after the second infusion. The patient was subsequently response duration reported in the literature is listed in treated with IVIG and underwent splenectomy. Patient 14 Table and ranges between 20 and 128 weeks (median was previously diagnosed with hairy cell leukemia. There 39 weeks). In contrast to published data, only 5 of our 14 were no signs of hairy cell leukemia activity 1 year after the patients (36%) had a remission lasting longer than 8 weeks.
last treatment with purine analogues, blood counts were The duration of remission of the nine initially responding normal except for thrombocytopenia, and bone marrow patients is depicted in Fig. . Three of our initially aspiration revealed no evidence of recurrent leukemia or responding patients had decreasing platelet counts 1 to myelodysplasia. After receiving four cycles of rituximab, 3 weeks after the start of rituximab therapy. Two patients this patient had a long-lasting (26 weeks) normalization of stayed in complete remission for 8 and 9 weeks, respec- platelet counts. After relapsing, he successfully underwent tively. One patient was in complete remission for more than 26 weeks before relapse. At the end of follow up, we hadtwo patients still in CR for 59 and 156 weeks, respectively.
After a median of 11 weeks (range 3–64), salvage therapies had to be started in 6 of the 9 initially responding patients.
Up to now, there is no explanation why two thirds of the In this study, the effect of rituximab in the therapy for patients that initially responded to the anti-CD20 antibody autoimmune thrombocytopenias was evaluated. A retro- relapsed after only a few weeks. The therapeutic effect of spective analysis was performed with 14 patients exhibiting the anti-CD20 antibody rituximab, especially the duration ITP. Complete remission was achieved in 7 of 14 patients of response, may have been overestimated in the past.
Abstracts (A) and original articles (O) describing five or more adult patients treated with rituximab for ITP and discriminating between non- splenectomized patients and patients after splenectomy.
CR Complete remission, PR partial remission, MR minimal remission, DOR duration of remission, n.a. data not available a Includes patients from [, ]b Retreatment of 11 patients from [ An important aspect of ITP treatment with rituximab factors retrospectively, such as age, gender, or CD20 refers to the fact that, up to now, there is no way to expression. None of the investigated parameters, however, discriminate between patients that will respond and non- showed a significant difference between responders and responders. Attempts were made to evaluate some relevant non-responders ]. We observed a better response rate insplenectomized patients. Four of the 11 responding patientswere splenectomized, and all of them had a complete response after rituximab therapy. Two of these four patientshad long-lasting remissions for 26 and 156 weeks, respec-tively. The number of analyzed patients in this study is too low to allow an accurate estimation, but the anti-CD20therapy was more effective in patients after splenectomy.
This trend cannot be seen in the reviewed literature depictedin Table The rate of complete and partial responses is similar in the described 127 splenectomized patients (overallresponse rate 61%) as in the remaining 102 patients (63%).
Although one of the patients who positively responded to rituximab died unexpectedly about 8 weeks after theadministration of rituximab, we consider rituximab treat-ment a safe therapy for patients with immune thrombocy- topenias. Apart from few infusion-related minor allergicreactions, like fever and chills, we observed no severe toxicside effects and no infectious complications during the therapy. There are only few reports in the literature about rituximab-related toxicity like infectious complications]. Although a long-lasting depletion of the B cell compartment is observed after rituximab application [ Fig. 1 Remission duration in responding patients (n=11) long-term side effects have not been identified at this point.
Our data confirm that rituximab is a safe and promising patient with common variable immunodeficiency. Ann NY Acad therapeutic option for patients with refractory chronic ITP.
9. Choueiri T, Lichtin AE (2002) Hereditary hemorrhagic telangiec- Most of the data about rituximab in ITP at the moment are tasia, idiopathic thrombocytopenic purpura, and chronic lympho- from pretreated patients. Lately, it was reported that giving cytic leukemia treated with rituximab. Am J Med 113:700–701 rituximab earlier in the clinical course can lead to higher 10. Cines DB, Blanchette VS (2002) Immune thrombocytopenic rates of remissions ]. As the administration of rituximab 11. Cines DB, McMillan R (2005) Management of adult idiopathic is adopted from the lymphoma therapy, maybe optimizing thrombocytopenic purpura. Annu Rev Med 56:425–442 the dosing scheme can also improve the response rates.
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of B-cell depletion with anti-CD20 monoclonal antibody in adultswith chronic immune thrombocytopenic purpura. Br J Haematol Because remission duration tends to be short, a mainte- nance program compared to retreatment at relapse should 13. Cooper N, Stasi R, Michel M, Bussel JB (2003) Retreatment of 11 be incorporated for responding patients. Additionally, the patients with immune thrombocytopenic purpura with the anti- administration of thrombopoesis-stimulating proteins is CD20 monoclonal antibody rituximab [abstract]. Blood 102(Suppl):87b under current investigation []. The exact role of this new 14. Fianchi L, Rossi E, Murri R, de Stefano V, Pagano L, Leone G principle of ITP therapy is not yet clear. For the future, it (2007) Severe infectious complications in a patient treated with will be necessary to learn more about the physiological and rituximab for idiopathic thrombocytopenic purpura. Ann Hematol molecular action of rituximab in ITP patients. Understand- 15. George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, ing its mechanisms of action more precisely will possibly Ballem PJ, Blanchette VS, Bussel JB, Cines DB, Kelton JG, allow us to identify likely responders and non-responders.
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