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Copyright Ó Blackwell Munksgaard 2004 EUROPEAN JOURNAL OF HAEMATOLOGY
Monoclonal antibodies in the treatment of autoimmune cytopenias
Robak T. Monoclonal antibodies in the treatment of autoimmune cytopenias. Eur J Haematol 2004: 72: 79–88. Ó Blackwell Munksgaard 2004. Abstract: In recent years, clinical studies have been undertaken with selected monoclonal antibodies (MoAbs) in the treatment of several hematological diseases, especially in malignant disorders. However, some clinical observations indicate that MoAbs may be an important alternative for the conventional therapy of some autoimmune disorders. Two MoAbs directed against CD20 antigen (rituximab, Rituxan, Mabthera) and CD52 antigen (alemtuzumab, Campath-1H) seem to be especially useful for this purpose. Autoimmune cytopenias have been investigated in the last few years with positive preliminary results. Rituximab seems to be an eﬀective and safe agent for the treatment of immune thrombocytopenias, autoimmune hemolytic anemia, cold agglutinin disease and pure red cell aplasia. Although the case series are small, rituximab seems to be an eﬀective and safe agent for the treatment of these diseases. Clinical experience with alemtuzumab in patients with autoimmune cytopenias is even more limited than with rituximab. However, preliminary results indicate that further studies with this MoAb are warranted. A longer follow-up and the studies on larger number of patients are needed to determine the real value of these new approaches in autoimmune cytopenias. Recent experiences with the use of MoAbs in treatment of these diseases are the subject of this review.
Department of Hematology, Medical University of Lodz and Copernicus Hospital, Lodz, Poland
Key words: rituximab; alemtuzumab; campath-1H; autoimmune hemolytic anemia; immune thrombocytopenia; cold agglutinin disease; pure red cell aplasia Correspondence: Tadeusz Robak, Department of Hematology, Medical University of Lodz, 93-513 Lodzd, Pabianicka 62, Poland Tel: +4842 6895191 Fax: +4842 6895192 e-mail: email@example.com Accepted for publication 23 October 2003
The autoimmune cytopenias (AC) include autoimmune hemolytic anemia (AIHA), pure red cell aplasia (PRCA), immune thrombocytopenia (ITP), autoimmune neutropenia (AIN) and various combinations of these disorders, such as autoimmune pancytopenia and EvansÕ syndrome (1). These disorders are idiopathic or associated with other malignant or non-malignant diseases including lymphoma, chronic lymphocytic leukemia (CLL), systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjogren’s disease and ulcerative colitis (2). Despite the complex pathogenetic mechanism of autoimmune cytopenias, B cells play a crucial role in the pathogenesis of these disorders (3). They are responsible for the production of autoantibodies that are directly or indirectly (e.g. immune complex formation) destructive. These cells also act as highly eﬃcient antigen presenting cells supporting the activation and auto-reactivity of T cells involved in the process (3). The treatment of associated neoplastic or autoimmune diseases may induce remission of AC in some patients. However,
in other patients speciﬁc therapy for cytopenia is needed. The majority of patients with AC require only standard immunosuppression, mainly steroids, to achieve long-lasting remission. In a proportion of refractory disease, second-line treatment such as splenectomy, or cytotoxic drugs for ITP or AIHA and granulocyte-colony stimulating factor (G-CSF) for AIN is needed. However, as some patients are resistant to conventional therapy or have signiﬁcant side eﬀects after administration of immunosuppressive agents, they need an alternative treatment. In the last few years monoclonal antibodies (MoAbs) directed against B and/or T cells have become a new approach in treating patients with severe, refractory AC, who have chronic refractory or relapsing cytopenias and suﬀer life-threatening anemia, hemorrhages or infections (1–7).
The most important clinical value in the patients with autoimmune cytopenias has human-mouse 79
as well as plasma cells. plasmapheresis. vinca alkaloids. and in the T-cell variant of prolymphocytic leukemia (T-PLL). Rituximab is administered as an intravenous infusion with a recommended dosage of 375 mg/ m2. which may protect B cells from this agent. chills. Splenectomy is usually considered as a second-line therapy. infusionrelated reactions occur in the majority of patients. other therapeutic modalities including immunosuppressive agents such as vincristine. The drug doses should be increased gradually. Basel. Similar to rituximab. CD20 is not expressed on all B-cell forms. Preliminary reports indicate that alemtuzumab (Campath-1H. rigors and rarely hypertension and bronchospasm. 10). In the ﬁrst week the ﬁrst dose of 3 mg should be administered and then increased to 10 mg and subsequently to 30 mg as soon as infusion-related reactions are tolerated. 4. including indolent and aggressive forms of B-cell non-Hodgkin’s lymphoma (NHL) and B-cell CLL (8. In general. Moreover. Moreover. ﬂu-like symptoms after the ﬁrst doses of alemtuzumab. after rituximab treatment plasma cells may still continue to be present – inducing autoantibodies for months or even years (3). These host responses could attenuate response to re-treatments and potentially mediate allergic reactions. especially when administered intravenously. danazol. However. suggesting that it could be beneﬁcial in autoantibodymediated diseases by targeting the auto-reactive B cells (11). In CLL. patients with platelet counts exceeding 30 · 109/L require no treatment unless they are undergoing a procedure likely to induce blood loss (13). or in lymphoproliferation-associated conditions.Robak antibody rituximab (Rituxan. and . Similar to rituximab. For this reason anti-infective prophylaxis is mandatory. F. 9. Moreover. ADCC and induction of apoptosis (9. Until now. are a frequent event. dapsone. there is little or no data regarding depletion of B cells at sites other than blood. Rituximab rapidly eliminates most circulating B cells. Autoimmune thrombocytopenia Autoimmune thrombocytopenia [idiopathic thrombocytopenic purpura (ITP)] is an autoimmune disorder characterized by persistent thrombocytopenia because of autoantibody binding to platelet antigens causing their premature destruction by the reticuloendothelial system (12). Hoﬀman-La Roche Ltd. 10). whether B cells or T cells. may be devoid of CD20 and hence unresponsive to this agent. and hence. azathioprine. Traditionally. Switzerland) that targets CD20 antigen on B lymphocytes (5–7. 8). Alemtuzumab is a humanized rat IgG1 antiCD52 MoAb that binds to the cell membrane of virtually all normal as well as malignant lymphocytes. Treatment with this agent is usually well tolerated. USA). treated patients may be susceptible to the development of human anti-chimeric antibod80 ies which can have an impact on the responsiveness. some studies on other autoimmune diseases did not show any correlation between the decline of autoantibody levels and response. Alemtuzumab is highly active in cases of CLL are even refractory to ﬂudarabine. This MoAb demonstrates signiﬁcant activity in patients with various lymphoid malignancies. although the incidence of these side eﬀects decrease with subsequent rituximab infusion. This MoAb has also been incorporated in novel conditioning regimens designed to facilitate stem cell transplantation in hematological malignancies. 10). a humanized rat immunoglobulin G1 (IgG1) anti-CD52 MoAb that binds to the cell membrane of virtually all B and T-cells is also active in the treatment of AC (1. Moreover. However. These adverse events are typically fever. it is unknown whether all CD20 B cells are equally susceptible to rituximab-mediated deletion. Complement-dependent cytotoxicity. San Antonio. chronic ITP is deﬁned as persistence of a platelet count of <150 · 109/L for more than 6 months. progenitors. alemtuzumab is usually administered three times per week for at least 12 wk intravenously or subcutaneously. alemtuzumab has the ability to cause cell lysis using a host–eﬀector mechanism such as complement ﬁxation. the prolonged impairment of antibody production increases the risk of viral and bacterial infections. Thus. Administration of alemtuzumab results in prolonged and profound peripheral blood lymphopenia particularly aﬀecting T cells. More importantly this agent induces immunosuppression which lasts for several months after the cessation of treatment. antibody-dependent cell-mediated cytotoxicity (ADCC) and induction of apoptosis indicate that rituximab is cytotoxic to CD20-positive cells. once weekly for 4 wk. suggesting that additional mechanisms involving antigen presentation and help to T cells are important (7). cyclophosphamide. Mabthera. leading to increased susceptibility to infections. In patients refractory to splenectomy having signiﬁcant thrombocytopenia and hemorrhagic symptoms. TX. JLEX Pharmaceuticals. In particular. Rituximab was the ﬁrst MoAb approved in 1997 by the Food and Drug Administration (FDA) for the treatment of cancer (11). there may be pro-survival factors acting in certain autoimmune diseases. It should also be remembered that rituximab is a human–mouse chimeric antibody. First-line therapy comprises oral corticosteroids and high doses of intravenous Ig (HDIVIg).
Monoclonal antibodies in autoimmune cytopenias intravenous anti-D for Rh(D)-positive patients can be used. month. Three of nine patients (30%) who have received rituximab at doses close to or equal to the full dose had objective clinical response including two complete response (CR) and one partial response (PR). However. weekly for 4 wk. Rituximab was administered in a dose-escalating fashion using doses ranging from 50 to 375 mg/m2. (14) R 375 mg/m2/weekly · 4 Response OR (%) Table 1.and second-line therapy and who required treatment with monoclonal antibodies anti-CD20 (rituximab) or alemtuzumab were evaluated in several studies (14–23). All responding patients have maintained their platelet count longer than 2 months without additional therapy. In seven cases responses were sustained for 6 months or longer. (16) Zaja et al. Those who failed to respond to standard ﬁrst. (19) Giagounidis et al. day. Five patients showed a CR (platelet count >100 · 109/L) and a PR (platelet count between 50 and 100 · 109/L) was seen in another ﬁve. the same authors reported the results of the treatment with rituximab in seven additional cases with ITP (16). week. (23) 12 28–71 Refractory to steroids 24 (31) 21–455+ d 7–56+ wk Response duration Comments CR (%) 5 (20) 13 (52) 46 (22–74) 25 Stasi et al. Total 76 16–77 Refractory or relapsed Refractory or relapsed 40 (20–66) Refractory/relapsed >16 7 20 Stasi et al. It is worth noting that in some patients with relapsed disease repeated challenge with rituximab induced a new response. year. these doses did not eﬀectively deplete B cells. (18) 12 21–77 Refractory to 2–5 different regimens Refractory to steroids PatientsÕ characteristic R 50 to 375 mg/m2/weekly · 4 Treatment regimen 3 (25) 1 (8) 6 m in two patients. Patients began to respond only 2–5 wk after last antibody administration with In two patients R induced new response after relapse Responses only after higher doses >6 m in seven patients Better response in younger patients Two patterns of response: early and late Two patients relapsed and responded for retreatment 21–455+ d 5 (41) 9 (75) R 375 mg/m2/weekly · 4 9 (45) 4 (57) 13 (65) 6 (86) R 375 mg/m2/weekly · 4 R 375 mg/m2/weekly · 4 44 (58) R. In responding patients a signiﬁcant rise in platelet counts was observed usually 1 wk after the ﬁrst rituximab infusion. Subsequently Stasi et al. The results of larger trials are presented in Table 1. yr. Saleh et al. None of the three patients who received the lowest doses (50 mg/m2 followed by 150 mg/ m2) achieved a clinical response. rituximab. m. In contrast to the previous study. in ﬁve of the responders there was no signiﬁcant increase in the platelet count during rituximab treatment. pt. overall response. (14) presented the results of a prospective study in 25 patients with ITP treated with rituximab at a dose of 375 mg/m2 once weekly for 4 wk. More recently. wk. complete response. (18) reported the preliminary results of a prospective pilot phase I/II clinical trial in which they enrolled 13 patients with ITP who had failed corticosteroid therapy and whose platelet count was <75 · 109/L. patients. In additional three patients minor response (platelet count below 50 · 1010/L). In this group the platelet count rose to >50 · 109/L in six patients. 3 m in one patient 60 € 480 d 81 . Twelve patients completed treatment and were evaluable for response. Larger studies evaluating the efficacy of rituximab in immune thrombocytopenia Age (yr) Number of patients Reference Saleh et al. including four patients achieving CR and two PR. with no need for continued treatment was observed giving an overall response rate of 52%. CR. OR. The patients were resistant to previous two–ﬁve diﬀerent therapeutic options including eight patients who had already failed splenectomy. d. Rituximab-associated toxicity consisting of infusion-related fever and chills was seen in less than one-third of patients and none of the patients discontinued treatment because of toxicity.
chronic graft vs. The patients achieved a platelet count of >50 · 109/L on day 21. Alemtuzumab is currently approved for the treatment of B-CLL resistant to alkylating agents and ﬂudarabine (10). However. 16. Three patients had underlying CLL/non-Hodgkin’s lymphoma and one had Hodgkin’s disease. There is not much literature on the use of alemtuzumab in the treatment of ITP. However. Autoimmune hemolytic anemia Autoimmune hemolytic anemia results from the production of pathologic antibodies that bind to red blood cells and lead to their destruction. total and CD20+ lymphocyte count. A patient with ITP with severe hemorrhages associated with AIN had a sustained response. the peripheral blood count recovered with a normal platelet count. It is possible that in patients with early response. Similarly. It is possible. (21) ﬁrst reported the results of treatment with this MoAb in six patients with ITP refractory to conventional therapy. These results indicate that rituximab can rapidly reverse refractory ﬂudarabine-associated ITP. older age seems to be the factor correlated with a course response rate (5). (14. Hensel and Ho (27) described a case of the hairy cell leukemia with autoimmune thrombocytopenia after treatment with pentostatin. (19). Although the case series is small. However. In late responders the decreased production of antiplatelet antibodies is responsible for an increase in the platelet count (16). 10 yr ago Lim et al.Robak peak platelet count occurring 10–16 wk after the start of treatment. 19. In three patients the remission lasted more than 4–9 months. In secondary AIHA. In this group one patient had ITP. AIHA and AIN. More recently Willis et al. The established treatment of the warm type of AIHA consists of corticosteroids in monotherapy or combined with azathrioprine or cyclophosphamide. such as lymphoproliferative connective tissue disease. Hegde and his colleagues (25) reported three CLL patients with refractory ﬂudarabine-associated ITP treated with standard doses of rituximab (375 mg/m2/wk for 4 wk). 23). 29–44). three ITP. one ITP and AIN and one ITP and PRCA. level of CD20 expression on B cells before the therapy and pharmacokinetics of the drug. time between diagnosis and treatment. Four of ﬁve 82 evaluated patients responded to the treatement. in this disease the drug is administered at a dose of 30 mg in 2 h i. However. In a group of 20 patients with ITP treated with standard doses of rituximab the drug proved to be active in 13 patients with nine achieving CR. including those with purine nucleoside treatment associated ITP (19. These syndromes can be classiﬁed according to the characteristic temperature activity of the antibodies (28). some authors hypothesize that profound suppression of CD4 cells by ﬂudarabine or cladribine may cause aberrations of the immunoregulatory circuits involving malignant B cells and on this basis it is presumed that B-cell-mediated autoimmune complications may improve by anti-CD20 therapy (25). opsonized B cells block the reticulo-endothelial system. a search for an underlying factor that requires speciﬁc therapy. However. no clear explanation for the eﬀect of rituximab or for the lack of response could be found in those and other studies (14. that the method of its administration in ITP and other cytopenias is not optimal and better results could be obtained with longer treatment. It should be noted that rituximab is active not only in ITP but also in secondary immunothrombocytopenia in the patients with connective tissue diseases. host disease and B-cell lymphoproliferative disorders. Alemtuzumab was administered at a dose of 10 mg/ d for 10 d. One week after the ﬁrst administration of rituximab. One patient with ITP and PRCA responded to ITP but relapsed 3 months later. Quartier and colleagues (29) treated ﬁve .v. three ITP and AIHA (EvansÕ syndrome). interesting results have been observed in idiopathic AIHA with warm autoantibodies in children. 24– 26). It should be noted that patients entering the study received cyclosporine after alemtuzumab in an attempt to reduce the incidence of relapse. worsening of thrombocytopenia during antibody therapy was observed in two patients and in most cases the response began between 4 and 6 wk after the start of the antibody therapy. both idiopathic or associated with B-cell chronic lymphoproliferative disorders (Table 2) (7. observed in most patients. A response was seen in two patients with EvansÕ syndrome but both relapsed in 3 months. is indicated. Rituximab appeared to have eﬃcacy in the treatment of AIHA. infusion three times weekly for a maximum period of 12 wk. 16) identiﬁed two patterns: early response with an increase in platelet count after the ﬁrst or second infusion and late response with rise of platelet count at weeks 6–8. Stasi et al. No correlation was observed between response and gender. The mechanism by which purine nucleoside treatment-associated cytopenias respond to the treatment with rituximab is not clear. In steroids refractory patients splenectomy may be indicated. Alemtuzumab was well tolerated in all patients apart from ﬁrst-day reactions. However. (4) described 21 patients with severe and life-threatening autoimmune cytopenias resistant to standard immunosuppression therapies and treated with alemtuzumab.
and all three patients were re-treated with rituximab. corticosteroids and immunosuppressive drugs could be stopped or their doses markedly reduced. month.Monoclonal antibodies in autoimmune cytopenias children with severe idiopathic AIHA and one child with autoimmune hemolysis after stem cell transplantation with rituximab. that there were no infusion-related side eﬀects and severe infections. (33) Trape et al. Response duration 15–22 m 7. All four patients became transfusion independent and were taken oﬀ prednisone completely. Who received four to six doses of rituximab at a dose of 375 mg/m2. The MoAb was administered at standard doses of 375 mg/m2/wk for 4 wk. The median time from chemotherapy to rituximab administration was 3 months. chronic lymphocytic leukemia. week.3–27. (38). 8 and 10 months after completion the treatment. NR. Moreover. (36) Total 38 0. All three patients were alive at ﬁrst CR of AIHA and LD at the time of publication from 8 to 20 months (median 8 months). It is important to note. Four rituximab infusions were given at a standard dose of 375 mg/m2 once per week. All patients had previously received two or more courses of immunosuppressive therapy. w. Trape and colleagues (36) reported ﬁve cases of LD who were treated successfully with rituximab resulting in a clinical improvement of both the AIHA and of the LD. This is the largest series of children with AIHA treated with this agent reported so far. Two patients had large B-cell NHL. (7) Reference R. ﬂudarabine. Ig. warm-reactive autoantibodies of the IgG type were demonstrated by the direct antiglobulin test. patients. With a median follow-up of 15 months 13 patients responded and two did not respond. median. achieving remission. and CHOP (cyclophosphamide. These results have recently been conﬁrmed by Zecca and colleagues (7) in a group of 15 children treated with rituximab. mitoxantrone.6 m 6 (100) NR CR (%) Response OR (%) 6 (100) 13 (87) 4 (100) 8 (100) 5 (100) NR NR 3 (60) R 375 mg/m /weekly · 4–12 w R 375 mg/m2/weekly · 2–4 w Refractory to prednisone Refractory to steroids and/or Ig PatientsÕ characteristic 3. year. CLL. m. He was previously treated with chlorambucil and prednisone. rituximab. respectively. Most of the patients were given three infusions of rituximab. LD. In 13 cases. (38) Gupta et al.3–70 yr Number of patients 6 15 R 375 mg/m2/weekly · 4–6 w R 375 mg/m2/weekly · 2–5 R 375 mg/m2/weekly · 4 Treatment regimen 2 36 (95) 9 (24) 3–22 m . Three patients relapsed 7. All patients remained in complete remission 15–22 months after the start of rituximab therapy. lymphoproliferative disorders. M. Larger studies evaluating efficacy of rituximab in autoimmune hemolytic anemia Quartier et al. All the patients were initially treated with chemotherapy but none of them achieved a stable improvement of AIHA. Some recent reports indicate that rituximab should be considered in the management of lymphoproliferative disorders (LD) with steroid refractory AIHA (33–37). yr. not reported. pt. months. 83 Long-lasting B-cell deficiency Three patients relapsed and 2nd response after retreatment Infections complications in two patients All patients with CLL Four patients in CR of LD NR M 13 m (7–23+) M 8 m (3–20) Comments Table 2. All patients showed a recovery from AIHA and three of them also had CR. m. All patients were refractory to glucocorticosteroids and two also to splenectomy. Two patients received eight additional infusions at the same dose over 14 wk. and dexamethasone. two had B-CLL and one had B-cell prolymphocytic leukemia (PLL). immunoglobulins. Four further children were treated by Motto et al.5–4 yr 60 (46–70) yr 44–66 yr Median age (range) 7–35 m 0.3–14 yr Refractory to steroids Refractory to prednisone Refractory to steroids and chemotherapy all patients with LD 4 8 5 Motto et al. Iannitto and colleagues (37) used rituximab as rescue therapy for a patient with CLL and secondary AIHA. (29) Zecca et al. In four children a concomitant autoimmune disease was present at the time of AIHA diagnosis.
Successful treatment of AIHA complicating haplo-identical hematopoietic stem cell transplantation was reported by Ship et al. The responding patients had warm-type AIHA. However. Combined use of rituximab with cytotoxic agents can be even more eﬀective in the treatment of AIHA in the course of CLL.Robak hydroxyrubicin. A patient with AIHA associated with SLE was also among the six patients described by Quartier and colleagues (29).v. The increase in hemoglobin was evident as early as two cycles. Red blood cell transfusions were discontinued 14 d after the start of rituximab and normal hemoglobin concentration and reticulocyte counts were achieved within 4 months. infusion for 10 d. Larger and prospective trials of this MoAb in the treatment of AIHA who have failed ﬁrst-line therapy with steroids are desirable. Unfortunately. Hongeng and colleagues observed a case of pediatric b-thalassemia major patients who underwent unrelated hematopoietic stem cell transplantation and developed AIHA refractory to corticosteroids and i. 84 Autoimmune hemolytic anemia occurring after hematopoietic stem cell transplantation is poorly responsive to corticosteroids. Subsequently. .2 g/dL following treatment and a median duration of hemoglobin response of 13 months. recent reports of this complication with rituximab treatment seem to be encouraging (40– 42). ﬁve patients who were strongly Coombs positive before treatment turned to Coombs negative. These three case reports indicate that rituximab is an active agent for the treatment of AIHA complicating hematopoietic stem cell transplantation and provide a basis for future prospective trials. starting a few days after therapy and the patient remained disease-free 7 months later. The response to i. at the time of writing the paper. The steroid doses could be reduced to 10 mg of prednisone per day.v. The ﬁrst infusion of MoAb induced a signiﬁcant reduction of lymphocytes and after 5 d the hemoglobin (Hb) level started to increase. Ig therapy (42). Further evidence for eﬃcacy of rituximab in the treatment of refractory AIHA comes from the patients with SLE. Ig or splenectomy is usually also unsatisfactory. Complete remission was observed in one patient and PR in two. He has not had a recurrence of his hemolytic anemia 1 yr after the treatment. azathioprine and cyclosporine. Another child with unrelated hematopoietic stem cell transplantation complicated by steroid refractory AIHA and successfully treated with rituximab has been recently presented by Corti and colleagues (40). These preliminary results indicate that alemtuzumab can induce response in severe AIHA patients who failed to respond to conventional immunosuppression. administered at a dose of 10 mg/d as an i.v. he received rituximab 375 mg/m2 once weekly at a total of two doses. At the end of week 8 there were no signs of AIHA with normal values of reticulocytes and hemoglobin and only slightly positive direct antiglobulin test (DAT) diagnosed as PR according to NCI criteria lasting 2 months at the time of publication. All eight patients achieved remission of AIHA with a median hemoglobin level of 14. cyclophosphamide at a dose 750 mg/m2 on day 2 and dexamethasone at a dose 12 mg given intravenously on days 1 and 2 and orally from day 3 to 7. vincristine and prednisone) and achieved only short PR after each line of therapy. on day 1. Perotta and colleagues (43) observed an 18-yr-old girl with SLE who developed AIHA that did not respond to conventional treatment with steroids. Experience with the use of alemtuzumab in patients with AIHA is very limited. Gupta and colleagues (33) treated eight patients with steroid refractory AIHA in patients with CLL using rituximab at a dose 375 mg/m2 i. One patient with cold-type AIHA had a partial response with reduction in red cell transfusion requirements. It is worth noting that ﬁve patients who relapsed following an initial response were re-treated with this regimen and all of them responded with long-lasting remission. one patient with strongly positive DAT did not respond to treatment with alemtuzumab and died of intractable hemolysis and systemic venous thrombosis. This 1-yr-old child also responded to rituximab therapy. Hemolysis was noted to be decreased during 3 months of observation after treatment and the corticosteroid was tapered oﬀ and discontinued in a month after the second infusion of MoAb.v. Moreover. Willis and colleagues (4) treated four patients with alemtuzumab. Treatment cycles were repeated at 4-wk intervals till a best response was achieved. (41). he was treated with rituximab at a dose of 375 mg/m2/wk for 4 wk. Subsequently. She received three standard doses of rituximab and Hb reached the level of 10 g/dL 15 d after the ﬁrst dose of MoAb. Direct Coombs test positivity progressively declined and she subsequently become negative. Her hemolytic disorder markedly ameliorated after treatment with rituximab. Successful treatment with rituximab of steroid and cyclophosphamide-resistant hemolysis in a CLL patient was also described by Chemnitz and colleagues (35). at the time of publication. A 7-yr-old patient received rituximab 375 mg/m2 weekly at four doses and hemoglobin level stabilized at 11 g/dL 1 wk prior to the ﬁnal dose. The patient’s condition rapidly improved after standard doses of rituximab and the hemolysis parameters tended to normalize on a slightly elevated plateau.
Two patients failed to show any response to rituximab despite high levels of CD20 expression on the neoplastic cells. rituximab was used in combination with IFN-a (47) or corticosteroids and cyclophosphamide (50). (45) Camou et al. some case reports have suggested that rituximab may eﬀectively restore erythropoiesis in Response Treatment regimen R 375 mg/m /weekly · 4 R 375 mg/m2/weekly · 4 R 375 mg/m2/weekly · 4 R 375 mg/m2/weekly · 4 R 375 mg/m2/weekly · 4 R 375 mg/m /weekly · 4 R 375 mg/m2/weekly · 4 R 375 mg/m2/weekly · 4 2 2 Reference Berentsen et al. (54) Lee et al.Monoclonal antibodies in autoimmune cytopenias Cold agglutinin disease Cold agglutinin disease (CAD) is an uncommon hemolytic anemia associated with B-cell lymphoproliferative disorders. OR. overall response. This rare occurrence is related to the production of anti-erythrocyte Ig by neoplastic cells. further studies of this MoAb in patients with this diseases are warranted. Three patients were previously untreated and three pretreated with corticosteroids. (47) Zaja et al. AZ. (46) Mori et al. Recently. mean 68 NR 50. rituximab. Similar results. In some patients. azathioprine. non-Hodkgin's lymphoma NR. CR. (49) Cohen et al. The treatment a remission in all the cases including four PR and one CR. These results suggest that rituximab may represent a true alternative to conventional immunosuppressive therapy for the treatment of CAD. Several small prospective studies and some case reports have demonstrated the beneﬁcial eﬀects of rituximab on CAD associated with the clonal lymphoproliferation as well as idiopathic disease (Table 3) (45–55). (48) Total OR (%) 4 (67) CR (%) 1 (57) Response duration Comments 5 (100) 1 (20) 2 (100) 2 (100) 1 1 NR 1 1 1 1 16 (89) 1 1 0 1 8 (44) 6–14 m. However. treatment with certain drugs and infections. Treatment of PRCA usually involves steroids and/or immunosuppressive drugs including cyclosporine and cyclophosphamide. only about half of the patients respond to such therapy. Corticosteroids are of little value in treating primary CAD. Other therapeutic approaches include alkylating agents. The disease may present in acute or chronic form. months. Primary PRCA is considered to result from the presence of a soluble inhibitory factor which is localized to the Ig fraction and targets undeﬁned molecules on erythroid cells at any stage of diﬀerentiation between erythrocyte burst forming units (BFU-E) and erythroblasts. Monoclonal antibodies in the treatment of pure red cell aplasia Pure red cell aplasia is a rare hematological syndrome that results from an isolated depletion of erythroid precursors from the bone marrow. interferon. However. Others single case reports presenting successful treatment of steroids and chemotherapy refractory CAD have also been presented (46–49. m. One patient achieved CR and three PR. (51) Layios et al. Studies evaluating efficacy of rituximab in cold agglutinin disease Number of patients 6 5 2 1 1 1 1 1 18 Age (years) 55–80. cold agglutinin disease. but they are also usually not eﬀective. autoimmune diseases. not reported. (45) in a prospective study treated six patients with clonal CD20+ j+ B-cell lymphoproliferations with CAD. cladribine and splenectomy. lymphoproliferative disorders. 54). These preliminary results indicate that rituximab may represent an eﬀective option to conventional immunosuppressive therapy for the treatment of CAD and other autoimmune hemolytic disorders. 50. Signiﬁcant improvement has also been shown in a patient with refractory mixed cryoglobulin syndrome (type 2) (56) and in a patient with mixed warm and cold AIHA not associated with lymphoproliferative disease who relapsed after tapering of corticosteroids (52). Among the 28 observations published. the rate of response was 16 (89%) of which eight (44%) achieved CR (Table 3). 60 75 67 72 52 65 50–80 Patients' characteristic Primary CAD. It is unlikely that these additional agents play a role in inducing remission of hemolysis but they may inﬂuence the underlying lymphoproliferative diseases. were observed by Camou and colleagues who treated ﬁve patients with four weekly rituximab infusions (53). three patients untreated Primary CAD Refractory Secondary NHL Refractory to CY Secondary NHL Refractory Refractory to prednisone and AZ Primary CAD Primary CAD improved during rituximab therapy. NHL. frequently in association with thymomas. One relapsed patient median 11 m responded for R re-treatment 9 and 11 m Rapid and sustained response after R therapy Patient was treated with IFN-a simultaneously with R therapy 8m 10 m 3+m 8+m 3 € 14 m Lymphoma cells disappeared after R therapy CAD. (53) Eneglhardt et al. Berentsen et al. IFN-a. However. cyclophosphamide and/or cladribine. CY. chlorambucil. complete response. 85 . in these patients hemolysis Table 3. cyclophosphamide. R. interferona.
Simultaneously. PRCA. he received rituximab at a dose of 375 mg/m2. In particular. another patient with PRCA coexisting with CLL and unresponsive to corticosteroids and Ig was also successfully treated with alemtuzumab (63). Nevertheless. pure red cell aplasia. Similar results were presented by Battle and colleagues (59). MoAb was administered at standard doses weekly for 4 wk. ALG MP. AIHA PRCA. Rituximab was administered 6 wk after last cycle of 86 ﬂudarabine treatment at a dose of 375 mg/m2/wk for 8 wk and her reticulocyte count increased gradually from 0. CS. patients with acquired PRCA.0 g/dL. His reticulocyte count rose to 25% and by the eighth week on rituximab his hemoglobin level was 12. Auner and colleagues treated a 68-yr-old man with acquired PRCA refractory to conventional treatment including prednisone. CLL PRCA. Subsequently. (57) Zecca et al. prednisone and i. This case report suggests that lower doses of rituximab than those needed for the treatment of lymphomas may be highly eﬀective in eliminating the erythropoietic inhibitor from the patient’s serum. Conclusions The results presented above indicate that MoAbs are highly active and well tolerated in autoimmune cytopenias. They reported a patient with CLL in prolymphocytic transformation who developed PRCA without response to cyclosporin A but who responded to rituximab therapy. The treatment resulted in marked depletion of B cells and rise in reticulocyte count and hemoglobin levels leading to transfusion independence and normal values of these parameters for 5 months without therapy at the time of publication. IVIG. A year after the initiation of rituximab treatment the patient’s hemoglobin and reticulocyte count were normal. IVIG. that a case of PRCA caused by chronic persistent parvovirus B19 infection in a patient treated with rituximab for nonHodgkin’s lymphoma has been also reported (62). AIHA. CS All refractory R R R R R 375 375 375 375 375 Treatment mg/m2/weekly mg/m2/weekly mg/m2/weekly mg/m2/weekly mg/m2/weekly · · · · · 8 8 3 2 4 CR CR CR CR CR Response of PRCA of PRCA of PRCA 5+m of PRCA 10 + m 12 + m 12 + m 6+m 18 m to 79 yr 100% CR NHL. respectively. CS P. 60). months. The second patient developed PRCA after ﬁve cycles of ﬂudarabine. P FA CS. intravenous immunoglobulins. Ig is an eﬀective treatment of this complication. rituximab. Pure red cell aplasia occurs in approximately 5% of CLL. chlorambucil. non-Hodgkin's lymphoma.8 g/ dL without red cell transfusion. and two patients were non-responders. (60) Total 79 47 68 18 58 Age yr yr yr m yr Disease characteristic PRCA. Maschan and colleagues reported successful treatment of PRCA with a single dose of rituximab (200 mg/m2) in a child after major ABOincompatible peripheral blood allogeneic stem cell transplantation for acquired aplastic anemia (61).1% to 10% by the eighth week of rituximab therapy. fludarabine. Clinical experience with alemtuzumab in patients with PRCA is very limited. m. Ig and then responded dramatically to rituximab administered at 375 mg/m2/wk for eight consecutive wk. The ﬁrst patient did not respond to cyclosporin A. even if immunosuppressive therapies have failed (57–63).v. autoimmune hemolytic anemia. prednisone. rituximab appeared to have signiﬁcant eﬃcacy in the treatment of refract- . Pure red cell aplasia is also a well-recognized complication of allogeneic hematopoietic cell transplantation. P. MP. CR. one detected during de novo presentation and one during therapy with ﬂudarabine (60). complete response. CLL. Response was obtained in two patients at 2 months and at 6 wk. Six months after rituximab therapy the patient remained well with a stable hemoglobin level of 12. The rapid increase in reticulocyte counts a few days after ﬁrst rituximab infusion was observed. administered weekly for a total of three doses. Administration of i. chronic lymphocytic leukemia. Ghasal observed two patients with B-cell CLL and PRCA. Chl. yr. R. Chl. CLL Primary PRCA Acquired PRCA. Studies evaluating rituximab in pure red cell aplasia Reference Ghazal (59) Ghazal (59) Auner et al. almost complete disappearance of CD19+ B cells from the peripheral blood was seen.Robak Table 4.v. Two recent case reports suggest that rituximab is an eﬀective treatment of this CLL complication (59. (58) Battle et al.1 g/dL and did not need a transfusion during 8 months follow-up. most often in the course of disease but also at presentation. Willis and colleagues treated four patients with PRCA with alemtuzumab (4). FA. erythropoietin and antithymocyte globulin (ATG) with rituximab (57). Its development poses diﬃcult therapeutic problems. It should be noted however. ALG. cyclosporine. methyl prednisolone. Three months after completion of therapy the reticulocyte count was 89 · 109/L and the hemoglobin had reached 12. Recently. years. The results are summarized in Table 4. CLL Previous treatment IVIG. Similar observation was made by Zecca and colleagues who gave rituximab only twice in an 18-month-old girl (58). antilymphocyte globulin.
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