|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Medical Sciences, Regina
Apostolorum Hospital, Albano Laziale, Italy; and the Department of
Hematology, University of Rome "Tor Vergata," S. Eugenio Hospital,
Rome, Italy.
The role of rituximab, a chimeric monoclonal antibody
directed against the CD20 antigen, in the treatment of patients with chronic idiopathic thrombocytopenic purpura (ITP) has not been determined. The effectiveness and side effects of this therapeutic modality were investigated in a cohort of 25 individuals with chronic
ITP. All patients had ITP that had been resistant to between 2 and 5 different therapeutic regimens, including 8 patients who had already
failed splenectomy. Patients were scheduled to receive intravenous
rituximab at the dose of 375 mg/m2 once weekly for 4 weeks.
Rituximab infusion-related side effects were observed in 18 patients,
but were of modest intensity and did not require discontinuation of
treatment. A complete response (platelet count greater than
100 × 109/L) was observed in 5 cases, a partial response
(platelet count between 50 and 100 × 109/L) in 5 cases,
and a minor response (platelet count below 50 × 109/L,
with no need for continued treatment) in 3 cases, with an overall
response rate of 52%. In 7 cases, responses were sustained (6 months
or longer). In 2 patients with relapsed disease, repeat challenge with
rituximab induced a new response. In patients with a complete or
partial response, a significant rise in platelet concentrations was
observed early during the course of treatment, usually 1 week after the
first rituximab infusion. No clinical or laboratory parameter was found
to predict treatment outcome, although there was a suggestion that
women and younger patients have a better chance of response. In
conclusion, rituximab therapy has a limited but valuable effect in
patients with chronic ITP. In view of its mild toxicity and the lack of
effective alternative treatments, its use in the setting of chronic
refractory ITP is warranted.
(Blood. 2001;98:952-957) Idiopathic thrombocytopenic purpura (ITP) is an
immune-mediated disorder in which platelets are opsonized by
autoantibodies and prematurely destroyed by the reticuloendothelial
system.1 Approximately 25% to 30% of adult patients
develop a chronic disease that will become refractory to
corticosteroids and splenectomy, as well as other available agents.
Because the 10-year mortality rate for this group of refractory
patients ranges from 10% to 20%,2-5 there is a need for
more effective therapeutic interventions.
Novel approaches to treatment of chronic refractory ITP are based on a
better understanding of the immunologic abnormalities associated with
this disorder,6,7 as well as the availability of
sophisticated biotechnology products.8 One such approach involves the use of monoclonal antibodies directed against the CD20
antigen, a transmembrane protein found on the surface of normal and
malignant B cells, but not on hematopoietic stem cells, pro-B cells,
normal plasma cells, or other normal tissues. The CD20 molecule appears
particularly suitable for targeted therapy because it does not shed
from the cell surface and does not internalize upon antibody
binding.9
Rituximab is a genetically engineered chimeric murine/human anti-CD20
monoclonal antibody currently used for the treatment of non-Hodgkin
lymphoma. The antibody is an IgG1 kappa immunoglobulin containing
murine light- and heavy-chain variable region sequences and human
constant region sequences.10 The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes, and the Fc domain recruits
immune effector functions to mediate B-cell lysis in vitro. Possible
mechanisms of cell lysis include complement-dependent cytotoxicity,
antibody-dependent cellular cytotoxicity, and induction of apoptosis.
Rituximab is highly effective for in vivo depletion of B
cells,10 and the rationale for its use in chronic ITP
rests on the attempt to eliminate autoreactive B-cell clones.
In the current report, we detail the effectiveness and side effects of
rituximab treatment in a cohort of 25 individuals with chronic ITP.
Patients
In accordance with the guidelines published by the American Society of
Hematology, treatment was considered appropriate for these patients
either because of a platelet count less than 20 × 109/L,
regardless of their symptoms, or because of the presence of purpura or
significant mucous membrane bleeding, regardless of platelet
count.2,3 All patients had already received at least 2 lines of treatment, with a median of 3. Previous treatments included:
standard dose (1 to 2 mg · kg On study entry, patients had signed an institutional review board-approved informed consent. Treatment regimen Rituximab (Mabthera; Roche, Milan, Italy) at a dose of 375 mg/m2 was administered intravenously once weekly for a total of 4 infusions (days 1, 8, 15, and 22) on an outpatient basis. The drug was reconstituted in normal saline to a concentration of no more than 1 to 4 mg/mL. The initial infusion rate was 50 mg/h, with subsequent infusion-rate increase if no toxicity was seen. Premedication with oral acetaminophen 500 mg and diphenhydramine 50 mg was given to all patients. Those who experienced any treatment-related nausea or vomiting with the first treatment received subsequent premedication with a serotonin receptor antagonist. Administration of corticosteroids was avoided.Laboratory studies Laboratory evaluation before enrollment included: complete hemogram; serum chemistry profiles; direct and indirect Coombs test; prothrombin time; partial thromboplastin time; fibrinogen levels; and serologic tests for hepatitis B and C, HIV, cytomegalovirus, and toxoplasmosis. Immunology studies included tests for C3 and C4 fractions of complement, antinuclear antibodies, anti-double-stranded DNA antibodies and anticardiolipin antibodies (ACA), lymphocyte subsets, and serum immunoglobulin (IgG, IgA, and IgM) concentrations. ACA and the lupuslike anticoagulant were determined as described previously.11 Platelet-associated IgG (PAIgG) was quantified by an enzyme-linked immunosorbent assay. Briefly, blood was collected into EDTA and platelet concentrates were obtained by differential centrifugation. Afterward, platelets were incubated for 5 minutes at room temperature (RT) with ammonium oxalate to remove residual erythrocytes, washed twice, and resuspended in a Ringer's/2-mM EDTA solution. Platelet suspensions were then disrupted by 3 cycles of freeze-thawing, sonicated, and centrifuged, and the supernatant was employed for IgG detection. Fifty-microliter aliquots of the platelet extracts at appropriate dilutions were pipetted into each well of a microtiter plate and incubated at RT for 3 hours. The plate had been coated with anti-human IgG (Dakopatts A/S, Glostrup, Denmark) and treated overnight with 1% bovine serum albumin-phosphate-buffered saline (PBS) (Sigma Chemical, St Louis, MO) to block residual binding sites. After triple washing with PBS-1% Tween (Sigma), 50 µL horseradish peroxidase-conjugated rabbit anti-human IgG (Dakopatts A/S) was added to each well and further incubated at RT for 90 minutes. A substrate solution of O-phenylenediamine dihydrochloride (Sigma) was added, the reaction was stopped after 30 minutes with 1 N H2SO4, and the color reaction was read at 490 nm. A standard curve for IgG was made in each plate by using reference standard sera (Dakopatts A/S). The intra-assay and interassay variabilities were 8.3% and 10.4%, respectively. The upper limit of normal was 10 ng/106 platelets.Monitoring of patients included a weekly hemogram and determination of lymphocyte subsets, and monthly determinations of serum immunoglobulin and PAIgG concentrations. Response criteria Response was evaluated after the 4 weeks of treatment. Criteria for response were defined as follows: (1) complete response (CR), a rise of platelets to normal counts (ie, more than 100 × 109/L); (2) partial response (PR), a rise of platelets to counts between 50 and 100 × 109/L; (3) minor response (MR), a rise of platelets to counts below 50 × 109/L with no need for continued treatment; and (4) no response or refractory disease, when there was no rise in platelet count or a rise that did not exceed 50 × 109/L, with a need for continued treatment. Responses were considered sustained when they lasted at least 6 months.Statistical analysis Statistical analysis was carried out with the STATISTICA for Windows (Kalmia, Cambridge, MA) software package on an IBM-compatible computer. Comparisons between the groups were performed with Mann-Whitney U test or the Kruskal-Wallis test, and correlation analysis with the Spearman rank correlation test. A P value of .05 or less was designated as statistically significant.
Response All patients completed the scheduled treatment. As illustrated in Table 3, after the 4 courses of rituximab, the platelet count was at least 50 × 109/L in 10 patients (40%), with 5 achieving a CR and 5 a PR. Three additional patients (nos. 4, 24, 25) had a clinical improvement classified as MR because their platelet counts did not rise above 50 × 109/L but they had no need for continued treatment. Six of the patients with a major (CR+PR) response (nos. 2, 5, 11, 14, 19, 22) and one with a minor response (no. 4) have remained in remission with stable platelet counts during follow-up intervals of 6 to more than 27 months after the end of treatment. In 4 patients who achieved either a CR (no. 3) or a PR (nos. 6, 13, 20), response was not sustained. In 2 other patients (nos. 24 and 25) with a minor response, the follow-up was less than 6 months. There were no late responses (ie, responses observed after the end of therapy). In patients with a major response, an increase in platelet counts occurred during rituximab therapy, with peak responses observed up to 4 weeks following the end of treatment (Table 3, Figure 1). The median peak platelet count in these individuals was 117 × 109/L (range, 62-395 × 109/L) 1 week after the last infusion of rituximab.
A representative course of a responding patient (no. 19) is shown in
Figure 2. This patient had a 3-year
history of ITP that had relapsed after conventional-dose steroids,
intravenous immunoglobulins, and splenectomy, and had not responded to
vincristine and pulse cyclophosphamide. She was dependent on 50 mg/d of
oral prednisone to keep a safe platelet count. A significant rise in
the platelet count was observed after the first antibody infusion, with
a progressive increase until a platelet peak of
463 × 109/L recorded in week 7. She is still in
remission with a stable platelet count at 9 months after the end of
treatment.
Four relapsed patients (nos. 3, 5, 6, 11) were rechallenged with rituximab at the same dose and schedule. Repeat treatment resulted in a new response in 2 patients (nos. 6, 11), with one patient (no. 6) having maintained counts in excess of 100 × 109/L for 8 months. The relation between patient variables and their response to rituximab
is reported in Table 4. None of the
parameters analyzed (age, sex, pretreatment platelet values, duration
of disease, number and type of previous treatments, and PAIgG
levels) were related to treatment outcome (P value
not significant for all parameters). From our data, however, there is
at least a suggestion that women and younger patients respond better to
rituximab.
Adverse events Eighteen patients experienced a total of 27 adverse events during therapy (Table 5). Most of these side effects were recorded during the first infusion and were typically brief and of mild intensity (grades 1 and 2 according to the National Cancer Institute criteria). The antibody infusion was temporarily stopped only once in the single patient who had grade 2 chills (no. 18). In this patient, adjustment of subsequent infusion rates avoided recurrence of symptoms.
Three patients had hemoglobin levels decrease to as low as 10 to 11 g/dL at 6 to 8 weeks upon conclusion of rituximab infusions; recovery occurred in a median of 7 days. One patient (no. 15) had granulocytes decrease to a level of 1 to 1.5 × 109/L 4 weeks after therapy, with recovery by 10 days. No infections occurred during therapy. Those that occurred for up to a year thereafter were predominantly bacterial, and the majority were of minor clinical relevance (16 of 19 grade 1; none grade 3 or 4). The respiratory tract was the source in 16 and the urinary tract in 2; gastroenteritis occurred in 1. Viral infections included herpes zoster in one patient. Monitoring of immunologic parameters Increased PAIgG levels before rituximab treatment were detected in all 19 patients in whom this analysis could be performed. No relation was observed between PAIgG concentrations and clinical parameters. Serial determinations for up to 6 months after treatment indicated that the clinical response was not associated with normalization or significant reduction of PAIgG. In particular, PAIgG declined to normal levels in 3 of the responders and in 5 of the nonresponders (Table 6).
Median serum IgG, IgA, and IgM levels remained within normal limits throughout the study, although 6 patients had reductions of IgM, IgG, or both to subnormal levels. A nonsignificant decrease from baseline in the C3 component of serum complement was noted in 8 patients. Peripheral blood B cells, evaluated by flow cytometry as
CD19+ cells, had a median baseline count of
189 × 106/L (range, 56-418 × 106/L). This
count declined with treatment, to subnormal levels after the first dose
for the majority of patients (Figure 3).
In all patients, we recorded nadir values of B cells below the normal range (Table 6). Recovery of B cells started between 6 and 9 months,
reaching normal values between 9 and 12 months.
Median absolute T-cell counts in peripheral blood, using CD3, CD4, and CD8 as well as natural-killer-cell counts, remained stable during the study period.
Rituximab was administered to 25 patients with chronic ITP over a 4-week period. All patients had ITP that had been resistant to between 2 and 5 different therapeutic regimens, including 8 patients who had already failed splenectomy. Ten patients (40%) had a PR or CR to treatment, and 3 (12%) had a clinical improvement classified as MR. In 7 patients (28%), responses had a duration of 6 months or longer. No clinical or laboratory parameter was found to predict treatment outcome. The rituximab schedule employed in the current study has been borrowed from earlier trials in which this antibody was used to treat relapsed or refractory low-grade or follicular B-cell non-Hodgkin lymphomas.12-14 With this schedule, adverse events were mild and did not require discontinuation of treatment. Side effects occurred mainly during the first infusion, and typically included moderate and brief fever and chills. By the second and subsequent infusions, the majority of patients experienced no further infusion-related toxicities. Because this agent depletes normal B cells, it is also notable that the infectious episodes observed during the follow-up period had modest clinical relevance. Apart from anecdotal reports, the only 2 other studies of rituximab
therapy in chronic ITP with a significant number of patients have been
published in abstract form. Perotta et al15 described 10 patients, of whom 6 had already failed splenectomy. Using the antibody
with the same schedule as in the present study, they attained 1 PR and
5 CRs. Response duration ranged from 1 to more than 14 months. Saleh et
al16 reported the preliminary results of a phase I/II
dose-escalation trial. Objective responses were observed only in 3 of
the 13 patients (23%) who received the highest dose level of 375 mg · m The modality of response raises some issues about the mechanism of action of rituximab in chronic ITP. In responders, the rise in platelet counts is observed rapidly, usually 1 week after the first rituximab dose. This is unlikely to be due to a fall in circulating antiplatelet antibodies. In fact, only a minority of patients develop reductions of IgM and IgG below the normal range, seen 5 to 11 months after administration. On the other hand, our flow cytometry studies have confirmed previous data that a depletion of peripheral blood B cells occurs after just one antibody infusion.12-14 Thus, it is tempting to speculate that opsonized B cells can inhibit macrophage Fc-receptor function and clearance of IgG-coated platelets, a mechanism that has analogy with the proposed effect of reticuloendothelial blockade by anti-D immuglobulin.17 This effect eventually adds to the suppression of autoreactive B-cell clones that can account for the sustained remission observed in some patients. Unfortunately, we were not able to monitor patients for the development of human anti-chimeric antibodies (HACA) because this assay has not yet been made commercially available. However, from earlier experience in patients with non-Hodgkin lymphoma, it appears that less than 1.0% of patients evaluated for HACA were positive.14,18 Although monitoring of PAIgG did not allow a correlation with clinical response, the importance of the quantity of PAIgG in chronic ITP is controversial. Results are obviously dependent on the sensitivity and specificity of the assay19 and are complicated by the fact that antiplatelet antibodies are a pool of immunoglobulins including different isotypes with varying affinities.20 In this study, we used a "second-generation" assay, based on the detection of the total IgG content of lysed platelets, that is not able to discriminate antiplatelet antibodies from immune complexes that bind to platelets via the Fc receptor. Therefore, it is clear that this assay does not have a specific diagnostic value and should be used in conjunction with clinical findings and other test results. Another weak point is that this technique does not provide comparable results with respect to the amount of measured PAIgG.19 Rituximab therapy in our series gave results that compare favorably with those of standard secondary ITP agents such as vinca alkaloids, danazol, oral cyclophosphamide, and azathioprine. All of these agents are expected to have, at best, response rates in the range of 40% to 50%, but sustained-remission rates are usually well below 20%.2-5 Data in the literature suggest that intensive chemotherapy, particularly pulse cyclophosphamide, may produce better results by virtue of the suppression of lymphocyte numbers and function.21,22 In our series, however, 4 patients had received pulse cyclophosphamide with no response. Besides, 2 of these patients had a complete and sustained response with rituximab, indicating either different immunologic targets or a greater efficacy of the antibody in eliminating autoreactive clones. Several patient characteristics were examined for an association with rituximab treatment outcome. Because of the small number of patients studied, none of the associations reached statistical significance. There is a suggestion, however, that women and younger patients respond better to rituximab. The biologic significance of these findings, if confirmed, remains to be determined. In conclusion, our results indicate that rituximab therapy has a limited but valuable effect in patients with chronic ITP. In view of its mild toxicity and the lack of effective alternative treatments, it should be strongly considered in severely affected patients who do not respond to standard therapy. Some issues about this agent, such as the optimum dose and treatment schedule, the exact mechanisms of action, and long-term side effects, remain to be explored and warrant further investigation.
We acknowledge Roche Company for supplying, in part, the rituximab monoclonal antibody used in this study. We also thank Franco Nasella for bibliographic assistance.
Submitted January 23, 2001; accepted April 10, 2001.
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: Roberto Stasi, Department of Medical Sciences, Regina Apostolorum Hospital, Via S. Francesco, 50, 00041 Albano Laziale, Italy; e-mail: roberto.stasi{at}schering-plough.it.
1.
George JN, El-Havake MA, Raskob GE.
Chronic idiopathic thrombopenic purpura.
N Engl J Med.
1995;331:207-211
2.
George JN, Woolf SH, Raskob GE, et al.
Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology.
Blood.
1996;88:3-40
3.
Diagnosis and treatment of idiopathic thrombocytopenic purpura: recommendations of the American Society of Hematology. The American Society of Hematology ITP Practice Guideline Panel.
Ann Intern Med.
1997;126:319-326
4.
McMillan R.
Therapy for adults with refractory chronic immune thrombocytopenic purpura.
Ann Intern Med.
1997;126:307-314 5. Stasi R, Stipa E, Masi M, et al. Long-term observation of adults with chronic idiopathic thrombocytopenic purpura: a study of 208 cases. Am J Med. 1995;98:436-442[CrossRef][Medline] [Order article via Infotrieve]. 6. McMillan R. Autoantibodies and autoantigens in chronic immune thrombocytopenic purpura. Semin Hematol. 2000;37:239-248[CrossRef][Medline] [Order article via Infotrieve]. 7. Semple JW, Lazarus AH, Freedman J. The cellular immunology associated with autoimmune thrombocytopenic purpura: an update. Transfus Sci. 1998;19:245-251[CrossRef][Medline] [Order article via Infotrieve]. 8. Aster RH, George JN, McMillan R, et al. Workshop on autoimmune (idiopathic) thrombocytopenic purpura: pathogenesis and new approaches to therapy. Am J Hematol. 1998;58:231-234[CrossRef][Medline] [Order article via Infotrieve]. 9. Einfeld DA, Brown JP, Valentine MA, et al. Molecular cloning of the human B cell CD20 receptor predicts a hydrophobic protein with multiple transmembrane domains. EMBO J. 1988;7:711-717[Medline] [Order article via Infotrieve].
10.
Reff ME, Carner K, Chambers KS, et al.
Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20.
Blood.
1994;83:435-445
11.
Stasi R, Stipa E, Masi M, et al.
Prevalence and clinical significance of elevated antiphospholipid antibodies in patients with idiopathic thrombocytopenic purpura.
Blood.
1994;84:4203-4208 12. Maloney DG, Grillo-Lopez AJ, Bodkin DJ, et al. IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J Clin Oncol. 1997;15:3266-3274[Abstract].
13.
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.
1997;90:2188-2195 14. McLaughlin P, Grillo-López AJ, Link BK, 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. 1998;16:2825-2833[Abstract]. 15. Perotta A, Sunneberg TA, Scott J, et al. Rituxan in the treatment of chronic idiopathic thrombocytopenic purpura [abstract]. Blood. 1999;94:49a. 16. Saleh MN, Gutheil J, Moore M, et al. A pilot study of anti-CD20 MoAb rituximab in patients with refractory immune thrombocytopenic purpura (ITP) [abstract]. Blood. 2000;96:252a. 17. Bussel JB. Fc receptor blockade and immune thrombocytopenic purpura. Semin Hematol. 2000;37:261-266[CrossRef][Medline] [Order article via Infotrieve].
18.
Czuczman MS, Grillo-López AJ, White CA, et al.
Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy.
J Clin Oncol.
1999;17:268-276 19. Berchtold P, Muller D, Beardsley D, et al. International study to compare antigen-specific methods used for the measurement of antiplatelet autoantibodies. Br J Haematol. 1997;96:477-483[CrossRef][Medline] [Order article via Infotrieve]. 20. Karpatkin S. Autoimmune (idiopathic) thrombocytopenic purpura. Lancet. 1997;349:1531-1536[CrossRef][Medline] [Order article via Infotrieve].
21.
Figueroa M, Gehlsen J, Hammond D, et al.
Combination chemotherapy in refractory immune thrombocytopenic purpura.
N Engl J Med.
1993;328:1226-1229
22.
Reiner A, Gernsheimer T, Slichter SJ.
Pulse cyclophosphamide therapy for refractory autoimmune thrombocytopenic purpura.
Blood.
1995;85:351-358
© 2001 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  J. B. Bussel, D. J. Kuter, V. Pullarkat, R. M. Lyons, M. Guo, and J. L. Nichol Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP Blood, March 5, 2009; 113(10): 2161 - 2171. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kelly, M. Gleeson, and P. T. Murphy Slow responses to standard dose rituximab in immune thrombocytopenic purpura Haematologica, March 1, 2009; 94(3): 443 - 444. [Full Text] [PDF]
|
|
|
|
|
|
F. Zaja and R. Fanin Slow responses to standard dose rituximab in immune thrombocytopenic purpura. Author reply Haematologica, March 1, 2009; 94(3): 444 - 445. [Full Text] [PDF]
|
|
|
|
|
|
F. Zaja, M. L. Battista, M. T. Pirrotta, S. Palmieri, M. Montagna, N. Vianelli, L. Marin, M. Cavallin, M. Bocchia, M. Defina, et al. Lower dose rituximab is active in adults patients with idiopathic thrombocytopenic purpura Haematologica, June 1, 2008; 93(6): 930 - 933. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T Fukushima, L Dong, T Sakai, T Sawaki, M Miki, M Tanaka, Y Masaki, Y Hirose, M Kuwana, and H Umehara Successful treatment of amegakaryocytic thrombocytopenia with anti-CD20 antibody (rituximab) in a patient with systemic lupus erythematosus Lupus, March 1, 2008; 17(3): 210 - 214. [Abstract] [PDF]
|
|
|
|
|
|
M. Ruggeri, S. Fortuna, and F. Rodeghiero Heterogeneity of terminology and clinical definitions in adult idiopathic thrombocytopenic purpura: a critical appraisal from a systematic review of the literature Haematologica, January 1, 2008; 93(1): 98 - 103. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. DiLillo, Y. Hamaguchi, Y. Ueda, K. Yang, J. Uchida, K. M. Haas, G. Kelsoe, and T. F. Tedder Maintenance of Long-Lived Plasma Cells and Serological Memory Despite Mature and Memory B Cell Depletion during CD20 Immunotherapy in Mice J. Immunol., January 1, 2008; 180(1): 361 - 371. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Berentsen Rituximab for the treatment of autoimmune cytopenias Haematologica, December 1, 2007; 92(12): 1589 - 1596. [Full Text] [PDF]
|
|
|
|
|
|
D. Provan, T. Butler, M. L. Evangelista, S. Amadori, A. C. Newland, and R. Stasi Activity and safety profile of low-dose rituximab for the treatment of autoimmune cytopenias in adults Haematologica, December 1, 2007; 92(12): 1695 - 1698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Semple Rituximab disciplines T cells, spares platelets Blood, October 15, 2007; 110(8): 2784 - 2785. [Full Text] [PDF]
|
|
|
|
|
|
R. Stasi, G. Del Poeta, E. Stipa, M. L. Evangelista, M. M. Trawinska, N. Cooper, and S. Amadori Response to B-cell depleting therapy with rituximab reverts the abnormalities of T-cell subsets in patients with idiopathic thrombocytopenic purpura Blood, October 15, 2007; 110(8): 2924 - 2930. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. R. Sperr, K. Lechner, and I. Pabinger Rituximab for the treatment of acquired antibodies to factor VIII Haematologica, January 1, 2007; 92(1): 66 - 71. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Chung, A. A. Funke, E. F. Chakravarty, J. P. Callen, and D. F. Fiorentino Successful use of rituximab for cutaneous vasculitis. Arch Dermatol, November 1, 2006; 142(11): 1407 - 1410. [Full Text] [PDF]
|
|
|
|
 |
|
 R. Stasi, E. Stipa, G. Del Poeta, S. Amadori, A. C. Newland, and D. Provan Long-term observation of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with rituximab Rheumatology, November 1, 2006; 45(11): 1432 - 1436. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Z. Latifzadeh and V. Entezari Chronic Refractory Idiopathic Thrombocytopenic Purpura (ITP) and Anti-CD20 Monoclonal Antibody: A Case Report Clinical and Applied Thrombosis/Hemostasis, October 1, 2006; 12(4): 489 - 492. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Salvi, G. Vannucchi, I. Campi, S. Rossi, P. Bonara, F. Sbrozzi, C. Guastella, S. Avignone, G. Pirola, R. Ratiglia, et al. Efficacy of rituximab treatment for thyroid-associated ophthalmopathy as a result of intraorbital B-cell depletion in one patient unresponsive to steroid immunosuppression. Eur. J. Endocrinol., April 1, 2006; 154(4): 511 - 517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Bennett, Z. R. Rogers, D. D. Kinnamon, J. B. Bussel, D. H. Mahoney, T. C. Abshire, H. Sawaf, T. B. Moore, M. L. Loh, B. E. Glader, et al. Prospective phase 1/2 study of rituximab in childhood and adolescent chronic immune thrombocytopenic purpura Blood, April 1, 2006; 107(7): 2639 - 2642. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Perrotta Re-treatment of Chronic Idiopathic Thrombocytopenic Purpura With Rituximab: Literature Review Clinical and Applied Thrombosis/Hemostasis, January 1, 2006; 12(1): 97 - 100. [Abstract] [PDF]
|
|
|
|
|
|
G. Luzzatto, G. Cella, and F. Fabris Sustained Response to Anti-CD20 Monoclonal Antibody in Severe Acute Primary Immune Thrombocytopenic Purpura: Report of One Adult Case Clinical and Applied Thrombosis/Hemostasis, January 1, 2006; 12(1): 120 - 121. [PDF]
|
|
|
|
 |
|
 D. S. Beardsley ITP in the 21st Century Hematology, January 1, 2006; 2006(1): 402 - 407. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. R. Ahn, C. J. Bidot, V. Fontana, P. Dudkiewicz, W. Jy, L. Horstman, and Y. S. Ahn Rituximab Therapy Induces Long Lasting Clinical Remissions and Reduction of Anti-Platelet Glycoprotein Autoantibodies in Patients with Chronic Immune Thrombocytopenic Purpura (ITP). Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 4006 - 4006. [Abstract]
|
|
|
|
|
|
K. Dunussi-Joannopoulos, G. E. Hancock, A. Kunz, M. Hegen, X. X. Zhou, B. J. Sheppard, J. Lamothe, E. Li, H.-L. Ma, P. R. Hamann, et al. B-cell depletion inhibits arthritis in a collagen-induced arthritis (CIA) model, but does not adversely affect humoral responses in a respiratory syncytial virus (RSV) vaccination model Blood, October 1, 2005; 106(7): 2235 - 2243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. B. Cines and J. B. Bussel How I treat idiopathic thrombocytopenic purpura (ITP) Blood, October 1, 2005; 106(7): 2244 - 2251. [Full Text] [PDF]
|
|
|
|
|
|
S A Chambers and D Isenberg Anti-B cell therapy (Rituximab) in the treatment of autoimmune diseases Lupus, March 1, 2005; 14(3): 210 - 214. [Abstract] [PDF]
|
|
|
|
|
|
M. Tokunaga, K. Fujii, K. Saito, S. Nakayamada, S. Tsujimura, M. Nawata, and Y. Tanaka Down-regulation of CD40 and CD80 on B cells in patients with life-threatening systemic lupus erythematosus after successful treatment with rituximab Rheumatology, February 1, 2005; 44(2): 176 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. W. Edwards and G. Cambridge Prospects for B-cell-targeted therapy in autoimmune disease Rheumatology, February 1, 2005; 44(2): 151 - 156. [Full Text] [PDF]
|
|
|
|
|
|
H Tahir and D A Isenberg Novel therapies in lupus nephritis Lupus, January 1, 2005; 14(1): 77 - 82. [Abstract] [PDF]
|
|
|
|
|
|
J. Cabrera, F. J. Penalver, I. Millan, V. Jimenez-Yuste, M. Almagro, A. Alvarez-Larran, L. Rodriguez, and other 36 participants in the multicentric retrospe Mabthera (Rituximab) in the Treatment of 92 Patients with Refractory Immune Thrombocytopenic Purpura. Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 2074 - 2074. [Abstract]
|
|
|
|
 |
|
 R H Carter B cell signalling as therapeutic target Ann Rheum Dis, November 1, 2004; 63(suppl_2): ii65 - ii66. [Full Text] [PDF]
|
|
|
|
 |
|
 H. Knecht, M. Baumberger, A. Tobon, and A. Steck Sustained remission of CIDP associated with Evans syndrome Neurology, August 24, 2004; 63(4): 730 - 732. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Stasi, M. Brunetti, E. Stipa, and S. Amadori Selective B-cell depletion with rituximab for the treatment of patients with acquired hemophilia Blood, June 15, 2004; 103(12): 4424 - 4428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C Gorman, M Leandro, and D Isenberg Does B cell depletion have a role to play in the treatment of systemic lupus erythematosus? Lupus, May 1, 2004; 13(5): 312 - 316. [Abstract] [PDF]
|
|
|
|
|
|
R J Looney, J Anolik, and I Sanz B lymphocytes in systemic lupus erythematosus: lessons from therapy targeting B cells Lupus, May 1, 2004; 13(5): 381 - 390. [Abstract] [PDF]
|
|
|
|
 |
|
 R. Stasi and D. Provan Management of Immune Thrombocytopenic Purpura in Adults Mayo Clin. Proc., April 1, 2004; 79(4): 504 - 522. [Abstract] [PDF]
|
|
|
|
|
|
M. Kuwana, S. Nomura, K. Fujimura, T. Nagasawa, Y. Muto, Y. Kurata, S. Tanaka, and Y. Ikeda Effect of a single injection of humanized anti-CD154 monoclonal antibody on the platelet-specific autoimmune response in patients with immune thrombocytopenic purpura Blood, February 15, 2004; 103(4): 1229 - 1236. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Vesely, J. J. Perdue, M. A. Rizvi, D. R. Terrell, and J. N. George Management of Adult Patients with Persistent Idiopathic Thrombocytopenic Purpura Following Splenectomy: A Systematic Review Ann Intern Med, January 20, 2004; 140(2): 112 - 120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Dupuy, M. Viguier, C. Bedane, F. Cordoliani, S. Blaise, F. Aucouturier, J.-M. Bonnetblanc, P. Morel, L. Dubertret, and H. Bachelez Treatment of Refractory Pemphigus Vulgaris With Rituximab (Anti-CD20 Monoclonal Antibody) Arch Dermatol, January 1, 2004; 140(1): 91 - 96. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Hassan, J. Williams-Gould, T. Watson, L. Pai-Scherf, and I. Pastan Pretreatment with Rituximab Does Not Inhibit the Human Immune Response against the Immunogenic Protein LMB-1 Clin. Cancer Res., January 1, 2004; 10(1): 16 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. D. Shanafelt, H. L. Madueme, R. C. Wolf, and A. Tefferi Rituximab for Immune Cytopenia in Adults: Idiopathic Thrombocytopenic Purpura, Autoimmune Hemolytic Anemia, and Evans Syndrome Mayo Clin. Proc., November 1, 2003; 78(11): 1340 - 1346. [Abstract] [PDF]
|
|
|
|
|
|
T Shaw, J Quan, and M C Totoritis B cell therapy for rheumatoid arthritis: the rituximab (anti-CD20) experience Ann Rheum Dis, November 1, 2003; 62(90002): ii55 - 59. [Full Text] [PDF]
|
|
|
|
|
|
K Saito, M Nawata, S Nakayamada, M Tokunaga, J Tsukada, and Y Tanaka Letter to the Editor Lupus, October 1, 2003; 12(10): 798 - 800. [PDF]
|
|
|
|
|
|
D. Sansonno, V. De Re, G. Lauletta, F. A. Tucci, M. Boiocchi, and F. Dammacco Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon alpha with an anti-CD20 Blood, May 15, 2003; 101(10): 3818 - 3826. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zecca, B. Nobili, U. Ramenghi, S. Perrotta, G. Amendola, P. Rosito, M. Jankovic, P. Pierani, P. De Stefano, M. R. Bonora, et al. Rituximab for the treatment of refractory autoimmune hemolytic anemia in children Blood, May 15, 2003; 101(10): 3857 - 3861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-G. Fischer, B. Deschler, M. Lubbert, A. Wiestner, B. B. Weksler, and G. P. Schechter Acquired high-titer factor VIII inhibitor: fatal bleeding despite multimodal treatment including rituximab preceded by multiple plasmaphereses Blood, May 1, 2003; 101(9): 3753 - 3754. [Full Text] [PDF]
|
|
|
|
 |
|
 A Pestronk, J Florence, T Miller, R Choksi, M T Al-Lozi, and T D Levine Treatment of IgM antibody associated polyneuropathies using rituximab J. Neurol. Neurosurg. Psychiatry, April 1, 2003; 74(4): 485 - 489. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Boye, T. Elter, and A. Engert An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab Ann. Onc., April 1, 2003; 14(4): 520 - 535. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Zheng, A. M. Pallera, L. T. Goodnough, J. E. Sadler, and M. A. Blinder Remission of Chronic Thrombotic Thrombocytopenic Purpura after Treatment with Cyclophosphamide and Rituximab Ann Intern Med, January 21, 2003; 138(2): 105 - 108. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. G. DeLoughery Thrombocytopenia in Critical Care Patients J Intensive Care Med, November 1, 2002; 17(6): 267 - 282. [Abstract] [PDF]
|
|
|
|
|
|
A. Wiestner, H. J. Cho, A. S. Asch, M. A. Michelis, J. A. Zeller, E. I. B. Peerschke, B. B. Weksler, and G. P. Schechter Rituximab in the treatment of acquired factor VIII inhibitors Blood, October 16, 2002; 100(9): 3426 - 3428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R J Looney Treating human autoimmune disease by depleting B cells Ann Rheum Dis, October 1, 2002; 61(10): 863 - 866. [Full Text] [PDF]
|
|
|
|
|
|
U. P. Hegde, W. H. Wilson, T. White, and B. D. Cheson Rituximab treatment of refractory fludarabine-associated immune thrombocytopenia in chronic lymphocytic leukemia Blood, August 28, 2002; 100(6): 2260 - 2262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Engelhardt, A. Jakob, B. Ruter, M. Trepel, F. Hirsch, and M. Lubbert Severe cold hemagglutinin disease (CHD) successfully treated with rituximab Blood, August 13, 2002; 100(5): 1922 - 1923. [Full Text] [PDF]
|
|
|
|
|
|
R. Stasi, E. Stipa, V. Forte, P. Meo, and S. Amadori Variable patterns of response to rituximab treatment in adults with chronic idiopathic thrombocytopenic purpura Blood, May 15, 2002; 99(10): 3872 - 3873. [Full Text] [PDF]
|
|
|
|
|
|
M. Morselli, M. Luppi, L. Potenza, L. Facchini, S. Tonelli, D. Dini, G. Leonardi, A. Donelli, F. Narni, and G. Torelli Mixed warm and cold autoimmune hemolytic anemia: complete recovery after 2 courses of rituximab treatment Blood, May 1, 2002; 99(9): 3478 - 3479. [Full Text] [PDF]
|
|
|
|
 |
|
 D. B. Cines and V. S. Blanchette Immune Thrombocytopenic Purpura N. Engl. J. Med., March 28, 2002; 346(13): 995 - 1008. [Full Text] [PDF]
|
|
|
|
|
|
G. Emilia, M. Morselli, M. Luppi, G. Longo, R. Marasca, G. Gandini, L. Ferrara, N. D'Apollo, L. Potenza, M. Bertesi, et al. Long-term salvage therapy with cyclosporin A in refractory idiopathic thrombocytopenic purpura Blood, February 15, 2002; 99(4): 1482 - 1485. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Catlett and B. M. Alving Update in Hematology Ann Intern Med, January 15, 2002; 136(2): 136 - 143. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2001 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
1 · d
