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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Rituximab for the treatment of refractory autoimmune hemolytic anemiain children Marco Zecca, Bruno Nobili, Ugo Ramenghi, Silverio Perrotta, Giovanni Amendola, Pasquale Rosito, Momcilo Jankovic,Paolo Pierani, Piero De Stefano, Mario Regazzi Bonora, and Franco Locatelli Autoimmune hemolytic anemia (AIHA) in
undergone splenectomy. After complet-
8, and 10 months after rituximab infusion,
children is sometimes characterized by a
ing treatment, all children received intra-
respectively. All 3 children received a
severe course, requiring prolonged ad-
venous immunoglobulin for 6 months.
second course of rituximab, again achiev-
Treatment was well tolerated. With a me-
ing disease remission. Our data indicate
therapy. Rituximab is able to cause selec-
dian follow-up of 13 months, 13 patients
that rituximab is both safe and effective in
tive in vivo destruction of B lymphocytes,
(87%) responded, whereas 2 patients did
reducing or even abolishing hemolysis in
with abrogation of antibody production.
not show any improvement. Median hemo-
children with AIHA and that a sustained
In a prospective study, we have evaluated
globin levels increased from 7.7 g/dL to a
response can be achieved in the majority
the use of rituximab for the treatment of
2-month posttreatment level of 11.8 g/dL
of cases. Disease may recur, but a sec-
AIHA resistant to conventional treatment.
(P < .001). Median absolute reticulocyte
ond treatment course may be successful
Fifteen children with AIHA were given
counts decreased from 236 to 109 ؋ 109/L
in controlling the disease. (Blood. 2003;
rituximab, 375 mg/m2/dose for a median
(P < .01). An increase in platelet count
of 3 weekly doses. All patients had previ-
was observed in patients with concomi-
ously received 2 or more courses of immu-
tant thrombocytopenia (Evans syndrome).
nosuppressive therapy; 2 patients had
Three responder patients had relapse, 7,
2003 by The American Society of Hematology
Autoimmune hemolytic anemia (AIHA) in children is usually Rituximab is a chimeric, human, IgG1/␬ monoclonal anti- characterized by a good prognosis; the disease often presents as an body (MoAb) specific for the CD20 antigen, expressed on the acute, self-limited illness, with good response to short-term steroid surface of B lymphocytes. This antibody has induced rapid in therapy in nearly 80% of patients.1 However, in some cases, AIHA vivo depletion of both normal B lymphocytes and lymphoma can be characterized by a chronic course and an unsatisfactory control of hemolysis, thus requiring prolonged immunosuppressive Its in vivo mechanisms of action include complement- therapy. Especially in children younger than 2 years of age or in mediated cytotoxicity, antibody-dependent cytotoxicity, inhibi- teenagers, the clinical course of the disease may show either tion of B-cell proliferation, and induction of apoptosis.4 resistance to steroids or dependence on high-dose steroids,2 with Rituximab has demonstrated good clinical activity in the subsequent development of severe side effects on growth, bone treatment of relapsed, low-grade B-cell CD20ϩ non-Hodgkin mineralization, and the endocrine system. The mortality rate in lymphoma (NHL), particularly in patients with follicular NHL.5-8 these children with primary AIHA has been reported to be on the The good therapeutic efficacy, coupled with its limited toxicity, consisting primarily of infusion-related events, has led Splenectomy, administration of immunosuppressive drugs such to the recent use of this agent for the treatment of autoimmune as azathioprine, cyclosporine A, or cyclophosphamide, or immuno- disorders, with the aim of interfering with or, at best, abolishing modulating agents, such as intravenous immunoglobulin, have been used frequently, alone or in combinations, with the aim of Preliminary results of this application appeared encourag- reducing steroid dependence and controlling hemolysis. However, ing9-17 and prompted us to evaluate, in a prospective multicenter these therapies are not consistently effective and present a non- study, the efficacy of rituximab for treatment of children negligible risk of infectious complications due to their profound affected by AIHA resistant to conventional immunosuppressive therapy or requiring continuous high-dose steroid treatment.
From the Oncoematologia Pediatrica, IRCCS Policlinico San Matteo, Pavia, Supported in part by grants from AIRC (Associazione Italiana per la Ricerca sul Italy; Clinica Pediatrica I, Seconda Universita` degli Studi, Napoli, Italy; Clinica Cancro), CNR (Consiglio Nazionale delle Ricerche), and IRCCS Policlinico Pediatrica, Universita` di Torino, Ospedale Regina Margherita, Torino, Italy; Ematologia-Oncologia Pediatrica, Ospedale di Nocera Inferiore, Italy; ClinicaPediatrica, Universita` di Bologna, Policlinico Sant’Orsola, Bologna, Italy; Reprints: Franco Locatelli, Oncoematologia Pediatrica, IRCCS Policlinico San
Clinica Pediatrica, Universita` di Milano Bicocca, Nuovo Ospedale San Matteo, P.le Golgi 2, I-27100 Pavia, Italy; e-mail:
Gerardo, Monza, Italy; Clinica Pediatrica, Universita` di Ancona, Italy; and The publication costs of this article were defrayed in part by page charge Farmacologia Clinica, IRCCS Policlinico San Matteo, Pavia, Italy.
payment. Therefore, and solely to indicate this fact, this article is herebymarked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
Submitted November 25, 2002; accepted January 8, 2003. Prepublished online asBlood First Edition Paper, January 16, 2003; DOI 10.1182/blood-2002-11-3547.
2003 by The American Society of Hematology BLOOD, 15 MAY 2003 ⅐ VOLUME 101, NUMBER 10 combination with cyclosporine A (2 cases) or with cyclosporine A and Patients and methods
azathioprine (2 cases), at time of rituximab treatment.
After completing the treatment, all children received intravenous Patient characteristics
substitutive therapy with a commercial immunoglobulin preparation (400mg/kg every 3 weeks for 6 months) to prevent therapy-induced Five boys and 10 girls, with a median age at diagnosis of 2 years (range, 0.3-14 years), were prospectively enrolled in this study, approved by theinstitutional review boards of the participating centers. Written informedconsent was obtained from the parents. Data on one of these patients have Definitions
Treatment response was defined as at least a 1.5 g/dL increase of Nine children were affected by AIHA, and the other 6 patients had hemoglobin concentration (Hb) together with a 50% reduction of absolute Evans syndrome. We found no evidence of primary T- or B-lymphocyte reticulocyte count, observed within 2 months from MoAb administration.
In all patients, a complete blood and reticulocyte count was performed In 13 cases, warm-reactive autoantibodies of IgG type were demon- twice weekly for the first 2 months or until a clinical response, meeting the strated by the direct antiglobulin test (DAT), whereas in another case IgM criteria, was achieved. Subsequently, patients were followed once weekly cold agglutinins were present, and in another DAT remained In 4 children a concomitant autoimmune disease was present at time of Surface marker analysis
AIHA onset: systemic lupus erythematosus in 1, rheumatoid arthritis in 2,and vitiligo in 1. In one child, AIHA developed after allogeneic bone The MoAbs used in this study for characterizing phenotype of circulating T and B marrow transplantation, performed for treatment of mucopolysaccharidosis.
cells were: anti–Leu-4 (CD3), anti–Leu-3a (CD4), anti–Leu-2a (CD8), anti– Further details on the clinical features of the patients enrolled and on Leu-12 (CD19), anti–Leu-16 (CD20), anti-human IgM, antihuman IgG, and pretreatment hematologic values are reported in Table 1.
antihuman IgA (Becton Dickinson, Mountain View, CA). Appropriate isotype- All children had received 2 or more courses of immunosuppressive matched controls were included. Phenotypic analysis of cell populations was treatment. Eleven patients were given also a third immunosuppressive performed by means of indirect immunofluorescence with fluorescein- course, and splenectomy had been performed in 2 patients, in an attempt to conjugated Fab2 goat anti-mouse or by direct immunofluorescence in 2-color control hemolysis. Details on immunosuppressive therapy before rituximab analysis using directly labeled antibodies on a FACScan flow cytometer (Becton Dickinson). Results obtained from these patients were compared with those Ten patients had received a median of 4 packed red blood cell (RBC) observed in age-matched healthy children.19 transfusions before MoAb treatment (range, 2-11 transfusions). Four patientswere transfusion dependent at time of beginning of rituximab treatment.
Data analysis and presentation
Treatment with rituximab
Data were analyzed as of October 1, 2002. Results were expressed as Rituximab (kindly provided by Roche, Milan, Italy) was administered median and range or as absolute number and percentage, as appropriate or intravenously at a dosage of 375 mg/m2/dose, as a 5-hour infusion. Three children received 2 weekly doses, whereas 10 patients received 3 doses and Normal distribution of pretreatment and posttreatment hematologic the remaining 2 were treated with 4 doses of rituximab. Before each values was evaluated with the Shapiro-Wilk W test. Pretreatment and infusion, all children received premedication with methylprednisolone and posttreatment hematologic values were compared using the Wilcoxon matched-pairs test and the Student t test for dependent samples, as In 2 patients, no concomitant therapy was administered, whereas the appropriate. P Ͻ .05 was considered statistically significant and expressed remaining 13 children were receiving steroids, alone (9 cases) or in in detail; P from .05 to .1, even though not statistically significant, was Table 1. Patient characteristics
Hematologic values before rituximab treatment Evans indicates Evans syndrome; post-BMT, patient given allogeneic bone marrow transplantation for treatment of type 1 mucopolysaccharidosis; Rheum arth, rheumatoid arthritis; SLE, systemic lupus erythematosus; —, not applicable.
Table 2. Therapies administered before rituximab treatment
IV MPDN indicates intravenous methylprednisolone; oral PDN, oral prednisone; IV IgG, intravenous immunoglobulin; AZA, azathioprine; Cs-A, cyclosporine A; CY, cyclophosphamide; —, not applicable.
shown in detail, whereas P Ͼ .1 was expressed as nonsignificant (NS). The Figure 1A). Median pretreatment and 2-month posttreatment SAS package (SAS Institute, Cary, NC) was used for the analysis of absolute reticulocyte count was 236 ϫ 109/L (range, 118-750 ϫ 109/L; mean, 320 Ϯ 175 ϫ 109/L) and 109 ϫ 109/L (range, 35-288 ϫ 109/L;mean, 109 Ϯ 67 ϫ 109/L), respectively (P Ͻ .01; Figure 1B).
In the 13 responding patients the median increase in Hb level 2 months after completion of treatment was 4 g/dL (range, 1.5-9g/dL; mean 4.2 Ϯ 2.2 g/dL), and the median decrease in absolute The median follow-up for the 15 patients is 14 months (range, 7-28 reticulocyte count was Ϫ210 ϫ 109/L (range, Ϫ22 to Ϫ600 ϫ months). All patients completed the therapeutic program.
109/L; mean, Ϫ217 Ϯ 200 ϫ 109/L).
DAT, positive in 14 of the 15 children before treatment, became Treatment safety and infectious complications
negative in 6 of them (43%) at the evaluation performed 2 months The treatment was generally well tolerated. Only 3 children after the first MoAb infusion, whereas indirect antiglobulin test presented moderate side effects during the infusions: fever in 2 (IAT) became negative in 2 of the 5 previously positive patients.
children and upper airway edema in the other. In all, side effects Transfusion-dependent patients did not require any more RBC promptly resolved with appropriate therapy (oral acetaminophen transfusions 2 months after treatment discontinuation. The median for the first 2 cases, and intravenous hydrocortisone plus inhalatory time from the first dose of rituximab to the last RBC transfusion salbutamol and budesonide for the third case).
One child developed primary varicella-zoster virus (VZV) A raise in platelet count, concomitant with Hb increase, was infection 2 months after rituximab administration; the infection observed in patients with Evans syndrome; platelet number in- resolved with antiviral therapy without sequelae.
creased from a pretreatment median value of 27 ϫ 109/L (range,4-61 ϫ 109/L; mean, 30 Ϯ 27 ϫ 109/L) to a value of 140 ϫ 109/L Treatment response
(range, 64-150 ϫ 109/L; mean, 118 Ϯ 47 ϫ 109/L) 2 months afterstart of treatment.
On the whole, 13 of the 15 patients enrolled (87%) responded totreatment, showing at least a 1.5 g/dL increase of Hb and a morethan 50% reduction of absolute reticulocyte count. Two patients(13%), both affected by isolated AIHA with warm-reactive IgGautoantibodies, did not show any improvement after 3 doses ofrituximab and were considered as nonresponders (Figure 1A).
In responding patients, the 1.5 g/dL increase in Hb level was observed after a median of 12 days from the first MoAb administra-tion (range, 5-72 days); the 50% reticulocyte reduction wasdetected after 21 days (range, 5-82 days; Table 3).
Figure 1. Hemoglobin and absolute reticulocyte counts. Pretreatment and
Considering the whole study population, median Hb level 2-months posttreatment levels of hemoglobin (A) and absolute reticulocyte count (B), increased from a pretreatment value of 7.7 g/dL (range, 3.5-10.0 as well as pretreatment and posttreatment mean values Ϯ SD for the whole studypopulation. The difference between pretreatment and posttreatment values is g/dL; mean, 7.7 Ϯ 1.8 g/dL) to a 2-month posttreatment level of statistically significant (P Ͻ .001). Small circles indicate the value for each patient; 11.8 g/dL (range, 6.0-14.2 g/dL; mean, 11.4 Ϯ 2.1 g/dL; P Ͻ .001; large circles, median values for the entire study population.
BLOOD, 15 MAY 2003 ⅐ VOLUME 101, NUMBER 10 Table 3. Details of treatment with rituximab and results
*At least a 1.5 g/dL increase of hemoglobin. — indicates not applicable.
Figure 2A shows the raise of haptoglobin level after treatment, Disease status at last follow-up
increasing from undetectable to 20 mg/dL (range, 0-160 mg/dL; Three responder patients (23%) experienced a recurrence of mean, 44 Ϯ 55 mg/dL) 2 months after start of treatment.
hemolysis at 7, 8, and 10 months after the first rituximab infusion, In all responding patients corticosteroids and concomitant respectively. All these children received a second treatment course immunosuppressive drugs were progressively tapered and stopped, with rituximab and all achieved a second disease remission. One of in 10 of them at a median time of 12 weeks (range, 9-25 weeks).
these children subsequently received a third and a fourth course of The 10 patients with sustained response are free from any rituximab, due to further relapses of hemolysis, with a new positive Immunophenotype analysis
The remaining 10 patients (77% of the responders) are alive and free from immunosuppressive drugs at a median of 13 months after Pretreatment absolute number of B lymphocytes was 0.7 ϫ 109/L treatment (range, 10-28 months). At time of last follow-up, median (range, 0.25-1.6 ϫ 109/L; normal values in our laboratory being Hb level in this subgroup of patients was 12.3 g/dL (range, 10-14.7 0.15-0.8 ϫ 109/L), with the median percentage of B lymphocytes g/dL) and median reticulocyte count was 57 ϫ 109/L (range, being 22% (range, 14%-39%; normal values in our laboratory 21-73 ϫ 109/L). Also total and direct bilirubin, as well as lactic being 5%-20%). After treatment, B lymphocytes became undetect- dehydrogenase and haptoglobin, were within the normal ranges able in all patients, without any difference between responders and (data not shown). Nevertheless, DAT remains positive in 3 of these nonresponders (Figure 2B). As expected, no significant modifica- 10 patients (30%) and IAT is positive in 2 (20%).
tion in the levels of CD3ϩ, CD4ϩ, and CD8ϩ cells were documented.
B-lymphocyte count returned to normal 6 months after treat- ment in 10 of the 15 patients (67%), whereas it was still below thenormal range in 5 (33%; Figure 2B). Possibly due to the relatively Discussion
limited number of patients, no statistically significant correlationwas observed between the B-lymphocyte number 6 months after The anti-CD20 MoAb rituximab has been shown to be effective for treatment and the risk of recurrence of hemolysis in the 13 the treatment of B-cell malignancies, in particular low-grade lymphomas.3,6,7,20 More recently, this new agent was described, inpreliminary reports, as a possible promising treatment for patientswith refractory AIHA.9-18,21 However, treatment of a rather limitednumber of patients was reported, with heterogeneous clinicalfeatures and a relatively short follow-up period. Only the study ofQuartier et al9 evaluated the efficacy of rituximab on a relativelyhomogenous group of 6 children with AIHA.
In our trial, the efficacy and safety of rituximab was prospec- tively evaluated in the largest series of children with AIHA reportedso far. Whereas in the paper by Quartier et al9 all patients achieved Figure 2. Haptoglobin and absolute B-lymphocyte counts. Pretreatment and
sustained remission, in our cohort rituximab was not effective in 2 2-month posttreatment levels of haptoglobin (A) and pretreatment, 2-month posttreat- patients and 3 more children had relapses. Remarkably, our study ment, and 6-month posttreatment absolute B lymphocyte counts (B), as well as mean population comprised a significant number of very young patients, values Ϯ SD for the whole study population. Small circles indicate the value for eachpatient; large circles, median values for the entire study population.
the median age at diagnosis being 2 years. In children with onset of AIHA before the age of 2 years the course of disease is commonly humoral immunity, was successfully cured with administration protracted and immunosuppressive treatment is not consistently effective and carries a risk of death from infections.2,9 In our cohort Compared with the other immunosuppressive agents used for of patients, only 1 of the 8 children younger than 2 years of age was the treatment of antibody-mediated autoimmune disorders, ritux- refractory to treatment with rituximab. On the other hand, 2 of the 3 imab presents the advantage of inducing selective B-cell immuno- relapses occurred in this subgroup of patients.
suppression, sparing cellular immunity mediated by T cells and Rituximab could be safely readministered in the 3 patients with natural killer (NK) cells. The specific impairment of antibody relapses, confirming the low immunogenicity of the MoAb due to production can be easily corrected by prophylactic intravenous its human component, which would not preclude retreatment.
immunoglobulin administration, which allows maintenance of As concerns the type of autoantibody responsible for the normal IgG levels for the whole period of B-cell depletion. For this hemolysis, Finazzi, reviewing the data available in the literature, reason, we gave replacement therapy with intravenous immuno- suggested that a better response could be achieved in patients with globulins. However, the need for prophylactic infusion of immuno- cold-agglutinin disease, as compared with warm-autoantibody globulins has not been proved in a controlled study and most AIHA.22 In our study population, only one child had cold- patients treated with rituximab for B-cell malignancies did not agglutinin disease; this child had a good response to the treatment, but had a relapse 7 months after the first course of rituximab.
The mechanism by which treatment with rituximab is effective In the study published by Quartier et al,9 all patients received at in AIHA is still not completely defined. The simplest explanation is least 4 infusions of rituximab, which is the standard schedule of that the source of pathogenetic antibodies is removed. However, treatment used in patients with B-cell malignancies. However, some studies on other autoimmune diseases did not show any because B cells have been reported to disappear from peripheral correlation between the decline of autoantibody levels and re- blood as soon as after 2 to 3 doses of rituximab,10 most of our sponse,26,27 suggesting that additional mechanisms involving anti- patients were given 3 infusions of the MoAb, thus reducing costs.
gen presentation and help to T cells are involved.
One possible reason for concern regarding this form of treat- In conclusion, our data indicate that rituximab is effective in ment is represented by the prolonged impairment of antibody reducing or even abolishing hemolysis in most pediatric patients production, leading to an increased risk of viral and bacterial with AIHA and that a sustained response can be achieved in the infections. Pure RBC aplasia due to parvovirus B19 infection has majority of cases. Moreover, the effects of prolonged therapy with been reported after administration of rituximab,8,23 as well as acute steroids (growth impairment, fluid retention, avascular necrosis of viral hepatitis B24 and bacterial pneumonia.25 In our series of bone) or other nonspecific immunosuppressive drugs (eg, life- patients, we did not observe an increased risk of infectious threatening infections) are avoided. Recurrence of the hemolysis complication. Only one child had primary VZV infection, 2 months may occur, but a second treatment course is feasible and may be after rituximab infusion. This infection, despite the impairment of successful in controlling the disease.
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