Prolonged Hypogammaglobulinemia After Rituximab Therapy for Post-Transplant EBV-Lymphoproliferative Disorder Following Hematopoietic Stem Cell Transplantation in Pediatric Patients

Abstract 4480

Post-transplant lymphoproliferative disorder (PTLD) caused by Epstein Barr Virus (EBV) is a severe complication in allogeneic hematopoietic stem cell transplantation (HSCT). Rituximab is an effective treatment, now commonly used as early therapy against B-cell PTLD and preemptive treatment of EBV reactivation. In first trials, rituximab was considered to have little adverse events. As exposure to this therapy is increasing worldwide, special toxicities are recognized including prolonged hypogammaglobulinemia (PH). Few details are known about duration and severity of rituximab induced low serum immunoglobulin status, especially in pediatric population treated with this drug for PTLPD after HSCT.

This retrospective study was conducted in one pediatric HSCT center (Robert Debré Hospital, Paris, France). Between December 2008 and June 2011, among 138 transplanted children, 39 children received rituximab (Mabthera®, Roche, Paris, France) for either EBV reactivation or B-cell PTLD. 28 children were then followed for immune status more than 12 months after rituximab based therapy. Median age at HSCT was 7 years (range 1 to 18). There were 17 males and 11 females. Indications for HSCT were hematological malignancy (n=17), sickle cell disease (n=3), B thalassemia (n=1), severe aplastic anemia (n=4) and inherited bone marrow failure (n=3). 23 children underwent 1 HSCT, 4 children received 2 while 1 received 3 HSCT. They received HSCT from either MSD (n=10), 9 to 10/10 HLA MUD (n=16), haploidentical familial donor (n=1) or unrelated 5/6 cord blood (n=1). PH was defined as serum Ig G level < 3.3g/l (1 year old), < 5g/l (1 to 5 year old), < 5.5 g/l (5 to 15 years old) and <6.5 g/l after 15 years old or serum IgM level < 0.5g/l, more than 12 months after HSCT. IV-Ig replacement therapy was used when serum immunoglobulin level was under the median range for age.

Median duration of hypogammaglobulinemia was 13 months (range 0 to 38): 60% (17/28) of patients had PH that last in 3 cases more than 24 months (24, 27 and 38 months) after HSCT. 6 children still have a low immunoglobulin status. Among patients with PH, 6 underwent HSCT from 9/10 MUD, 1 from haploidentical family donor and 1 from unrelated cord blood. 3 patients received 2 HSCT and 1 patient 3 HSCT. 10 children with PH had abnormal levels of immunoglobulin before rituximab therapy. Regarding B-cell reconstitution, normalization of B cell count for age was obtained in every child, by a median time of 7.5 months (range 5 to 19) after HSCT in PH cases and 7 months (range 4 to 9) in non PH cases. Among patients with PH, 5 presented repeated lower or upper respiratory track infections (vs. 1 without PH). 2 had pancytopenia secondary to a Parvovirus B 19 infection, 1 presented an extensive VZV infection 17 month after HSCT, and 1 had Pneumocystis jirovecii pneumonia 9 month after HSCT. 1 child presented invasive aspergillosis 8 months after HSCT and 2 months after IV-Ig supplementation interruption.

Although rituximab induces almost complete depletion of normal B lymphocytes in peripheral blood for an average of 6–9 months, prolonged serum immunoglobulin suppression is unusual. However, PH has been reported in patients treated with rituximab in association with chemotherapy, or after either autologous or allogeneic HSCT. In some of these studies, phenotypical analysis of B cell recovery help to find abnormalities in naïve B cell differentiation into memory B cells and plasma cells. It may help to explain that normalization of B-cell count is not systematically followed by a rapid increase in immunoglobulin. It seems that during the period of post HSCT immune reconstitution, rituximab could affect, in association with other immunosuppressive factors, not only B cell quantity but also B cell quality. PH may be then a frequent event as we report in our study. Consequences of PH on infection severity and frequency are controversial. Infectious complications secondary to rituximab-associated PH are rare but some are reported as a fatal invasive aspergillosis, frequent pulmonary infections, parvovirus or VZV infections. We also report such severe infections in our patients with PH. Thus, every EBV-PTLD patient treated with rituximab must be monitored closely with regard to serum Ig levels and probably have to receive IV-Ig supplementation, even if its interest remains unproved. B-cell sub-population monitoring may probably help to understand mechanism of PH and identify high-risk patients.