We explored the safety and efficacy of rituximab administered in combination with the standard transplant conditioning regimen of cyclophosphamide (Cy) 120 mg/kg and total body irradiation (TBI) 12 Gy for adult patients with acute lymphoblastic leukemia (ALL). Patients were eligible if their disease expressed CD20. Rituximab was administered at 375 mg/m2 weekly for four doses beginning on day −7 of the conditioning regimen. Graft-versus-host-disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Thirty-five patients undergoing matched sibling (n=23) or unrelated donor (n=12) transplantation were studied, with a median age of 30 years (range 15–55 years). At 2 years, progression-free survival, treatment-related mortality, and overall survival were 30, 24, and 47%, respectively. There was no delay in engraftment or increased incidence of infection. The cumulative incidence of grade II–IV acute GVHD was 17%, and limited and extensive chronic GVHD was 43% at 2 years. The addition of rituximab to the standard Cy/TBI transplant conditioning regimen in ALL was safe and well tolerated, and there was a suggestion of decreased incidence of acute GVHD when compared to historically reported GVHD rates for this group of patients.
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment option for adults with high-risk or recurrent acute lymphoblastic leukemia (ALL). Current survival rates for ALL patients who undergo transplantation after completing a standard total body irradiation (TBI)-based preparative regimen range broadly from 20 to 60%, depending primarily on the disease status at the time of the transplant.1, 2, 3, 4, 5 Among the primary causes of morbidity and treatment-related mortality (TRM) after a transplant are acute and chronic graft-versus-host disease (GVHD). TRM remains a serious problem, occurring in 20–45% of patients receiving a TBI-based preparative regimen.6, 7, 8 Finding a solution to this problem could greatly improve the outcome for ALL patients.
Rituximab (Rituxan; Genentech Inc., South San Francisco, CA, USA)9 is a humanized monoclonal antibody directed at the CD20 antigen, which is present on one third of B-lineage precursor ALL blasts and on 80–90% of mature B-lineage ALL blasts.10 Adding rituximab to the intensive hyper-CVAD chemotherapy regimen (fractionated cyclophosphamide (Cy), vincristine, doxorubicin, and dexamethasone) commonly used for ALL has improved response rates and disease-free survival (DFS) rates.11, 12 Furthermore, it has been postulated that rituximab, a B-cell-depleting agent, may impede the development of acute and chronic GVHD, which is believed to be promoted by antigen-presenting B cells.13 In several small trials, rituximab has shown activity in treating steroid-resistant chronic GVHD.14, 15, 16 In addition, a retrospective study by Ratanatharathorn et al.17 revealed that prior treatment with rituximab was associated with a lower rate of acute GVHD in patients receiving allogeneic HSCT for non-Hodgkin's lymphoma.
We therefore hypothesized that adding rituximab to the standard Cy/TBI-based transplant conditioning regimen for ALL would reduce the rate of GVHD and improve the antileukemic effects of the regimen. In order to assess the impact of rituximab on this regimen, we compared these patients to a contemporaneous control group who did not receive rituximab.
Patients and methods
Patients were treated at The University of Texas MD Anderson Cancer Center from May 1999 to May 2004. Eligibility criteria included the presence of B-cell, CD20-positive ALL, in remission or with refractory disease, and between ages 15 and 60 years (for patients receiving unrelated donor transplants, the upper age limit was 45 years). In addition, eligible patients needed a Zubrod performance status score of less than 2, no evidence of active infection, and adequate organ function, including a left ventricular ejection fraction greater than 50%, a serum creatinine level less than 1.6 mg/dl, a serum bilirubin level less than 1.5 mg/dl, and diffusing capacity of the lung for carbon monoxide greater than 50% of the predicted value.
All patients and donors gave written informed consent. The protocol was approved by the MD Anderson Cancer Center institutional review board.
All donors were human leukocyte antigen (HLA)-A, -B, and -DR compatible with the patients. HLA typing for class I antigens was performed using standard serologic or low-resolution molecular techniques. Low-resolution molecular typing using hybridization techniques, followed by high-resolution molecular typing using polymerase chain reaction, was performed for class II alleles and as needed for selected class I loci. After January 2002, high-resolution molecular typing of class I and II antigens was performed for all unrelated donor transplants.
Peripheral blood stem cells were obtained from donors using standard mobilization protocols and apheresis techniques; bone marrow was used if peripheral blood could not be used. Stem cells from all related donors were collected at MD Anderson Cancer Center. The cells were not depleted of T lymphocytes. Bone marrow procured from unrelated donors was obtained through the National Marrow Donor Program.
With the day of stem cell infusion designated day 0, patients received 375 mg/m2 of rituximab intravenously (i.v.) on days −7, −1, +7, and +14, plus 60 mg/kg of Cy i.v. on days −7 and −6. This was followed by 12 Gy of TBI administered in daily 3-Gy fractions on days −4 to −1 through anteroposterior fields, with partial lung shielding (5 half-value layers) used during the third dose to reduce the central axis dose by 76–83%, as previously described.18, 19
GVHD prophylaxis consisted of a combination of tacrolimus and methotrexate, a standard regimen used at MD Anderson Cancer Center over the last decade. Methotrexate (5 mg/m2) was given i.v. on days +1, +3, and +6, and also administered on day +11 for unrelated donor transplants. Tacrolimus was administered at a dose to maintain levels between 5 and 15 ng/ml. Tacrolimus was continued for 6 months and then tapered at the discretion of the treating physician. Two patients with ALL that were positive for the Philadelphia chromosome (Ph) were started on imatinib maintenance therapy from 2 to 5 months after transplant. Patients who experienced grade II or higher acute GVHD received i.v. methylprednisolone at a dosage of at least 0.5 mg/kg every 6 h and, if possible, were enrolled in treatment protocols for GVHD.
Institutional transplant guidelines for antimicrobial, antifungal, and antiviral prophylaxis were followed. Specifically, prophylaxis consisted of trimethoprim and sulfamethoxazole for Pneumocystis carinii and acyclovir or valacyclovir for herpes simplex virus. Surveillance cytomegalovirus (CMV) antigenemia testing was performed for all patients, and a positive test triggered the pre-emptive use of ganciclovir or foscarnet. All patients received 5 μg/kg filgrastim subcutaneously (s.c.) daily from day +7 until their absolute neutrophil count was greater than 1.5 × 109/l for 3 consecutive days. Immunoglobulins at dose of 200 mg/kg were infused weekly until day 100 following transplant in patients receiving unrelated donor grafts.
Packed red blood cells were administered to maintain hemoglobin levels ⩾8 g/dl. Platelet transfusions were administered to keep platelet counts ⩾10 × 109/l. All blood products were filtered and irradiated.
Contemporaneous control group
Study patients were retrospectively compared with 31 patients between the ages of 15 and 60 years who were treated for ALL at MD Anderson Cancer Center during the time period from 1999 to 2004. These patients did not have CD20-positive ALL, and received the same Cy/TBI regimen, but without rituximab, followed by allogeneic HSCT from a fully HLA-matched related or unrelated donor. GVHD and supportive care measures were identical to the rituximab group.
Clinical outcome variables
Engraftment was defined as occurring on the first of 3 consecutive days on which the patient had an absolute neutrophil count ⩾0.5 × 109/l. Platelet engraftment was defined as occurring on the first of 7 consecutive days with a platelet count ⩾20 × 109/l without transfusion support. Failure to engraft by day +30 was considered primary engraftment failure. Hematopoietic chimerism was evaluated in bone marrow by restriction fragment length polymorphisms at the AY-29 or YNH24 loci, by conventional cytogenetic analysis by G-banding, or by fluorescence in situ hybridization studies in sex-mismatched cases for the Y chromosome, to determine donor engraftment.
Criteria for a complete response before transplantation included the absence of circulating blasts, less than 5% marrow blasts, and a platelet count ⩾100 × 109/l. A complete response after transplantation was defined using the same criteria except for the omission of the platelet count requirement and for the additional requirement of donor cell engraftment. Standard morphologic criteria, conventional cytogenetics, or both were used to diagnose recurrent disease. Toxicity was scored using the modified National Cancer Institute Common Toxicity Criteria version 3.0.
The diagnosis of GVHD was confirmed by biopsy in some cases but was ultimately determined by clinical presentation. Acute GVHD was clinically graded as 0–IV based on standard published criteria;20 chronic GVHD was classified as none, limited, or extensive.21 GVHD occurring within the first 100 days after the transplant was considered acute, and that occurring after day +100 was defined as chronic. Acute GVHD, which persisted or progressed after day 100 was also scored as chronic GVHD in this study.
Adverse events and hematologic parameters were monitored daily and clinical chemistry parameters at least twice weekly during the initial hospitalization and then at increasing intervals up to day +100. Subsequently, patients were followed up at least quarterly during the first year with physical examinations, assessments for GVHD, blood counts, and bone marrow aspiration and biopsy with chimerism analysis.
Disease progression was defined as greater than 5% marrow blasts, or recurrence of leukemia at any site. TRM was defined as any death attributed to causes other than progression or relapse of leukemia.
The primary end points of the retrospective analysis were overall survival (OS), progression-free survival (PFS), and the incidence of acute and chronic GVHD. Data were analyzed in January 2006. OS was estimated from the date of the transplantation to the time of death or the date of last follow-up. PFS was estimated from the date of the transplantation to the earliest indication of disease progression or to death. Surviving patients in remission were censored at last follow-up.
OS and PFS were estimated using the Kaplan–Meier method.22 The cumulative incidence method was used to estimate the incidence of TRM, disease progression, and GVHD to account for competing risks (disease progression, TRM, and death without GVHD, respectively). Patient characteristics were compared between treatment groups by the χ2-test or Fisher exact test for categorical variables and by the Wilcoxon rank sum test for continuous variables. The Cox's proportional hazards model was used to determine the univariate association between variables and the rate of disease progression and GVHD. A comprehensive multivariate analysis to evaluate the effect of adding rituximab to the preparative regimen independently of patient and disease characteristics was not possible in this study because of the small sample size. Statistical significance was defined as P⩽0.05. The statistical analysis was performed using Stata 7.0 software (Stata Corp., College Station, TX, USA).
Patient demographics and baseline disease characteristics for the study and control group are listed in Table 1. Thirty-five patients (18 males, 17 females) with median age at transplant 30 years (range 15–55) were enrolled on study. All of the patients had B-lineage disease, with the majority having the common ALL antigen (cALLa) phenotype. With respect to commonly accepted features at diagnosis that signify a poor prognosis,23 46% of patients presented with a high-risk karyotype, 32% of patients presented with a white blood cell count greater than 30 000/μl, and 23% of patients took greater than 4 weeks to achieve first complete remission. Finally, the majority of patients were transplanted with advanced disease, with 54% of patients transplanted beyond first remission, and 20% transplanted with active disease.
In the contemporaneous control group, 31 patients (22 males and nine females) with a median age of 35 years (range, 18–53) were treated with Cy/TBI without rituximab (Table 1). Nineteen percent (n=6) of the patients in the control group had T-lineage disease, in contrast to the study group in which all patients had B-lineage disease. With respect to high-risk features, 29% (n=9) of patients had a white blood cell count greater than 30 000/μl, 19% (n=6) required more than 4 weeks to achieve complete remission, and 52% (n=16) of patients in the control group presented with a high-risk karyotype. Unlike the patients in the study group, nearly half of the control group patients were transplanted in first remission (n=17); this difference was statistically significant (P=0.02).
Graft content and engraftment
Stem cell graft characteristics and engraftment data for the study population and for the contemporaneous control group are listed in Table 2. Twenty-three patients in the study group received a matched related graft and 12 received grafts from unrelated donors. Sixteen patients received an unrelated donor transplant before 2002 and had less extensive HLA molecular typing. The source of stem cells was bone marrow for 15 patients and peripheral blood for 20 patients. Peripheral blood stem cell products for related donors only were cryopreserved. Donor/recipient mismatching for CMV seropositivity, ABO blood typing, and sex was evaluated and listed in the table. There were no significant differences noted between the two groups with regards to the graft characteristics.
The median days to absolute neutrophil count >0.5 × 109/l and platelet count >20 × 109/l were 12 (range 9–24) and 13.5 (range 7–74), respectively, for the study group; this was similar to the time to engraftment for the control group. All patients in both study and control groups engrafted with 100% donor chimerism at day 30 following HSCT, except for one patient treated with rituximab who had 2.5% residual recipient cells at day 30. This patient eventually attained 100% donor chimerism.
OS, PFS, and disease progression
With a median follow-up time among survivors of 21 months (range 3–46), OS and PFS for patients in the study group were 47% (95% CI, 28–63%) and 30% (95% CI, 15–46%), respectively, at 2 years (Figure 1). The cumulative incidence of disease progression was 46% (95% CI, 31–69%) at 2 years (Figure 2). Although not statistically significant, there was a trend for increased risk of disease progression in patients transplanted beyond first remission compared to those transplanted in first remission, with hazard ratio 2.2 (95% CI, 0.6–7.8%) at 2 years, P=0.2.
Overall survival, PFS, and disease progression at 2 years were 37% (95% CI, 17–56%), 38% (95% CI, 18–58%), and 29% (95% CI, 17–50%), respectively, for patients in the contemporaneous control group treated without rituximab. A direct comparison to the study group was not possible due to different patient characteristics.
The rates of acute GVHD, grades II–IV and III–IV, were 17% (95% CI, 8–35%) (n=6) and 9% (95% CI, 3–25%) (n=3), respectively, for the study group. The cumulative incidence of chronic GVHD, limited plus extensive, and extensive, were 43% (95% CI, 27–66%) (n=14) and 34% (95% CI, 21–57%) (n=11), respectively (Table 2). The incidence of acute and chronic GVHD was also analyzed for sibling and unrelated donor grafts separately, with no statistically significant difference between the two groups. Of note, however, among 22 evaluable sibling transplants, only one patient developed grade II acute GVHD; no grade III/IV acute GVHD was noted. The incidence of GVHD for the rituximab study group was compared to the control group treated without rituximab. Although there was no difference in the rate of chronic GVHD (Table 2), there was a trend for lower acute GVHD in the rituximab treated group: 17% (95% CI, 8–38%) vs 39% (95% CI, 25–61%), P=0.07 (Figure 3).
The regimen was well tolerated, with no unexpected toxicities, and no regimen-related deaths in the first 100 days. Specifically, no significant infusional toxicities with rituximab were noted. Grade IV toxicity was noted in only one patient who developed a myocardial infarction during unrelated donor bone marrow infusion. Grade III bacterial infection requiring systemic antibiotic therapy occurred in 63% of patients (n=22), and reactivation of CMV occurred in six patients, with no subsequent development of CMV disease. Infections with aspergillus and Escherichia coli were the cause of death in two patients. The cumulative incidence of TRM was 9% (95% CI, 3–25%) and 24% (95% CI, 13–44%) at 100 days and 2 years, respectively (Figure 2). Overall, 19 patients died: infection (n=2), GVHD (n=6), and relapse (n=11). Infection rates and TRM were similar in the control group. Bacterial infections occurred in 58% of patients (n=18), and CMV reactivation was noted in four patients. The cumulative incidence of TRM in the control group was 10% (95% CI, 4–27%) and 33% (95% CI, 18–60%) at 100 days and 2 years, respectively.
To our knowledge, this is the first published study to investigate the effects of rituximab in the allogeneic HSCT setting for ALL. Our study showed that adding rituximab to the standard Cy/TBI transplant conditioning regimen for patients with CD20-positive ALL was feasible, without delayed engraftment or added toxicity. Disease control appeared similar to other TBI-based regimens, with OS and PFS rates similar to what is reported in the literature for adult ALL. However, the observed rate of 17% for acute grade II–IV GVHD was lower than that noted in our contemporaneous control group (Figure 3), and lower compared to rates reported in the literature. In a study of 264 adult ALL patients receiving matched related or unrelated transplants with mostly TBI-based myeloablative conditioning, the rate of grade II–IV acute GVHD was noted to be 30%, with no difference between related or unrelated transplants.8 Cornelissen et al.24 reported on 127 adult patients receiving unrelated donor transplants for high-risk ALL, and observed acute grade II–IV GVHD in 55% of patients.
In a mouse model of acute GVHD25, 26 and in a model of chronic GVHD,27 it has been observed that donor- and host-derived antigen-presenting cells prime T-cells in vivo, thereby contributing to the pathogenesis of GVHD. It has also been found that antigen-presenting B-cells prime T-cells in vivo.28, 29 Schultz et al.30 observed a lower incidence of GVHD in B-cell-deficient host mice than in controls, and the incidence was further reduced when B-cell-deficient mice received B-cell-depleted grafts. Taken together, these studies suggest that antigen-presenting B cells may play an important role in the development of GVHD.
Rituximab, which depletes B cells, was shown to inhibit GVHD in earlier studies. Khouri et al.31 reported a low rate of acute GVHD in patients receiving a rituximab-containing nonmyeloablative transplant regimen to treat indolent lymphoma. The cumulative incidence of acute grade II–IV GVHD was 20%, and the actuarial probability of being alive and in remission after 2 years was 84%. In a study by Shimoni et al.,32 24 patients with refractory non-Hodgkin's lymphoma were treated with rituximab after autologous or allogeneic stem cell transplantation in efforts to reduce the risk of relapse. None of the 10 allogeneic transplant recipients treated with rituximab developed severe GVHD.
The antileukemic effect of HSCT is related to the cytoreductive effect of the preparative regimen, and the subsequent immune-mediated disease eradication via donor-derived T cells, termed the graft-versus-leukemia (GVL) effect. The GVL effect for ALL is less pronounced compared to other types of leukemia, but still associated with the development of GVHD and often consequent extensive morbidity.33 Therefore, efforts to reduce the incidence of GVHD in ALL may not be at the expense of disease control. As observed in this study, despite the modest rate of GVHD, there did not appear to be an excessively high rate of disease relapse for patients treated with rituximab. Rituximab's elimination of malignant cells may occur through any of several potential mechanisms, including direct effects on the malignant cells, complement-dependent cytotoxicity, and antibody-dependent cellular cytotoxicity,34, 35, 36, 37 which may augment donor-derived immune antileukemic effects. Pfeiffer et al.38 found that effector cells and complement from pediatric patients in the presence of rituximab after allogeneic transplantation of T-cell-depleted stem cells elicited both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against B-lineage primary ALL blasts. Clinical data also suggest that rituximab enhances the GVL effect against other lymphoid malignancies. Khouri et al.39 reported longer DFS in chronic lymphocytic leukemia patients receiving a nonmyeloablative preparative regimen of rituximab, fludarabine, and Cy than in patients receiving fludarabine and Cy alone; many patients who had a relapse after transplantation had durable remissions induced by rituximab alone or combined with donor lymphocyte infusions. Thus, the direct antileukemic effect of rituximab may offset a reduction of the GVL effect attributable to GVHD.
In conclusion, we found that adding rituximab to the standard Cy/TBI transplant conditioning regimen for patients with CD20-positive ALL is well tolerated, and results in low rates of acute GVHD without an increased risk of relapse. These observations warrant further investigation in prospective, randomized trials to determine whether including rituximab in the preparative regimen for allogeneic stem cell transplantation can improve the overall treatment outcomes for patients with ALL.
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Kebriaei, P., Saliba, R., Ma, C. et al. Allogeneic hematopoietic stem cell transplantation after rituximab-containing myeloablative preparative regimen for acute lymphoblastic leukemia. Bone Marrow Transplant 38, 203–209 (2006) doi:10.1038/sj.bmt.1705425
- stem cell transplant
- acute lymphoblastic leukemia
- graft-versus-host disease
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