Safety of Addition of Inotuzumab Ozogamicin (CMC 544) to Bendamustine, Fludarabine, and Rituximab (BFR) Allogeneic Conditioning for Lymphoid Malignancies

Background: The cell-surface glycoprotein CD22 is expressed in more than 90% of patients with B-cell lymphoid malignancies, and has emerged as an attractive therapeutic target for B-cell cancers. Inotuzumab ozogamicin (CMC-544) is a humanized anti-CD22 monoclonal antibody conjugated to calicheamicin, a cytotoxic antibiotic agent. After the conjugate binds to CD22, the CD22-conjugate complex is rapidly internalized, and calicheamicin is released. Calicheamicin binds to the minor groove of DNA and thus induces double-strand cleavage and subsequent apoptosis. Retrospective studies have suggested that inotuzumab ozogamicin is associated with a high risk of veno-occlusive disease (VOD) in patients receiving allogeneic stem cell transplantation (alloSCT). Our report is the first to prospectively study the safety of the drug when added to our standard non-myeloablative conditioning regimen, BFR (Khouri IF, et al. Blood 2014;124:2306-2312). Methods: Inotuzumab ozogamicin was infused intravenously (IV) on day -13 outpatient, with a dose cohort of 0.6, 1.2 or 1.8 mg/m2, using the study design by Ji, Li, and Bekele (2007) to determine the maximum tolerated dose . Bendamustine 130 mg/m² IV daily on days -5 to -3 together with 30 mg/m² IV of fludarabine on days -5 to -3 were given prior to transplantation. Rituximab was given at a dose of 375 mg/m² IV on days -6, +1, and +8. Tacrolimus and mini-methotrexate were used for graft versus host disease (GvHD) prophylaxis. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving an unrelated donor transplant. Results: This study included 21 patients (CLL=9; 3 with 17p- and 1 Richter's), mantle cell=7, follicular=3, and diffuse large cell=2; including 1 double-expresser). Median age was 59 (range, 31-70) years. Median prior treatments was 3 (range, 1-6); this includes ibrutinib+/-R (n=5), idelalisib (n=2), venetoclax (n=4), CAR-T cell with progression (n=1) and a prior autologous SCT (n=1). At study entry, 13 (62%) patients were in CR/CRu, 6 (29%) in PR, and 2 (10%) had SD. Three of the 17 scans performed (18%) were PET+. Ten (48%) received their transplants from HLA-compatible siblings and 11 (52%) from unrelated donors. The number of patients who received the 0.6, 1.2 or 1.8 mg/m2 of inotuzumab ozogamicin were 4, 2 and 15 patients, respectively. Median number of CD34+ cells infused was 6.7 x 10⁶/kg. Twenty (95%) patients received transplants from peripheral blood and 1 (5%) from marrow. Neutrophil counts recovered to > 0.5 x 10⁹/L a median of 6 days after transplantation (range, 0-12 days). Fifteen patients (71%) never experienced an ANC < 0.5 x 10⁹/L nor required platelet transfusions. All patients engrafted donor cells and no secondary graft failure occurred. By day 30, median donor myeloid and T-cells were 89% and 99%, respectively. Both increased to 100% by day 90. The cumulative incidence of acute grade 2-4 GvHD and chronic extensive GvHD were 29% (5% of grade 3, and 0% of grade 4) and 35%, respectively. Two patients died due to GvHD complications. One patient with underlying cholelithiasis developed acute cholecystitis with inotuzumab ozogamicin and was able to proceed with alloSCT after recovery. No dose-limiting toxicities or VOD were observed. With a median follow-up time of 23.5 (range, 3-54) months, the OS rate was 89% (90% CLL/follicular, 86% mantle cell and 100% in diffuse large cell; also 100% for siblings, 81% for unrelated) and the PFS rate was 78%(Figure). Conclusions: Our results show that inotuzumab ozogamicin at a dose level of 1.8 mg/m2 is well-tolerated when combined with the BFR non-myeloablative allogeneic conditioning regimen for lymphoid malignancies. No added toxicity or increased myelosuppression were observed compared to our past experience with the BFR alone. The study is now expanded to further evaluate efficacy in a larger cohort of patients.

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