Rituximab Infusion Two Months after Nonmyeloablative Transplantation Maintains B-Cell Disease Control with Minimal GVHD.

Abstract

Abstract B cells are implicated in the pathophysiology of chronic GVHD, as evidenced by the association of Ab production against minor histocompatibility Ags with chronic GVHD, and rituximab efficacy in chronic GVHD. We hypothesize that anti-B cell therapy beginning 56 days after nonmyeloablative total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) transplantation reduces chronic GVHD. Cognizant of possible GVL loss with B cell depletion, we treated patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) because any loss of GVL may be offset by rituximab’s direct anti-B cell tumor efficacy. Patients were conditioned with TLI (80 cGy in 10 fractions, d-11 to d-1) and ATG (1.5mg/kg/day, d-11 to d-7, total 7.5mg/kg). PBSC were infused on day 0. Primary GVHD prophylaxis was MMF from day 0 until d28 for MRD, d100 for URD and cyclosporine (CSA) tapered off by 6 months. To diminish donor B cell alloimmunity, rituximab (375 mg/m2) was infused on days 56, 63, 70, and 77 post-transplant. Fourteen patients have received HCT, and 11 (median age 57, range 46–65 yrs) have received four rituximab infusions (5 fludarabine-refractory, unmutated immunoglobulin heavy-chain variable region gene (IgVH) CLL; 6 MCL). Median follow-up is 290 days (108–381 days). No infusion related toxicities occurred. Transient leukopenia in all patients and frank neutropenia in one patient was noted as early as 30 days post-rituximab. There was one graft loss at day 50 in a patient with MCL progression. Only 3/11 patients had peripheral blood CD3 donor chimerism >95% before rituximab infusion day 56, but 6/7 patients achieved full donor chimerism post-rituximab day 180, showing rituximab has no detrimental effect on engraftment. Peripheral blood CD19+ B cells were undetectable in all patients days 90–270, and 2/2 evaluable patients at one year now have CD27+ CD19+ donor B cell reconstitution. Infections post-transplant include early CMV reactivation (5), influenza B (1), aspergillus sinusitis (1), ecthyma gangrenosum (1), VZV (1). All infections resolved. Non-relapse mortality at 100 days and currently is 0%. Four of the 5 unmutated IgVH CLL patients with diffuse lymphadenopathy and marrow involvement by 4-color flow and IgVH quantitation prior to HCT have achieved molecular CR by IgVH PCR. One CLL patient progressed 9 months after HCT and has received DLI. Four MCL patients were transplanted in PR; one achieved CR, 3 progressed before rituximab infusion and 2 subsequently died. The third progressed MCL patient responded to salvage chemotherapy with development of chronic GVHD and achieved CR. No patients developed acute GVHD. One patient developed chronic GI GVHD that resolved with six weeks of steroids. Rituximab infused 56–77 days after TLI-ATG is well tolerated and able to modulate donor B cell reconstitution without detrimental effect on engraftment or infection incidence. No acute GVHD occurred. This novel approach of rituximab infusion two months after TLI-ATG HCT provides safe in vivo peripheral donor B cell depletion with low chronic GVHD incidence thus far. Importantly, GVL is maintained with four CLL and two MCL patients achieving molecular CR after HCT. CLL/MCL Med Age Med f/u MRD/URD GVHD CD3>95% Donor Chimerism Disease status pre-HCT»last f/u 5/6 57 yrs 290 days 9/2 aGVHD- none cGVHD- one,d257 D56 pre-rituximab: 3/11 pts>95%; D180: 6/7 pts>95% CLL: 4 PR»CR; 1PR»PD--DLI; MCL: 1PR»CR; 3PR»PD-2 deaths; 2CR»CR