Immunoablative Chemotherapy before Reduced-Intensity Allogeneic Stem Cell Transplantation: A Strategy to Provide Disease Control and to Enhance Early Graft-Versus-Lymphoma Effects.

Abstract

Published data raise concerns about the efficacy of reduced-intensity allogeneic hematopoietic stem cell transplantation (RIST) in chemotherapy-resistant lymphomas. Reduced-intensity conditioning, compared with myeloablative regimens, has attenuated cytotoxic antitumor activity and can result in mixed donor-recipient chimerism, which may diminish potential graft-versus-lymphoma (GVL) activity after RIST. To compensate for these limitations, we prospectively studied a novel, conventional-dose chemotherapy regimen (EPOCH-F/R: etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and fludarabine; +rituximab for CD20+ lymphomas) designed to provide both disease control and host T-lymphocyte depletion before RIST, and to enhance early GVL effects by facilitating rapid and complete donor engraftment after RIST. The objectives of this study were to determine the toxicity, immune depletion, and antitumor activity of EPOCH-F/R in pts with relapsed/refractory lymphoid malignancies. EPOCH-F/R was administered until blood CD4 level < 100/μL to a maximum of 3 cycles. If disease progression occurred during EPOCH-F/R, the regimen was discontinued and pts proceeded to RIST, regardless of CD4 count. Twenty-one pts were enrolled (median age 52 years; range 31–71). Diagnoses included Hodgkin's lymphoma (n=4) and NHL (n=17): DLBC=5, follicular=4 (3 transformed), CLL/SLL=3, mantle cell=1, T-cell=4. Prior regimens (median 4, range 1–6) included anthracyclines (90%), fludarabine (29%), rituximab (67%), and autologous SCT (43%). Sensitive and refractory disease was present at enrollment in 62% and 29%, respectively. Pts received EPOCH-F/R for 1 (n=8), 2 (n=6), or 3 (n=7) cycles; 15 pts received rituximab with the regimen. Toxicity in 41 cycles of EPOCH-F/R included grade 4 thrombocytopenia (34%), grade 4 neutropenia (85%), and neutropenic fever/infection (21%). Grade 3/4 non-hematologic toxicity occurred in 28 cycles but was generally brief and reversible; no treatment-related deaths occurred. Median (range) CD4 before and after EPOCH-F/R were 165/μL (4–1,098) and 72/μL (4–380), respectively. Similarly, CD8 before and after EPOCH-F/R were 189/μL (1–1,763) and 42/μL (1–1,195), respectively. Overall response rate was 34% with 2 CR, 5 PR, 12 SD, and only 2 PD. Response to EPOCH-F/R was not associated with aggressive vs. indolent histology, sensitivity to prior treatment, specific prior therapies, or inclusion of rituximab with the induction regimen. All 22 pts proceeded as planned to reduced-intensity conditioning with fludarabine/cyclophosphamide and T-cell replete peripheral blood stem cell transplantation from a matched sibling. All pts engrafted, and 16/21 pts achieved > 95% donor myeloid and lymphoid chimerism by day 28 post RIST (median 100%). Thus, EPOCH-F/R achieved profound host immune depletion and provided disease stability with acceptable toxicity prior to RIST, setting the stage for enhanced potential GVL effects after RIST. Incorporation of an immunoablative chemotherapy regimen such as EPOCH-F/R into RIST strategies for resistant lymphomas may be considered an alternative to autologous SCT in preparation for RIST.