Nonmyeloablative stem cell transplantation for lymphoma

Nonmyeloablative Stem Cell Transplantation for Lymphoma Issa F. Khouri and Richard E. Champlin High-dose chemotherapy and allogeneic stem cell transplantation is a potentially curative therapy for younger patients with non-Hodgkin’s lymphoma (NHL). The benefits of this therapy, however, are largely offset by the high rate of treatment-related mortality, exceeding 40% in many studies. Risks increase with comorbidities, advanced age, histocompatibility, and disease-related prognostic factors. Given the potential efficacy of graft-versus-malignancy effects against many lymphoid malignancies, we evaluated an alternative strategy utilizing less toxic, nonmyeloablative conditioning regimens to allow engraftment of donor cells, and then exploit the graft-versus-lymphoma (GVL) effects of allogeneic transplantation as the primary therapy. This strategy involved fludarabine-based preparative regimens ⴙ/ⴚ high-dose rituximab, graftversus-host disease (GVHD) prophylaxis for 6 months, and donor lymphocyte infusion (DLI) only for progressive or nonresponding disease. Results from these trials confirm the full potential on nonmyeloablative transplantation for patients with NHL. Semin Oncol 31:22-26. © 2004 Elsevier Inc. All rights reserved.

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IGH-DOSE chemoradiotherapy is responsible for most of the treatment-related morbidity and mortality that are associated with conventional myeloablative stem cell transplantation. The risks increase with advanced age, and depend on histocompatibility, disease, and patient factors. These have been particularly relevant for patients with lymphoma. In a series collected by the European Bone Marrow Transplantation Group (EBMT) in which the majority of patients received total-body irradiation-based preparative regimens, the treatmentrelated mortality for the allogeneic transplant group was 25% compared with 11% for the autologous group.1 More recently, a multicenter study of allogeneic transplantation in 113 patients with

From the Department of Blood and Marrow Transplantation, The University of Texas, M.D. Anderson Cancer Center, Houston, TX. Supported by grants from G & P Foundation for Cancer Research and Berlex Laboratories. Address reprint requests to Issa F. Khouri, MD, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 423, Houston, TX 77030. © 2004 Elsevier Inc. All rights reserved. 0093-7754/04/3101-0003$30.00/0 doi:10.1053/j.seminoncol.2003.10.017 22

advanced low-grade lymphoma reported a treatment-related mortality of 40%.2 A similar high mortality rate has been seen using the conditioning regimen of cyclophosphamide, carmustine, and etoposide (CBV).3 Nonmyeloablative allogeneic stem cell transplantation (NST) was developed following the observation that donor lymphocyte infusions (DLIs) could overcome relapse in patients who had received allogeneic transplants for hematological malignancies.4 This finding and others confirmed that a graft-versus-tumor effect, mediated by lymphocytes, is responsible for at least part of the efficacy of allogeneic stem cell transplantation. If donor lymphocytes can control, or even eradicate, malignant cells that have proved resistant to high-dose chemotherapy and irradiation, then these highly toxic myeloablative therapies may not be necessary for the success of allogeneic stem cell transplantation strategies. Lymphoid malignancies appear very sensitive to graft-versus-lymphoma (GVL) effects. Allogeneic transplants are associated with a substantially lower relapse rate than purged autologous transplants.5,6 Another observation to support the GVL effect is the fact that patients who develop chronic graft-versus-host disease (cGVHD) after allogeneic transplantation have a lower probability of relapsing than patients who do not develop cGVHD. Chopra et al demonstrated a lower incidence of relapse in patients who acquired cGVHD (0% relapse with cGVHD v 35% relapse with no cGVHD).1 Perhaps the most direct data supporting the evidence and clinical significance of GVL come from small series and case reports in which patients with progressive disease after allogeneic transplantation who underwent withdrawal of immunosuppression developed cGVHD, often accompanied by a simultaneous decrease in the size of their lymphomas. Van Besien et al demonstrated that of nine patients who relapsed after allogeneic transplantation, four (44%) responded to withdrawal of immunosuppression (two complete remissions [CRs], two partial remissions), with responses that lasted nearly 2 years.7 Seminars in Oncology, Vol 31, No 1 (February), 2004: pp 22-26

NST FOR LYMPHOMA

NONMYELOABLATIVE REGIMENS

As a working definition, a truly nonmyeloablative regimen should allow relatively prompt hematopoietic recovery (in ⬍28 days) without a transplant and, upon engraftment, mixed chimerism should occur. These regimens do not eradicate recipient immunity and depend on the activity of donor T cells to achieve engraftment.8 Success of the NST procedure also requires development of an effective GVL effect before the underlying disease can progress. Therefore, the pretransplant regimen must also suppress the lymphoma sufficiently to prevent any marked early progression. At M.D. Anderson Cancer Center, fludarabinebased chemotherapy was used at conventional doses.9 This treatment without hematopoietic transplantation produces only short-term myelosuppression. The dose used was established in a pilot trial in which donor-cell engraftment was achieved with minimal toxicity.10 Patients with indolent lymphoma received fludarabine 25 mg/m2 administered intravenously (IV) daily on days ⫺6 to ⫺2 before transplantation and cyclophosphamide 1,000 mg/m2 given IV daily on days ⫺3 and ⫺2 before transplantation. The fludarabine/cyclophosphamide schedule was later changed so the drugs were given sequentially at 4-hour intervals in order to maximize inhibition of DNA repair and subsequent tumor kill11 (Fig 1). Rituximab was also added to our treatment protocol with the

Fig 1. Nonmyeloablative preparative regimens for lymphoma.

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consideration that it might be synergistic with chemotherapy and produce no overlapping toxicity.12 The dose of rituximab was based on studies from our institution13 demonstrating a dose-response relationship in patients who had chronic lymphocytic leukemia. For patients with aggressive lymphoid histologies, the combination of cisplatin and cytarabine has well-established activity14 and is the basis of many standard salvage treatment regimens. In vitro, fludarabine enhances the cytotoxicity of both cytarabine and cisplatin, increasing cytarabine incorporation into DNA15 and inhibiting repair of cisplatin/DNA adducts,16 suggesting that combining these drugs (the PFA regimen) may be useful as a nonmyeloablative preparative regimen (Fig 1). PATIENT SELECTION AND METHODS

Patients We studied adult patients who had recurrent indolent, mantle cell, discordant, or transformed (follicular to diffuse) lymphomas after a prior response to conventional treatment. Patients with de novo diffuse, large cell lymphoma were included only if they were not eligible for autologous transplantation or if they had failed a prior autotransplant. Patients were required to have no uncontrolled medical illness or active infection. A

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normal serum creatinine level was specially required for patients receiving the cisplatin-containing PFA regimen. Currently, patients with all ages are eligible, because unlike patients with myeloid malignancies where there is an established benefit of ablative regimens in patients up to age 55 years, the role of high-dose therapy is less established in patients with lymphomas. This treatment of all ages was further justified with the early promising results in a pilot phase I trial.9 GVHD Prophylaxis and Supportive Care Post-transplantation, patients received immunosuppressive therapy with tacrolimus in combination with 5 mg/m2 of methotrexate on days 1, 3, and 6. Tacrolimus was administered daily from day ⫺2 as a continuous infusion of 0.015 to 0.03 mg/kg of body weight. Upon recovery, tacrolimus was administered orally in a twice-daily divided dose. Doses were adjusted to maintain whole-blood trough levels at 5 to 15 ng/mL. The dose of tacrolimus was tapered by days 60 to 90 if there were signs of residual disease; otherwise it was continued for 6 months. Filgrastim was administered in a subcutaneous injection of 5 ␮g/kg of body weight daily from day 0 until recovery of the granulocyte count to greater than 1 ⫻ 109 per liter of blood. Infection prophylaxis during the peritransplantation period consisted of 400 mg of norfloxacin given orally twice daily, 500 mg of penicillin VK given orally every 6 hours, and 200 mg of fluconazole given orally every 12 hours. Patients also received 500 mg of valacyclovir given orally daily and were screened biweekly for cytomegalovirus antigenemia; those who tested positive were treated with ganciclovir. All patients with neutropenic fever received broad-spectrum antibiotics. Blood-product transfusions were irradiated and filtered to remove leukocytes. After recovery of the neutrophil count to a level greater than 1.0 ⫻ 109 per liter of blood, each patient received prophylaxis against Pneumocystis carinii infection using trimethoprimsulfamethoxazole given orally twice weekly or pentamidine IV every 3 weeks. Assessment of Outcome Neutrophil count recovery was defined as the first of 3 consecutive days that the absolute neutrophil count exceeded 0.5 ⫻ 109 per liter of

KHOURI AND CHAMPLIN

blood, and platelet count recovery was defined as the day the platelet count exceeded 20 ⫻ 109 per liter of blood independent of platelet transfusions. Hematopoietic chimerism was initially evaluated by restriction fragment length polymorphisms. More recently, the polymerase chain reaction technique has been adopted. GVHD was graded according to the consensus criteria.17 Responses were scored by standard criteria in patients with lymphoma. Patients were monitored at regular intervals of one to three months with physical examinations, blood counts, bone marrow aspirate and biopsy with flow cytometry, chimeric analysis, and with computed tomography scans of the chest, abdomen, and pelvis. Actuarial estimates of time of relapse and death were calculated according to the method of Kaplan and Meier18 from the date of stem cell infusion. RESULTS

Forty-nine patients were included. The patients ranged in age from 21 to 68 years (median, 55 years). Twenty patients had follicular lymphoma, 15 had transformed or de novo diffuse large cell lymphoma, and 14 had mantle cell lymphoma. All patients had advanced, recurrent disease and were previously treated. The number of prior chemotherapy regimens received by each patient ranged from one to four (median, four). Eight patients (17%) had failed a prior autologous transplant. At the time of transplantation, 35 (71%) had chemosensitive and 14 (29%) had chemorefractory disease. Each patient had a human leukocyte antigen (HLA)-identical donor. Four donors were matched-unrelated. All patients had prompt hematopoietic recovery. Neutrophil counts recovered to more than 0.5 ⫻ 109/L a median of 11 days after transplantation (range, 8 to 19 days). Platelet counts recovered to more than 20 ⫻ 109/L in a median of 11 days (range, 0 to 25). The median percentage of donor cells at 1 month after transplantation was 80% (range, 0% to 100%). One patient had a primary graft failure. Three additional patients had a secondary graft failure in the setting of disease progression (one) or viral infection (two). All patients with graft failure were in the group who received the PFA regimen, and patients recovered autologous hematopoiesis promptly. Eleven patients had early withdrawal of immunosuppression due to persistent or progressive dis-

NST FOR LYMPHOMA

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Fig 2. Kaplan-Meier survival curves by histology. DLCL, diffuse large cell lymphoma (de novo or transformed); MCL, mantle cell lymphoma.

ease after transplantation, and five received DLI of 1 ⫻ 107 to 1 ⫻ 108 CD3⫹ cells/kg. Four of these patients also received rituximab with their immunomanipulation. Rituximab was given weekly for 4 weeks, with a first dose of 375 mg/m2 and subsequent doses of 1,000 mg/m2. Six patients were reinduced into durable CR. The two patients who had secondary graft failure were still in CR at the time of this analysis, at 20⫹, 24⫹ months after transplant. These two patients never had CR with any form of conventional chemotherapy prior to transplantation. The median follow-up interval is 19 months (range, 5 to 52 months). Actuarial overall survival is 79% (95% confidenc interval [CI], 61% to 89%) (Fig 2). Current progressionfree-survival (⫾SE) for the patients with indolent, diffuse or transformed large cell, and mantle cell lymphoma were 85% ⫾ 8%, 60% ⫾ 12%, and 68% ⫾ 21%, respectively. The cumulative incidence of acute grade II to IV GVHD was 20% (95% CI, 11% to 34%; Fig 3). Only two patients developed grade III GVHD. The cumulative incidence of extensive cGVHD was 36% (95% CI, 21% to 58%). One patient (2%) died within 100 days. Seven other patients died secondary to relapse (four patients), cGVHD (two patients), multiorgan failure (one patient), and secondary malignancy (one patient). Patients who died of relapse had refractory disease at the time of transplantation.

CONCLUSION

Use of relatively nontoxic, nonmyeloablative preparative regimens as described allowed engraftment, with a low incidence of acute GVHD and generation of GVL effects. More complete engraftment and lesser toxicity have been observed with the rituximab/fludarabine/cyclophosphamide (RFC) regimen compared to the PFA regimen. This result is probably related to a higher fludarabine dose and the absence of cisplatin in the RFC combination. Currently we are adopting the RFC nonmyeloablative regimen for all B-cell CD20⫹ malignancies. The EBMT group has addressed the use of NST

Fig 3. 2%.

Incidence of acute GVHD II-IV was 20% and III-IV was

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KHOURI AND CHAMPLIN

for lymphoma, and it was recently reported in abstract form.19 In their study, treatment-related mortality at 1 year was 39% for patients with low-grade and high-grade histologies. Acute and chronic GVHD contributed to 55% of the mortality rate. This difference in outcome with our study is probably related to their use of more intense preparative regimens, a shorter duration of GVHD prophylaxis, and their indication for DLI. DLI has been used in several centers to convert mixed chimerism into complete chimerism irrespective of the disease status. In our studies, we were cautious about the use of DLI because we have not observed a correlation between the percentage of donor cells and the ultimate response. Patients who engraft tend to move spontaneously toward complete chimerism, and DLI is not required. Lymphoid malignancies tend to slowly respond to the GVL effect and may gradually regress over the first year. For these reasons, we reserved DLI for patients who had residual disease that either progressed or did not continue to decrease during the first year of transplant. NST clearly has promise in the spectrum of lymphoma. Further evaluation versus alternative standard treatment is indicated. REFERENCES 1. Chopra R, Goldstone AH, Pearce R, et al: Autologous versus allogeneic bone marrow transplantation for nonHodgkin’s lymphoma: A case-controlled analysis of the European Bone Marrow Transplant Group registry data. J Clin Oncol 10:1690-1695, 1992 2. Van Besien K, Sobocinski A, Rowlings PA, et al: Allogeneic bone marrow transplantation for low-grade lymphoma. Blood 92:1832-1836, 1998 3. Demirer T, Weaver CH, Buckner CD, et al: High-dose cyclophosphamide, carmustine, and etoposide followed by allogeneic bone marrow transplantation in patients with lymphoid malignancies who had received prior dose-limiting radiation therapy. J Clin Oncol 13:596-602, 1995 4. Kolb HJ, Schattenberg A, Goldman JM, et al: Graft-vsleukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 86:2041-2050, 1995 5. Khouri IF, Keating MJ, Vriesendorp HM, et al: Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: Preliminary results. J Clin Oncol 12: 748-758, 1994 6. Verdonck LF, Dekker AW, Lokhorst HM, et al: Alloge-

neic versus autologous bone marrow transplantation for refractory and recurrent low-grade non-Hodgkin’s lymphoma. Blood 90:4201-4205, 1997 7. Van Besien KW, de Lima M, Giralt SA, et al: Management of lymphoma recurrence after allogeneic transplantation: The relevance of graft-versus-lymphoma effect. Bone Marrow Transplant 19:977-982, 1997 8. Champlin R, Khouri I, Kornblau S, et al: Reinventing bone marrow transplantation: reducing toxicity using nonmyeloablative, preparative regimens and induction of graft-versusmalignancy. Curr Opin Oncol 11:87-95, 1999 9. Khouri IF, Saliba RM, Giralt SA, et al: Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: Low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood 98:3595-3599, 2001 10. Khouri IF, Keating M, Ko¨ rbling M, et al: Transplantlite: induction of graft-versus-malignancy using fludarabinebased nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 16:2817-2824, 1998 11. Gandhi V, Kemena A, Keating MJ, et al: Cellular pharmacology of fludarabine triphosphate in chronic lymphocytic leukemia cells during fludarabine therapy. Leuk Lymph 10:4956, 1993 12. Czuczman MS, Grillo-Lopez AJ, White CA, et al: Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 17:268-276, 1999 13. O’Brien SM, Kantarjian H, Thomas D, et al: Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 19:2165-2170, 2001 14. Velasquez WS, Cabanillas F, Salvador P, et al: Effective salvage therapy for lymphoma in combination with high-dose Ara-C and dexamethasone (DHAP). Blood 71:117-122, 1998 15. Gandhi V, Kemena A, Keating MJ, et al: Fludarabine infusion potentiates arabinosylcytosine metabolism in lymphocytes of patients with chronic lymphocytic leukemia. Cancer Res 52:897-903, 1992 16. Li L, Keating MJ, Plunkett W, et al: Fludarabine-mediated repair inhibition of cisplatin-induced DNA lesions in human chronic myelogenous leukemia-blast crisis k562 cells: Induction of synergistic cytotoxicity independent of reversal of apoptosis resistance. Mol Pharmacol 52:798-806, 1997 17. Przepiorka D, Weisdorf D, Martin P, et al: Consensus conference on acute GVHD grading. Bone Marrow Transplant 15:825-828, 1995 18. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 19. Robinson SP, Mackinnon S, Goldstone AH, et al: Higher than expected transplant-related mortality and relapse following non-myeloablative stem cell transplantation for lymphoma adversely effects progression free survival. Blood 96: 554a, 2000 (abstr)