Volume 15, Issue 4 , Pages 517-518, April 2009
Does Extra Alemtuzumab Remove the Graft-versus-Leukemia Effect after Allogeneic Stem Cell Transplantation in Chronic Lymphocytic Leukemia?
Article Outline
Three recently reported large series 1, 2, 3 used allogeneic stem cell transplantation (allo-SCT) after a reduced-intensity conditioning (RIC) regimen to treat chronic lymphocytic leukemia (CLL) (Table 1). These studies raise some important questions, including whether or not all RIC regimens are equally effective in CLL and whether or not extra alemtuzumab, although effective in treating CLL, removes the graft-versus-leukemia (GVL) effect.
Table 1. Allo-SCT with an RIC Regimen in CLL
| Study | Number of Patients | Conditioning Regimen | Results | Comments |
|---|---|---|---|---|
| Delgado et al. [1] | 62 | Fludarabine and melphalan with alemtuzumab (100 mg, n = 23; 20-60 mg, n = 18) or without alemtuzumab (n = 21). | Alemtuzumab versus none (3-year events): •OS, 65% versus 57% •PFS, 39% versus 47% •NRM, 28% versus 34% •Relapse, 32% versus 20% •aGVHD, 37% versus 57% •cGVHD, 29% versus 68% (P = .016). •20 (49%) patients receiving alemtuzumab also received DLI for persistent mixed chimerism and MiRD or PD. | No comparison between patients receiving alemtuzumab 100 mg and those receiving a lower dosage (versus those receiving no alemtuzumab). |
| Schetelig et al. [2] | 44 | •All patients had 17p deletion. •89% received an RIC regimen. •12 patients received alemtuzumab before allo-SCT. •12 patients received alemtuzumab with graft (35- 100 mg). | •Patients receiving RIC with alemtuzumab had poor transplantation outcome (OS, 22% vs 51%; PFS, 0 vs 52%; relapse, 67% vs 19%). •Eight of 12 patients relapsed and 4 of 12 died of treatment-related complications within a median of 6 months post-SCT. | Half of the patients in the alemtuzumab group also received alemtuzumab previously; it is important to know how this group did. |
| Sorror et al. [3] | 82 | 2 Gy TBI with or without fludarabine. | •5 year: OS, 50%; PFS, 39%; progression/relapse, 38%; NRM, 23%. •aGVHD grade II-IV: MRD, 55%; MUD, 66%. •cGVHD (ext): MRD, 49%; MUD, 53%. •More than half of NRM was related to GVHD and associated infections. |
Delgado et al. [1] investigated outcomes in 62 patients with CLL after allo-SCT with RIC containing fludarabine (Flu) and melphalan (Mel) and found similar long-term outcomes in the patients receiving alemtuzumab and those not receiving alemtuzumab in the conditioning regimen. But, the interpretation of their data is limited by the lack of comparison between patients receiving 100 mg of alemtuzumab and those receiving low-dose alemtuzumab versus those receiving no alemtuzumab (because of the small sample size). Moreover, 7 of the 41 patients in the alemtuzumab group also received alemtuzumab previously as part of CLL therapy. Data have shown that patients receiving alemtuzumab (especially at a dose of 100 mg) have increased risk of infection, persistent disease/relapse, and prolonged mixed chimerism necessitating frequent donor lymphocyte infusion (DLI) after allo-SCT 1, 2, 4, 5, 6. In contrast to Delgado et al. [1], Schetelig et al. [2] reported poor outcomes in patients receiving an alemtuzumab-containing RIC regimen (Table 1). In that study, almost 90% of the patients received RIC before undergoing allo-SCT for CLL with 17p deletion. Poor results were reported in the alemtuzumab group, despite the fact that alemtuzumab is considered the most effective therapy for CLL with 17p deletion [7]. Overall, Schetelig et al. [2] found favorable outcomes in their patients, suggesting that the GVL effect may overcome the negative prognostic impact of 17p deletion [2].
Sorror et al. [3] reported outcomes of 82 patients who received RIC (without alemtuzumab) before undergoing allo-SCT for CLL. Long-term overall survival (OS) and progression-free survival (PFS) were similar to those reported in the aforementioned series (Table 1). Extensive chronic graft-versus-host disease (cGVHD) occurred in more than 50% patients; the median duration of cGVHD was 25 months (range, 12 to 61 months). More than half of the cases of nonrelapse mortality (NRM) were caused by GVHD and associated infections. As is well known, cGVHD and prolonged immunosuppressive therapy are also risk factors for numerous long-term complications that can affect late morbidity and mortality 8, 9, 10, 11.
Rituximab as part of an RIC regimen for CD20+ malignancies has demonstrated good disease control (sparing the GVL effect) in addition to a decrease in the rate of GVHD. Most of these data are from single-center experiences, however 12, 13.
As increasing numbers of patients are receiving RIC before allo-SCT [13], work is needed to optimize GVHD prophylaxis without compromising the GVL effect after allo-SCT for CLL. Rituximab has been reported to be as effective as low-dose alemtuzumab without compromising the GVL effect in CLL. More patients undergoing allo-SCT have been previously treated with alemtuzumab, leading to the important question of whether alemtuzumab-containing RIC regimens should be avoided in these patients, given alemtuzumab's prolonged T cell–suppressing effect, which could limit the GVL effect. This and other pertinent questions can be answered only by enrolling more patients in multi institutional studies.
References
- The effect of in vivo T cell depletion with alemtuzumab on reduced-intensity allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia. Biol Blood Marrow Transplant. 2008;14:1288–1297
- Allogeneic hematopoietic stem-cell transplantation for chronic lymphocytic leukemia with 17p deletion: a retrospective European Group for Blood and Marrow Transplantation analysis. J Clin Oncol. 2008;26:5094–5100
- Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol. 2008;26:4912–4920
- Results of alemtuzumab-based reduced-intensity allogeneic transplantation for chronic lymphocytic leukemia: a British Society of Blood and Marrow Transplantation study. Blood. 2006;107:1724–1730
- A study of a reduced-intensity conditioning regimen followed by allogeneic stem cell transplantation for patients with hematologic malignancies using Campath-1H as part of a graft-versus-host disease strategy. Biol Blood Marrow Transplant. 2006;12:868–875
- Impact of alemtuzumab as conditioning regimen component on transplantation outcomes in case of CMV-seropositive recipients and donors. Am J Hematol. 2008;83:649–653
- . Alemtuzumab in the treatment of chronic lymphocytic lymphoma. Expert Rev Anticancer Ther. 2008;8:525–533
- Long-term survival and late deaths after allogeneic bone marrow transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry. N Engl J Med. 1999;341:14–21
- Solid cancers after allogeneic hematopoietic cell transplantation. Blood. 2009;113:1175–1183
- Chronic GVHD and pretransplantation abnormalities in pulmonary function are the main determinants predicting worsening pulmonary function in long-term survivors after stem cell transplantation. Biol Blood Marrow Transplant. 2006;12:1261–1269
- Increased risk of cervical dysplasia in long-term survivors of allogeneic stem cell transplantation: implications for screening and HPV vaccination. Biol Blood Marrow Transplant. 2008;14:1072–1075
- Nonablative allogeneic stem cell transplantation for chronic lymphocytic leukemia: Impact of rituximab on immunomodulation and survival. Exp Hematol. 2004;32:28–35
- . Stem cell transplantation with reduced-intensity conditioning regimens: A review of ten years experience with new transplant concepts and new therapeutic agents. Leukemia. 2006;20:1661–1672
PII: S1083-8791(09)00004-4
doi:10.1016/j.bbmt.2008.12.511
© 2009 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 15, Issue 4 , Pages 517-518, April 2009
