A prospective study of an alemtuzumab containing reduced-intensity allogeneic stem cell transplant program in patients with poor-risk and advanced lymphoid malignancies

Abstract High-dose methlyprednislone (HDMP) is active in refractory chronic lymphocytic leukaemia (CLL), and rituximab, although showing limited efficacy as a single agent, is effective when used in combination with other cytotoxic agents. Early relapse (<12 months) after purine-analogue based treatment poses a difficult management problem as older patients may be unable to tolerate treatment intensification. This retrospective audit examines the outcome in patients with advanced, refractory/relapsed CLL treated with a combination of high-dose steroids and rituximab. Eleven patients with CLL were treated with rituximab (375mg/m2) and high-dose steroids between 2003 and 2007. Ten patients had advanced and/or refractory disease and one patient had severe autoimmune haemolytic anaemia complicating early-stage CLL. Median age was 70 (range 54–82) and there were 7 male and 4 female patients. Nine patients had Binet stage C disease. Six of the 7 patients for whom results were available had germ-line variable heavy chain immunoglobuliun genes. Median number of prior treatments was 2 (range 1–6) with 9 patients having already received a fludarabine based-regimen. Six patients received a combination of rituximab and high-dose methylprednisolone (1gm/m2 on days 1–5) and 5 patients received a combination of rituximab and high-dose dexamethasone (40mg daily on days 1–4) and. Cycles were repeated every 28 days and the median number of cycles received was 4 (3–6). Antiviral and anti-PCP prophlaxis with aciclovir and co-trimoxazole was routinely prescribed. Response was assessed according to the NCI working group criteria. There was one complete response (CR) and 7 partial responses (PR). Furthermore, 2 of the patients who achieved a PR were successfully salvaged prior to reduced-intensity allogeneic stem-cell transplant and both remain in complete remission (CR) post-transplant. The other 3 patients had minor responses that did not meet NCI response criteria. Median duration of response was 13 months (6–35), excluding the 2 patients who received allogeneic transplants. Three patients required hospital admission with infective complications during treatment. No other significant toxicity was observed. 3 patients have died, none of whom had attained a PR. In conclusion, we found that rituximab in combination with high-dose steroids is a safe and well-tolerated combination in patients with advanced refractory CLL. One patient achieved a CR and we observed a PR in 7/11 patients. Importantly, 2 of these patients were successfully salvaged prior to reduced-intensity conditioning allogeneic stem-cell transplant and both remain in CR at 4 and 12 months respectively post-transplant.

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Conditioning with Fludarabine, Busulfan, and ATG Prior to Reduced-Intensity Allogeneic Stem Cell Transplant for CLL Is Associated with a Low Incidence of Acute Graft-Versus-Host Disease.

Blood ◽

10.1182/blood.v116.21.4568.4568 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4568-4568

Author(s):

Samantha M. Jaglowski ◽

Diane Scholl ◽

Patrick Elder ◽

Thomas S. Lin ◽

John C. Byrd ◽

...

Keyword(s):

Stem Cell ◽

Graft Versus Host Disease ◽

Stem Cell Transplant ◽

Chronic Gvhd ◽

Cell Transplant ◽

Allogeneic Stem Cell Transplant ◽

Graft Versus Host ◽

Significant Difference ◽

Reduced Intensity ◽

Count Recovery

Abstract Abstract 4568 Introduction: Allogeneic stem cell transplant (SCT) is the only potentially curative treatment available for CLL. While transplant-related mortality has decreased with use of reduced-intensity conditioning (RIC) regimens, acute and chronic graft-versus-host-disease (GVHD) remain important causes of morbidity and mortality, with up to 50% of patients developing chronic GVHD (cGVHD). While the optimal way to combat this has not been established, in vitro T cell depletion with ATG or alemtuzumab has been employed to attempt to lessen its incidence. Herein, we report our institutional experience with each of these agents. Patients and methods: Information on all patients who underwent RIC allogeneic SCT at Ohio State from January 1, 2002 to June 29, 2010 was obtained following approval from the ORRP. Data collected by the transplant coordinators was correlated with data in our electronic databases. Comparative statistics were performed using the Fisher exact test and all p-values are two-sided. Results: Between January 1, 2002 and June 29, 2010, 50 patients with CLL/SLL underwent RIC allogeneic SCT at Ohio State. Pretransplant characteristics are listed in Table 1. Thirty patients received fludarabine, busulfan, and ATG (FBA) as a preparative regimen, and 8 patients received alemtuzumab, fludarabine, and TBI (Cam/Flu/TBI). Another 6 patients received fludarabine and busulfan, 4 received fludarabine and cyclophosphamide, one received pentostatin, fludarabine, and ATG, and the patient who had a cord blood transplant received fludarabine, cyclophosphamide, TBI, and ATG. The breakdown of characteristics between patients who received FBA and Cam/Flu/TBI is also provided in Table 1. None of the characteristics were statistically different. Time to count recovery is provided in Table 2. There was not a statistically significant difference in the time to count recovery between FBA and Cam/Flu/TBI. Patients who received Cam/Flu/TBI received significantly more DLIs; patients who received FBA have not required any DLIs. Incidence of acute and chronic GVHD is provided in Table 3. There was not a statistically significant difference in rates or grades of aGVHD, but patients who received Cam/Flu/TBI were more likely to develop extensive cGVHD. Conclusions: While patients who received Cam/Flu/TBI were more likely to receive DLI, these were all done to treat disease recurrence, reflecting changes in group practice over time. There were no failures to engraft with FBA, and while not statistically significant in comparison to Cam/Flu/TBI, only 10% of patients developed grade 3 or 4 aGVHD. All of the patients who received Cam/Flu/TBI and developed cGVHD developed extensive disease. While the Cam/Flu/TBI sample is small, the FBA patients appear to fare no worse in terms of count recovery and development of GVHD without exposure to TBI, and this has become our institutional practice for patients with CLL. Disclosures: Lin: GlaxoSmithKline: Consultancy, Employment.

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Reduced Intensity Allogeneic Stem Cell Transplant In Patients With Multiple Myeloma: A Comparison Of Planned Autologous-Reduced Intensity Allogeneic Stem Cell Transplant (Auto-Allo) and Reduced Intensity Allogeneic Stem Cell Transplant (RIC) As Upfront Transplant In Patients With Multiple Myeloma, An EBMT Analysis

Blood ◽

10.1182/blood.v122.21.920.920 ◽

2013 ◽

Vol 122 (21) ◽

pp. 920-920 ◽

Cited By ~ 1

Author(s):

Firoozeh Sahebi ◽

Simona Iacobelli ◽

Anja Van Biezen ◽

Liisa Volin ◽

Peter Dreger ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplant ◽

Cell Transplant ◽

Allogeneic Stem Cell Transplant ◽

Allogeneic Hsct ◽

Autologous Hsct ◽

Reduced Intensity

Abstract Background Despite the advances in the treatment of multiple myeloma using new targeted therapies and autologous hematopoietic stem cell transplant (HSCT) the disease remains largely incurable. Recent efforts in using reduced intensity allogeneic HSCT have been hampered by increased allograft-related morbidity and mortality. Several prospective studies comparing single or tandem autologous HSCT with planned tandem autologous-reduced intensity allogeneic HSCT (auto-allo) have shown no overall survival advantage despite improvements in progression-free survival (PFS) and lower relapse rates with reduced intensity allograft, mainly due to increased non-relapse related mortality (NRM) rates. However, two of these prospective studies; the European Group for Blood and Marrow Transplantation NMAM 2000 and the Italian group study with long term follow-up reported PFS and overall survival (OS) benefits in favor of the auto-allo arm. Currently allogeneic HSCT is recommended within the context of clinical trials and only in high risk multiple myeloma patients who continue to have a very poor outcome with autologous HSCT. While such clinical trials are ongoing there remains a need to address the role of autologous HSCT prior to reduced intensity allogeneic HSCT. The objective of this retrospective study is to evaluate the role of upfront cytoreductive autologous HSCT prior to allograft in the outcomes of patients who have undergone allograft following induction therapy. Study We performed a retrospective analysis of the EBMT database comparing the outcomes of patients who were planned to receive auto-allograft to those who underwent reduced intensity allograft (early RIC) without a prior autologous HSCT within one year from diagnosis. The data in 504 patients were previously reported at the ASH meeting 2010 (abstract 3512). We subsequently included additional patients and requested more information from the participating EBMT centers and updated the study. From 1996 to 2013 a total of 689 patients were registered as reduced intensity allograft. 517 patients were registered as planned auto-allograft; however, 73 did not receive the planned allograft. A total of 172 patients received reduced intensity allograft after induction treatment without prior auto-HSCT. Median age at first transplant was 53 years (range 20-72) in the auto-allo and 51 years (range 31-77) in the early RIC group. Median time from diagnosis was 6.6 months (range 2-156 months) in the auto-allo and 7.7 months (2.8-12.0) in the early RIC group. The disease status at the time of first transplant for the auto-allo group was CR - 8%, PR - 67%, other or missing - 25%; and for the RIC group was CR - 15%, PR - 62%, other or missing - 23%. Donors were HLA matched siblings in 88% and matched unrelated in 12% for the auto-allo group, and 84% siblings and 16% matched unrelated in the RIC group with no significant differences between the two groups. Results With a median follow-up of 93 months in the auto-allo and 84 months in RIC groups, PFS rates were significantly better at 3 and 5 years in the auto-allo group (45.6% and 34.2%) as compared to the RIC group (33.9% and 22.0%, p<0.001). Overall survival was also significantly improved in favor of the auto-allo (3 yr and 5 yr OS 67.9% and 58.9%) as compared to the RIC group (54.3% and 42.7%, P = 0.001). The non-relapse mortality (NRM) rates were lower in the auto-allo group as compared to RIC: 1 yr and 3 yr NRM were 8.1% and 14.1% in the auto-allo and 20.3% and 27.4% in early RIC group, p<0.001. We examined potential differences in outcomes based on use of novel agents, and used the year 2004 as a surrogate for introduction of novel agents to routine clinical practice. There were no significant differences by multivariate analysis in outcomes for patients transplanted before or after 2004. Conclusion This large multicenter retrospective study suggests that cytoreductive autologous HSCT prior to allograft is associated with improved PFS and OS. We are in the process of conducting an extended analysis to control for possible confounders. If the results are confirmed, future studies should be conducted to verify the importance of autologous stem cell transplant as part of the allograft treatment strategy. Disclosures: No relevant conflicts of interest to declare.

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