Boris Calmels

Two days of antithymocyte globulin are associated with a reduced incidence of acute and chronic graft-versus-host disease in reduced-intensity conditioning transplantation for hematologic diseases.

The optimal combination of fludarabine, busulfan, and antithymocyte globulin (ATG) for reduced‐intensity conditioning (RIC) transplantation has not been established. ATG plays a pivotal role in the prevention of graft‐versus‐host disease (GvHD), but it is associated with a higher relapse rate and an elevated incidence of infections when high doses are used.

Reduced-intensity conditioning with Fludarabin, oral Busulfan, and thymoglobulin allows long-term disease control and low transplant-related mortality in patients with hematological malignancies.

OBJECTIVE The development of reduced-intensity conditioning regimens rather than myeloablative regimens for allogeneic stem cell transplantation has led to decreased treatment-related mortality and increased use of this treatment modality, especially in older patients with hematological malignancies. No randomized controlled trials have been performed resulting in determining effectiveness on phase II studies, which rarely report on long-term survival. MATERIALS AND METHODS In an attempt to address this limitation, we analyzed a single-center cohort of 100 consecutive patients with hematological malignancies undergoing allogeneic stem cell transplantation from a human leukocyte antigen-matched related donor with median follow-up of 60 months. The reduced-intensity conditioning regimen consisted of oral Busulfan, rabbit anti-thymocyte globulin, and Fludarabin. RESULTS Median age was 50 years (range, 18-64 years). The incidences of acute and chronic graft-vs.-host disease were 43% and 81%, respectively. The probability of nonrelapse mortality at 1 and 5 years was 15% and 25%, respectively. Nonrelapse mortality was adversely associated with acute graft-vs.-host disease (hazard ratio = 6; p = 0.0002). Of the 52 patients with measurable disease, 37 (71%) achieved a response. Relapse/progression occurred at a median of 11 months (range 1-52 months) in 21 patients, for a cumulative incidence of 22%. The probability of overall survival and progression-free survival at 5 years were 60% and 54%, respectively. Overall survival and progression-free survival were favorably influenced by having had previous autologous stem cell transplantation and a low CD34(+) cell dose. Overall survival, progression-free survival, and nonrelapse mortality improved over time in this cohort of patients. CONCLUSIONS These results are encouraging for populations different in term of age, diagnosis, and disease status.

Lenalidomide plus donor-lymphocytes infusion after allogeneic stem-cell transplantation with reduced-intensity conditioning in patients with high-risk multiple myeloma

Myeloma relapse is the main cause of death after allogeneic stem cell transplantation. The aim of our observational study was to evaluate the anti-myeloma effect of lenalidomide followed by donor-lymphocyte infusion (DLI) as post-transplantation adoptive immunotherapy. Twelve patients with refractory myeloma were analyzed. The median age at transplantation was 56 years (range, 46-64 years). All patients received reduced-intensity conditioning. Patients were included if progressive or residual disease was observed at day +100 and if no signs of graft-vs-host disease were evident. DLIs were administered after two cycles of lenalidomide. Median dose of lenalidomide was 15 mg (range, 10-25 mg). Patients received a median of six cycles (range, 1-10 cycles). Nine patients (60%) received an escalating dose of DLI. The 1 and 2-year probability of progression-free survival was 75% and 50%, and overall survival was 83% and 69%, respectively. Median overall survival was not reached and median progression-free survival was 23 months. Lenalidomide is well tolerated after allogeneic stem cell transplantation; the combination with DLI did not cause a higher risk of graft-vs-host disease; an immunological synergistic effect was probably present with this strategy. This combination should be evaluated further in a larger cohort of patients.

Age at transplantation and outcome after autologous stem cell transplantation in elderly patients with multiple myeloma.

BACKGROUND AND OBJECTIVE The optimal treatment of patients with multiple myeloma (MM) is not well defined, in part because these patients are underrepresented in clinical studies. Autologous stem cell transplantation (auto-SCT) after high-dose melphalan chemotherapy can result in a prolonged response duration and survival in patients under 65 years of age. DESIGN AND SETTING Single-center, retrospective study of patients treated at Paoli-Calmettes Institute Cancer Centre, between January 1994 and January 2007 (96 months) PATIENTS AND METHODS We compared the outcome of elderly (age >65 years) patients with younger patients aged between 60 and 65 years with MM. RESULTS We compared 82 elderly patients with 104 younger patients. Except for age, both groups had comparable demographic features, disease characteristics, and prognostic factors. Induction VAD chemotherapy was comparable between the elderly (87%) and younger (94%) group. Prior to auto-SCT, the calculated hematopoietic cell transplantation-specific co-morbidity index was also comparable. With a median follow-up of 41 months (range, 5-227 months) after auto-SCT, 120 patients were still alive. Disease progression (n=40; 61%) was the main cause of death, and it was comparable in the two groups. Auto-SCT-related mortality was 3.8% (n=4/104) in younger and 3.7% (n=3/82) in older patients. Comparing younger/older subjects, progression-free survival was significantly higher in the younger group (P<.0001). However, disease response rates after the first auto-SCT was comparable and overall survival (OS) was also comparable (57% vs. 54% at 5 years, P=NS; 32% vs. 24% at 10 years, P=NS). In a Cox multivariate analysis model, none of the relevant characteristics was shown to be a critical prognostic feature for OS. CONCLUSIONS Age was insignificant for both OS and transplant-related mortality. We conclude that there is no biological justification for an age-discriminate policy for MM therapy. Physiologic aging is likely more important than chronologic aging.

CD34+-Selected Stem Cell Boost without Further Conditioning for Poor Graft Function after Allogeneic Stem Cell Transplantation in Patients with Hematological Malignancies

We retrospectively analyzed outcomes of a CD34(+)-selected stem cell boost (SCB) without prior conditioning in 32 patients (male/22; median age of 54 years; range, 20 to 69) with poor graft function, defined as neutrophils ≤1.5 x 10(9)/L, and/or platelets ≤30 x 10(9)/L, and/or hemoglobin ≤8.5 g/dL). The median interval between stem cell transplantation and SCB was 5 months (range, 2 to 228). The median number of CD34(+) and CD3(+) cells were 3.4 x 10(6)/kg (.96 to 8.30) and 9 x 10(3)/kg body weight (range, 2 to 70), respectively. Hematological improvement was observed in 81% of patients and noted after a median of 30 days (range, 14 to 120) after SCB. The recipients of related grafts responded faster than recipients of unrelated grafts (20 versus 30 days, P = .04). The cumulative incidence of acute (grade II to IV) and chronic graft-versus-host disease (GVHD) after SCB was 17% and 26%, respectively. Patients with acute GVHD received a higher median CD3(+) cell dose. The 2-year probability of overall survival was 45%. We suggest that SCB represents an effective approach to improve poor graft function post transplantation, but optimal timing of SCB administration, anti-infective, and GVHD prophylaxis needs further evaluation.

Long-term outcome after allogeneic stem-cell transplantation with reduced-intensity conditioning in patients with multiple myeloma.

This study examines the long‐term outcomes of a cohort of patients with myeloma who were treated with reduced‐intensity conditioning (RIC) regimens after a minimum follow‐up of 5 years at our centre. A total of 53 patients with multiple myeloma (MM) who received allogeneic hematopoietic stem‐cell transplantation (Allo‐SCT) between January 2000 and January 2007 were identified. The median follow‐up of living patients was 84 months (51–141). The median age of the MM patients was 50 (28–70) years. Fifty‐one patients (96%) received a transplant from a sibling donor. The median time between diagnosis and Allo‐SCT was 34 months (6–161), and the median time between auto‐SCT and Allo‐SCT was 10 months (1–89). Fifty‐one patients (96%) received at least one auto‐SCT; 24 patients (45%) received a tandem auto‐Allo‐SCT. At last follow‐up, 21 patients (40%) are alive > 5 years post RIC Allo‐SCT. At last follow‐up, 14 (26%) are in first complete remission (CR), and four patients (8%) in second CR after donor lymphocyte infusion or re‐induction with one of the new anti‐myeloma drugs (bortezomib or lenalidomide) after Allo‐SCT. Eight patients (38%) among these long survivors received one of these new drugs as induction or relapse treatment before Allo‐SCT. Disease status and occurrence of cGvHD were significantly associated with progression‐free survival (PFS); hazard ratio (HR) = 0.62 (0.30–1.29, P = 0.20). Acute GvHD was correlated with higher transplant‐related mortality; HR = 4.19 (1.05–16.77, P = 0.04). No variables were associated with overall survival (OS). In conclusion, we observe that long‐term disease control can be expected in a subset of MM patients undergoing RIC Allo‐SCT. After 10 years, the OS and PFS were 32% and 24%, respectively. The PFS curve after Allo‐SCT stabilizes in time with a plateau after 6 years post Allo‐SCT. Am. J. Hematol. 88:370–374, 2013.

Acute GVHD is a strong predictor of full donor CD3+ T cell chimerism after reduced intensity conditioning allogeneic stem cell transplantation.

The monitoring of chimerism is a standard procedure to assess engraftment and achievement of full donor lymphoid cells after reduced intensity conditioning (RIC) stem cell transplantation (Allo‐SCT). However, there is no consensus on when and how often to monitor post‐transplant chimerism. We retrospectively analyzed our experience regarding the impact of acute graft versus host disease (GVHD) for the prediction of allograft chimerism. One‐hundred‐and‐fifteen patients transplanted between 2001 and 2010 were identified. This group included 57 females and 58 males with a median age of 50 years (range: 26–68). Patients evaluated in this study were adult patients with hematologic malignancies, who received transplants from an HLA‐matched sibling donor or matched unrelated donor (MUD) at allele level so‐called 10/10, and received the RIC regimen including fludarabine/busulfan and anti‐thymoglobulin (ATG). Mixed T‐cell chimerism was defined as between 5 and 94% recipient cells, and full chimerism was defined as the presence of more than 95% donor T‐cell chimerism (TCC). Full donor TCC was achieved in 93 patients (81%) at a median of 77 days (range: 30–120) post‐transplant. The cumulative incidence of Grade 2–4 GVHD in our population was 25% (95% CI 17–34). The analysis of the population of patients with acute GVHD grade ≥2 showed that at day 120 after Allo‐SCT they all had a total full donor TCC. On the other hand, 78 (68%) patients without acute GVHD grade ≥2 presented with mixed chimerism (p = 0.002) on day 120 post‐transplant. Interestingly, patients who received ATG 5 mg/kg obtained a higher probability of complete chimerism compared with those receiving 2.5 mg/kg (p = 0.03). In conclusion, our study demonstrates that acute GVHD was predictive of full donor TCC after RIC Allo‐SCT. Therefore, our data may challenge the concept of the frequent or close monitoring of donor chimerism in some patients with ongoing acute GVHD. However, chimerism testing could represent an attractive modality for minimal residual disease detection or for impeding relapse warranting further prospective studies. Am. J. Hematol. 2012.

Older age does not influence allogeneic peripheral blood stem cell mobilization in a donor population of mostly white ethnic origin

To the editor: Several factors that affect peripheral blood stem cell (PBSC) mobilization were recently identified in a large cohort of healthy donors; factors included ethnic origin, weight, and the total dose of rhG-CSF received for mobilization.[1][1] However, the median age of this population

Comparable outcomes between unrelated and related donors after reduced‐intensity conditioning allogeneic hematopoietic stem cell transplantation in patients with high‐risk multiple myeloma

The purpose of this study was to assess the results of allogeneic stem cell transplantation (allo‐SCT) after reduced‐intensity conditioning (RIC) from matched related donors (MRD) and unrelated donors (URD) in 40 patients with high‐risk multiple myeloma (MM) in a single centre. Seventeen (43%) (Group 1) and 23 patients (57%) (Group 2) had URD and MRD, respectively. Thirty‐nine patients (98%) received one or more autologous transplantation. The median follow‐up was 22 months (1–49). None of our patient experienced a graft rejection. The cumulative incidence of grade II–IV acute GVHD was higher (47%) for the URD vs. (17%) for the MRD (P = 0.092). The cumulative incidence of chronic GVHD was no different between the two groups (24% vs. 30%, respectively). At 2 yr, the TRM probabilities were lower in the unrelated group 12% vs. 22% in the related group (P = 0.4). Also at 2 yrs, for patients receiving unrelated transplantation overall and progression‐free survivals, 59% and 42%, respectively compared to patients with related donor transplantation, 66% and 44% (P = 0.241). In conclusion, these results suggest that URD in MM is feasible. The small number of patients with URD emphasizes the need to delineate indications and perform prospective protocols.

Donor CD3+ lymphocyte infusion after reduced intensity conditioning allogeneic stem cell transplantation: Single-center experience

Donor lymphocyte infusions (DLI) can induce remission in patients with hematologic malignancies who relapse after allogeneic stem cell transplantation. However, graft-vs-host disease (GVHD) remains a major complication of this strategy. We have used escalating doses of DLI for many years, and wanted to assess the risk factors for GVHD and transplant-related mortality as well as disease outcomes according to the reason for DLI. We analyzed 65 patients who received a total of 111 DLI for different reasons and at different intervals after transplantation. Median number of DLI was 2 (range, 1-4), median interval between transplantation and DLI was 9 months (range, 1-41 months) and median number of infused CD3(+) cells/kg recipient body weight was 2.5 × 10(7) (range, 1 × 10(6)-11.8 × 10(7)). Reasons for DLI were relapse or progression in 37 patients (57%), residual disease in 15 patients (23%), and persistence of mixed chimerism in 13 patients (20%). Seven patients (11%) developed acute GVHD grade II to IV and 5 patients (8%) developed extensive chronic GVHD. In univariate analysis, we could identify a transplantation-DLI interval ≤6 months, the dose of DLI (≥1 × 10(7)), and DLI number as predictive factors of GVHD. In multivariate analysis, these results were confirmed only for the transplantation-DLI interval (hazard ratio = 19.48; 2.23-170.34; p = 0.007). Our findings indicate that this form of adoptive immunotherapy is well tolerated and induces a low incidence of GVHD and transplant-related mortality, supporting further investigation as an upfront modality to enhance the graft-vs-tumor response in high-risk patients.