Jean El Cheikh

Impact of Azacitidine Before Allogeneic Stem-Cell Transplantation for Myelodysplastic Syndromes: A Study by the Société Française de Greffe de Moelle et de Thérapie-Cellulaire and the Groupe-Francophone des Myélodysplasies

PURPOSE To investigate the impact of prior-to-transplantation azacitidine (AZA) on patient outcome after allogeneic stem-cell transplantation (alloSCT) for myelodysplastic syndrome (MDS). PATIENTS AND METHODS Of the 265 consecutive patients who underwent alloSCT for MDS between October 2005 and December 2009, 163 had received cytoreductive treatment prior to transplantation, including induction chemotherapy (ICT) alone (ICT group; n = 98), AZA alone (AZA group; n = 48), or AZA preceded or followed by ICT (AZA-ICT group; n = 17). At diagnosis, 126 patients (77%) had an excess of marrow blasts, and 95 patients (58%) had intermediate-2 or high-risk MDS according to the International Prognostic Scoring System (IPSS). Progression to more advanced disease before alloSCT was recorded in 67 patients. Donors were sibling (n = 75) or HLA-matched unrelated (10/10; n = 88). They received blood (n = 142) or marrow (n = 21) grafts following either myeloablative (n = 33) or reduced intensity (n = 130) conditioning. RESULTS With a median follow-up of 38.7 months, 3-year outcomes in the AZA, ICT, and AZA-ICT groups were 55%, 48%, and 32% (P = .07) for overall survival (OS); 42%, 44%, and 29% (P = .14) for event-free survival (EFS); 40%, 37%, and 36% (P = .86) for relapse; and 19%, 20%, and 35% (P = .24) for nonrelapse mortality (NRM), respectively. Multivariate analysis confirmed the absence of statistical differences between the AZA and the ICT groups in terms of OS, EFS, relapse, and NRM. CONCLUSION With the goal of downstaging underlying disease before alloSCT, AZA alone led to outcomes similar to those for standard ICT.

Bone Marrow Compared with Peripheral Blood Stem Cells for Haploidentical Transplantation with a Nonmyeloablative Conditioning Regimen and Post-transplantation Cyclophosphamide

Recently, the administration of high-dose cyclophosphamide (Cy) after T cell-replete haploidentical stem cell infusion has been reported to be feasible and effective. In the original study, bone marrow (BM) was used as the source of stem cells. Here, we retrospectively analyzed the use of BM versus peripheral blood stem cells (PBSCs) in a cohort of patients receiving haploidentical T cell-replete transplantation after a nonmyeloablative conditioning regimen with postinfusion Cy. In the PBSC versus BM groups, the incidence of acute graft-versus-host disease (GVHD) was 33% versus 25%, respectively, and the incidence of chronic GVHD was 13% versus 13%, respectively. The median time to achieve a safe and unsupported absolute neutrophil and platelet count was 20 versus 21 days and 27 versus 29 days, respectively. The incidence of engraftment was also similar in the 2 cohorts. The 1-year nonrelapse mortality rate was 12% versus 22%, respectively (P = .96). Finally, nonsignificant differences in survival were observed. In conclusion, the use of PBSCs instead of BM after T cell-replete haploidentical transplantation did not appear to be detrimental in terms of either GVHD or engraftment rate. PBSCs could be a valid alternative to BM after transplantation from a haploidentical donor using postinfusion Cy.

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.

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.

Efficacy and feasibility of sorafenib as a maintenance agent after allogeneic hematopoietic stem cell transplantation for Fms-like tyrosine kinase 3-mutated acute myeloid leukemia

Sorafenib has shown encouraging results in patients with Fms‐like tyrosine kinase 3 (FLT3)‐positive acute myeloid leukemia. Its role after allogeneic stem cell transplantation (HSCT) has been reported in a few cases with encouraging results.

Antithymocyte Globulin before Allogeneic Stem Cell Transplantation for Progressive Myelodysplastic Syndrome: A Study from the French Society of Bone Marrow Transplantation and Cellular Therapy

We investigated the impact of rabbit antithymocyte globulins (ATG) on patient outcomes after allogeneic stem cell transplantation (allo-SCT) for progressive myelodysplastic syndrome (MDS). Of the 242 consecutive patients who underwent allo-SCT for progressive MDS between October 1999 and December 2009, 93 received ATG (ATG group) at the median dose of 5 mg/kg, whereas 149 patients did not (no-ATG group). Donors were sibling (n = 153) or HLA-matched unrelated (n = 89). Patients received blood (n = 90) or marrow (n = 152) grafts after either myeloablative (n = 109) or reduced-intensity (n = 133) conditioning. Three-year overall and event-free survival, nonrelapse mortality, relapse, and chronic graft-versus-host disease (GVHD) development were not significantly different between the 2 groups. In contrast, acute grade II to IV GVHD occurred more often in the no-ATG group (55% of the patients) than in the ATG group (27%, P < .0001). Similar results were observed with acute grade III to IV GVHD (28% and 14% in the no-ATG group and ATG group, respectively; P = .009). In multivariate analysis, after adjustment with propensity score, the absence of ATG was the strongest parameter associated with an increased risk of acute grade II to IV GVHD (hazard ratio, 2.13; 95% confidence interval, 1.35 to 3.37; P = .001]. ATG had no impact on overall and event-free survival or cumulative incidence of the relapse. In conclusion, the addition of ATG to allo-SCT conditioning did not increase the incidence of relapse of patients with progressive MDS. The incidence of acute GVHD was decreased without compromising outcomes.

Reduced-toxicity conditioning prior to allogeneic stem cell transplantation improves outcome in patients with myeloid malignancies

The introduction of reduced intensity/toxicity conditioning regimens has allowed allogeneic hematopoietic cell transplantation to be performed in patients who were previously considered too old or otherwise unfit. Although it led to a reduction in non-relapse mortality, disease control remains a major challenge. We studied the outcome of 165 patients with acute myeloid leukemia (n=124) or myelodysplastic syndrome (n=41) transplanted after conditioning with fludarabine (30 mg/m2/day for 5 days), intravenous busulfan (either 260 mg/m2: reduced intensity conditioning, or 390–520 mg/m2: reduced toxicity conditioning), and rabbit anti-thymoglobulin (2.5 mg/kg/day for 2 days). The median age of the patients at transplantation was 56.8 years. The 2-year relapse incidence was 29% (23% versus 39% for patients transplanted in first complete remission and those transplanted beyond first complete remission, respectively; P=0.008). The 2-year progression-free survival rate was 57% (95% CI: 49.9–65). It was higher in the groups with favorable or intermediate cytogenetics than in the group with unfavorable cytogenetics (72.7%, 60.5%, and 45.7%, respectively; P=0.03). The cumulative incidence of grades 2–4 and 3–4 acute graft-versus-host disease at day 100 was 19.3% and 7.9%, respectively. The cumulative incidence of chronic graft-versus-host disease at 1 year was 21.6% (severe forms: 7.8%). Non-relapse mortality at 1 year reached 11%. The 2-year overall survival rate was 61.8% (95% CI: 54.8–69.7). Unfavorable karyotype and disease status beyond first complete remission were associated with a poorer survival. This well-tolerated conditioning platform can lead to long-term disease control and offers possibilities of modulation according to disease stage or further development.

Once-weekly liposomal amphotericin B for prophylaxis of invasive fungal infection after graft-versus-host disease in allogeneic hematopoietic stem cell transplantation: a comparative retrospective single-center study.

BACKGROUND AND OBJECTIVES The liposomal formulation of amphotericin B (LAmB) has been shown to cause few and mild infusion-related reactions, while achieving high plasma and tissue concentrations compared with conventional amphotericin B. We investigated the efficacy and safety of high-dose LAmB (7.5 mg/kg once weekly) prophylaxis of fungal infections in allogeneic stem-cell transplanted (allo-SCT) patients with graft-versus-host disease (GvHD). DESIGN AND SETTING Retrospective, comparative, single-center. METHODS Forty-two patients receiving high-dose prednisone for GvHD after allo-SCT had LAmB prophylaxis; 83 patients in the control group received other antifungal prophylaxis. RESULTS In the LAmB prophylaxis group, the median duration of treatment was 7 weeks. The cumulative incidence of invasive fungal infection was 8% at 1 year after transplantation, 8% at 2 years and 16% at 3 years in the LAmB group vs. 36% at 1 year, 44% at 2 years and 49% at 3 years in the other prophylaxis group (P=.008). Fungal infection-related mortality after transplantation was observed in none of the patients in the LAmB prophylaxis group vs. 12 patients (14%) at 1 year, 14 patients (17%) at 2 years and 16 patients (19%) at 3 years in the control group (P=.005). The tolerance of the treatment was good with only 5 patients (12%) having a reversible nephrotoxicity leading to temporary treatment discontinuation. CONCLUSIONS High-dose LAmB prophylaxis seems effective and well tolerated in this short series of allo-SCT patients with GvHD. Prospective clinical studies are required to confirm these results.

PET/CT Scanner and Bone Marrow Biopsy in Detection of Bone Marrow Involvement in Diffuse Large B-Cell Lymphoma

Evaluation of bone marrow involvement (BMI) is paramount in diffuse large B-cell lymphoma (DLBCL) for prognostic and therapeutic reasons. PET/CT scanner (PET) is now a routine examination for the staging of DLBCL with prognostic and therapeutic implications. This study evaluates the role of PET for detecting marrow involvement compared to bone marrow biopsy (BMB). This monocentric study included 54 patients diagnosed with DLBCL between 2009 and 2013 and who had FDG PET/CT in a pre-treatment setting. A correlation analysis of the detection of BMI by PET and BMB was performed. A prognostic evaluation of BMI by BMB and/or PET/CT and correlation with an overall 2-year survival were analyzed. PET was more sensitive for the detection of BMI than BMB (92.3% vs. 38.5%). It can be considered a discriminatory Pre-BMB test with a negative predictive value of 97.6%. In addition, BMI by PET had a prognostic value with strong correlation with progression-free survival (PFS) (HR = 3.81; p = 0.013) and overall survival (OS) (HR = 4.12; p = 0.03) while the BMB had not. PET shows superior performance to the BMB for the detection of marrow involvement in DLBCL. It may be considered as the first line examination of bone marrow instead of the biopsy.

Tandem autologous-allogeneic stem cell transplantation as a feasible and effective procedure in high-risk lymphoma patients

Although high-dose chemotherapy is the gold standard for the treatment of many relapsed or refractory lymphomas, the outcome remains unsatisfactory, particularly in some subsets of patients with adverse prognostic features. Here we report the outcome of 111 high-risk lymphoma patients treated with a