Sabine Furst

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.

Allogeneic haematopoietic stem cell transplantation for myelofibrosis: a report of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

Allogeneic haematopoietic stem‐cell transplantation (HSCT) is the only curative treatment for myelofibrosis. We report an analysis of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM‐TC) registry including patients with myelofibrosis transplanted between 1997 and 2008. Potential risk factors affecting engraftment, non‐relapse mortality (NRM), overall survival (OS) and progression‐free survival (PFS) were analysed. One hundred and forty‐seven patients, aged 20–68 (median 53) years, diagnosed with primary (53%) or secondary myelofibrosis underwent HSCT; 59% of patients were transplanted from a matched sibling donor. The conditioning regimen was myeloablative in 31% of patients. Ninety percent of the patients engrafted. Factors affecting favourably engraftment were splenectomy before HSCT, human leucocyte antigen (HLA) matched sibling donor, peripheral stem cell use as source of stem cells and absence of pre‐transplant thrombocytopenia. Four‐year OS, PFS and NRM survival were 39% (95%confidence interval [CI]: 31–50), 32% (95%CI: 24–43) and 39% (95%CI 30–48), respectively. Multivariate analysis indicated that HLA‐identical sibling donor, chronic phase disease and splenectomy in men had favourable impact on OS.

High response rate and improved graft-versus-host disease following bortezomib as salvage therapy after reduced intensity conditioning allogeneic stem cell transplantation for multiple myeloma

This study assess the use of bortezomib as a salvage therapy in myeloma patients who relapse after allogeneic transplantation with reduced intensity conditioning. Bortezomib treatment is associated with a high response rate and improved graft-versus-host disease, suggesting that it is a safe and efficient therapeutic option. We describe the results of 37 myeloma patients who received bortezomib following reduced intensity allogeneic stem cell transplantation (RIC-allo-SCT). Grade 1–2 peripheral neuropathy (35%), mild thrombocytopenia (24%) and fatigue (19%) were the most frequent adverse events, while there was no worsening of graft-vs-host disease symptoms. Twenty-seven patients (73%; 95% CI, 59–87%) achieved an objective response. With a median follow-up of 9 months from bortezomib initiation, the estimate of overall survival was 65% at 18 months while this was significantly higher (p=0.002) in the 27 patients achieving an objective response, suggesting that bortezomib is a safe and efficient option for myeloma patients after RIC-allo-SCT.

Rituximab as salvage therapy for refractory chronic GVHD

Chronic GVHD (cGVHD) remains a matter of concern after allo-SCT. Moreover, the incidence of cGVHD is likely to increase as a result of the increasing use of allo-SCT (especially with reduced-intensity conditioning regimens), peripheral blood stem cells as stem cell source and frequent donor lymphocyte infusions, all of which are known to increase the risk of cGVHD. Standard primary treatment of cGVHD remains a combination of corticosteroids (CS) and calcineurin inhibitors. There is no standard therapy for those who fail to respond to CS, and CS-resistant GVHD is associated with high morbidity. In addition, elderly patients are more exposed to the side effects of long-term CS. Thus, therapeutic options are usually limited for those patients. Rituximab (RTX) has been reported recently to be effective in cGVHD. The aim of this letter was to analyze the outcome of 15 patients treated with RTX as salvage therapy for refractory cGVHD in a single center. This retrospective report describes 15 consecutive patients experiencing severe or refractory cGVHD, and who received intravenous infusions of RTX (375mg/m per infusion) at weekly intervals for 4 weeks. Responding patients were allowed to receive one or two courses of maintenance therapy according to the attending physician’s decision. Response to RTX was assessed 1 month after the last infusion. CR was defined as resolution of all manifestations in involved organs, while PR was defined as an improvement in each involved organ without any new organ involvement, or progression in a previously involved organ. Resistance was defined as lack of a CR/PR 1 month after the last RTX infusion, requirement for alternative therapy or death from GVHD before the last RTX infusion. The benefit in cGVHD was also evaluated in term of CS taper. The CS dose received was assessed 1 month after the last administration of RTX, and compared with the previous CS dose received at the time of first infusion of RTX. Failure was defined as the absence of CR or PR. Patients’ characteristics, GVHD features and outcome are summarized in Table 1. RTX was administered at a median time of 178 (range, 69–1136) days after allo-SCT, and patients received a median of 5 (range, 1–12) infusions. Except for two patients (nos. 8 and 12) who received RTX as a second-line therapy, all patients had received and failed at least two lines of immunosuppressive therapy. With a median follow-up of 118 days (range, 21–834) from first infusion of RTX, no major toxicities directly related to RTX, according to investigator’s assessment, were observed. However, two patients received less than four infusions (three infusions, n1⁄4 1; one infusion, n1⁄4 1), because of early death from GVHD (no. 9) and patient non-compliance (no. 10). Overall, 10 patients responded to RTX administration (66%; 95% CI, 42–90%) with three CRs. In those responding patients, the patient felt improvement as early as 1 week after the first RTX infusion, with optimal response achieved after the fourth RTX infusion. In addition, RTX allowed a significant reduction of CS dosage (range, 0–83%). Four patients did not respond and died from refractory GVHD, while one responding patient died of disease progression (no. 5). With a median follow-up of 461 days from onset of cGVHD (range, 91–1192), the actuarial survival rate from the first RTX infusion was 60% at 1 year. Currently, there is no standard ‘second-line’ therapy for CS-resistant cGVHD. Several candidate drugs were already tested with variable results. At present, there is an urgent need for systematic research to test not only the efficacy of different approaches but also for implementing and developing better standardized, quantifiable and validated measures of therapeutic response in cGVHD. In our study, the global response rate to RTX was high if considered in terms of salvage therapy and/or CS dose reduction. On the other hand, toxicity was negligible. With this background,

Reduced-intensity conditioning allogeneic SCT as salvage treatment for relapsed multiple myeloma

The aim of this retrospective analysis was to assess the benefit of reduced-intensity conditioning allo SCT (RIC allo-SCT) in a cohort of 32 relapsed multiple myeloma (MM) patients. A total of 19 patients had an HLA-identical sibling donor (‘donor’ group), while 13 patients had no donor (‘no-donor’ group). There were no significant differences between these two groups as for prognosis risk factors. Eighteen patients from the ‘donor’ group could actually proceed to RIC allo-SCT. With a median follow-up of 36 (range, 21–60) months, six patients died from transplant-related toxicity (cumulative incidence, 33% (95% CI, 11–55%)). Only 4 patients from the 18 transplanted patients (22%; 95% CI, 7–48%) progressed after RIC allo-SCT, as compared to 12 (86%; 95% CI, 56–98%; P=0.0003) among the nontransplanted patients. In an ‘intention-to-treat’ analysis, the Kaplan–Meier estimate of PFS was significantly higher in the ‘donor’ group as compared to the ‘no-donor’ group (P=0.01; 46 versus 8% at 3 years). There was no difference in terms of overall survival. However, in multivariate analysis, actual performance of RIC allo-SCT was associated with better PFS (relative risk, 0.35; 95% CI, 0.15–0.82; P=0.01). These data suggest a potential benefit for RIC allo-SCT in the management of relapsed MM warranting further prospective investigations.

High-dose weekly liposomal amphotericin B antifungal prophylaxis following reduced-intensity conditioning allogeneic stem cell transplantation

The use of high-dose corticosteroids for graft-versus-host disease (GVHD) treatment represents a major risk factor for long-term invasive fungal infections. The aim of this study was to investigate the safety and tolerance of weekly prophylactic administration of once-weekly high-dose (7.5 mg/kg) of liposomal amphotericin B (L-AmB) therapy in 21 adult patients receiving high-dose prednisone (2 mg/kg/day) for acute GVHD therapy after reduced intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT). Patients received a median of 4 (range, 1–8) infusions of L-AmB. Seven patients (33%; 95% confidence intervals (CI), 13–53%) discontinued taking the study drug owing to study drug-related adverse events, including elevated serum creatinine (>1.5 times from baseline values; n=5), hypotension and pain (n=1), and violent chest pain and arrhythmia (n=1). The overall frequency of infusion-related reactions was 29% (n=6; 95% CI, 10–48%), but these reactions were always transient and relieved by stopping the infusion. This safety data provide support for an efficacy study of this prophylaxis strategy, because this may help further improving the outcome of RIC or nonmyeloablative allo-SCT.

Haploidentical T Cell-Replete Transplantation with Post-Transplantation Cyclophosphamide for Patients in or above the Sixth Decade of Age Compared with Allogeneic Hematopoietic Stem Cell Transplantation from an Human Leukocyte Antigen-Matched Related or Unrelated Donor.

It has recently been shown that a T cell-replete allogeneic (allo) hematopoietic stem cell transplantation (HSCT) from a haploidentical donor (haplo-ID) could be a valid treatment for hematological malignancies. However, little data exist concerning older populations. We provided transplantation to 31 patients over the age of 55 years from a haplo-ID and compared their outcomes with patients of the same ages who underwent transplantation from a matched related (MRD) or an unrelated donor (UD). All 3 groups were comparable, except for their conditioning. Patients in haplo-ID group received 2 days of post-transplantation high-dose cyclophosphamide followed by cyclosporine A and mycophenolate mofetil, whereas patients in other groups received pretransplantation antithymocyte globulin, cyclosporine A, and additional mycophenolate mofetil in case of 1-antigen mismatch. All patients but 1 in the haplo-ID group engrafted. The incidence of grades 2 to 4 acute graft-versus-host disease (GVHD) was not statistically different between recipients from haplo-ID (cumulative incidence, 23%) and MRD (cumulative incidence, 21%) transplantations but it was lower than after UD HSCT (cumulative incidence, 44%). No patient in the haplo-ID group developed severe chronic GVHD, compared with cumulative incidences of 16% and 14% after MRD (P = .02) and UD (P = .03) grafts, respectively. The cumulative incidences of relapse were similar in the 3 groups, whereas nonrelapse mortality after UD HSCT was 3-fold higher than after haplo-ID or MRD HSCT. Overall, 2-year overall survival (70%), progression-free survival (67%), and progression and severe chronic GVHD-free survival (67%) probabilities after haplo-ID did not statistically differ from MRD transplantation (78%, 64%, and 51%, respectively), although they were higher than after UD transplantation (51% [P = .08], 38% [P = .02], and 31% [P = .007]). We conclude that T cell-replete haplo-ID HSCT followed by post-transplantation high-dose- cyclophosphamide in patients over 55 years is associated with promising results, similar to MRD HSCT, and is deserving prospective evaluation.

Randomized study of 2 reduced-intensity conditioning strategies for human leukocyte antigen-matched, related allogeneic peripheral blood stem cell transplantation: prospective clinical and socioeconomic evaluation.

The optimal intensity of reduced‐intensity conditioning (RIC) before allogeneic hematopoietic stem cell transplantation (allo‐HSCT) remains uncertain.

Reduced intensity conditioning allogeneic stem cell transplantation for patients with acute myeloid leukemia: long term results of a ‘donor’ versus ‘no donor’ comparison

Reduced intensity conditioning allogeneic stem cell transplantation for patients with acute myeloid leukemia: long term results of a ‘donor’ versus ‘no donor’ comparison

The increase from 2.5 to 5 mg/kg of rabbit anti-thymocyte-globulin dose in reduced intensity conditioning reduces acute and chronic GVHD for patients with myeloid malignancies undergoing allo-SCT

We previously reported that reduced intensity conditioning (RIC) regimen with fludarabine, BU and 2.5 mg/kg of rabbit anti-thymocyte globulin (r-ATG) was effective but associated with a high rate of acute and chronic GVHD. Therefore, we increased the dose of r-ATG to 5 mg/kg. In this report, we analyzed 87 patients with AML or myelodysplastic syndrome (MDS) undergoing allo-SCT from an HLA-identical sibling donor from 2000 to 2010. RIC consisted of fludarabine, BU and r-ATG 2.5 mg/kg on 1 day (r-ATG1; n=53) or 2.5 mg/kg per day over 2 days (r-ATG2; n=22). Grade 2–4 acute GVHD incidence at day 100 was 30.2% and 8.8% in the r-ATG1 and r-ATG2 groups, respectively (P=0.038). Extensive chronic GVHD incidence was 60.4% and 12% in the r-ATG1 and r-ATG2 groups, respectively (P<0.001). The relapse incidences (RI) at 24 months were 18.9% and 28.5% in r-ATG1 and r-ATG2 groups, respectively (P=0.640). Overall and PFS were not different between the r-ATG1 and r-ATG2 groups. r-ATG dose at 5 mg/kg in the setting of RIC seems a good balance allowing GVHD prevention and antitumor effect with a remarkable reduction of GVHD incidence without an identical level of increased relapse rate.