Faculty Bibliography

BACKGROUND:To evaluate long-term outcome of myeloablative allogeneic stem cell transplantation (allo-SCT) (MAC) versus reduced-intensity allo-SCT (RIC) in patients with relapsed/refractory Hodgkin's lymphoma (HL) in recent years. PATIENTS AND METHODS:A total of 312 patients (63 MAC and 249 RIC) with relapsed/refractory HL who received allo-SCT between 2006 and 2010 and were reported to the EBMT Database were included in the study. RESULTS:With a median follow-up for alive patients of 56 (26-73) months, there were no significant differences in non-relapse mortality (NRM) between MAC and RIC. Relapse rate (RR) was somewhat lower in the MAC group (41% versus 52% at 24 months, P = 0.16). This lower RR translated into a marginal improvement in event-free survival (EFS) for the MAC group (48% versus 36% at 24 months, P = 0.09) with no significant differences in overall survival (73% for MAC and 62% for RIC at 24 months, P = 0.13). Multivariate analysis after adjusting for disease status at the time of allo-SCT showed that the use of MAC was of borderline statistical significance for predicting a lower RR and EFS [HR 0.7, 95% CI (0.5-1.0), P = 0.1] and [HR 0.7, 95% CI (0.5-1.0), P = 0.07], respectively, after allo-SCT. CONCLUSIONS:With modern transplant practices, the NRM associated with MAC for HL has strongly decreased, resulting into non-significant improvement of EFS because of a somewhat better disease control compared with RIC transplants. The intensity of conditioning regimens should be considered when designing individual allo-SCT strategies or clinical trials in patients with relapsed/refractory HL.

Patients with acute myeloid leukemia (AML) during induction chemotherapy and those who receive allogeneic hematopoietic stem cell transplantation (HSCT) are at higher risk of invasive fungal infections (IFI). In the present study, we investigated whether the risk of IFI in AML patients receiving HSCT might be affected by the antifungal prophylaxis with posaconazole administered during the induction/salvage chemotherapy treatment. Between August 2001 and April 2015, 130 patients with AML received itraconazole/fluconazole (group A) and 99 received posaconazole (group B) as antifungal prophylaxis after induction/salvage chemotherapy at 7 Italian centers and all patients received fluconazole as antifungal prophylaxis after HSCT. The median duration of antifungal prophylaxis after induction/salvage chemotherapy was significantly longer for patients in group A than for those in group B (24 days versus 20 days, P = .019). The 1-year cumulative incidence of proven/probable IFI after HSCT was 14% and 4% in group A and group B, respectively (P = .012). Fungal-free survival and overall survival at 1 year after HSCT were 66% and 70% in group A, and 75% and 77% in group B (P = .139 and P = .302), respectively. Multivariate logistic analysis identified the use of alternative donors (matched unrelated donor: odds ratio [OR], 3.25; haploidentical/partially matched related donor: OR, 3.19), antifungal prophylaxis with itraconazole/fluconazole (OR, 3.82), and reduced-intensity conditioning (OR, 4.92) as independent risk factors for the development of IFI after HSCT. In summary, the present study suggests that the protective effects of posaconazole during induction/salvage chemotherapy for AML patients may have long-lasting benefits and eventually contribute to reduce the risk of IFI when patients undergo allogeneic HSCT.

PURPOSE/OBJECTIVE:The genetic basis of myelodysplastic syndromes (MDS) is heterogeneous, and various combinations of somatic mutations are associated with different clinical phenotypes and outcomes. Whether the genetic basis of MDS influences the outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) is unclear. PATIENTS AND METHODS/METHODS:We studied 401 patients with MDS or acute myeloid leukemia (AML) evolving from MDS (MDS/AML). We used massively parallel sequencing to examine tumor samples collected before HSCT for somatic mutations in 34 recurrently mutated genes in myeloid neoplasms. We then analyzed the impact of mutations on the outcome of HSCT. RESULTS:Overall, 87% of patients carried one or more oncogenic mutations. Somatic mutations of ASXL1, RUNX1, and TP53 were independent predictors of relapse and overall survival after HSCT in both patients with MDS and patients with MDS/AML (P values ranging from .003 to .035). In patients with MDS/AML, gene ontology (ie, secondary-type AML carrying mutations in genes of RNA splicing machinery, TP53-mutated AML, or de novo AML) was an independent predictor of posttransplantation outcome (P = .013). The impact of ASXL1, RUNX1, and TP53 mutations on posttransplantation survival was independent of the revised International Prognostic Scoring System (IPSS-R). Combining somatic mutations and IPSS-R risk improved the ability to stratify patients by capturing more prognostic information at an individual level. Accounting for various combinations of IPSS-R risk and somatic mutations, the 5-year probability of survival after HSCT ranged from 0% to 73%. CONCLUSION/CONCLUSIONS:Somatic mutation in ASXL1, RUNX1, or TP53 is independently associated with unfavorable outcomes and shorter survival after allogeneic HSCT for patients with MDS and MDS/AML. Accounting for these genetic lesions may improve the prognostication precision in clinical practice and in designing clinical trials.

We describe the use and outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for multiple myeloma (MM) in Europe between January 1990 and December 2012. We identified 7333 patients, median age at allo-HSCT was 51 years (range: 18-78), of whom 4539 (62%) were males. We distinguished three groups: (1) allo-HSCT upfront (n=1924), (2) tandem auto-allo-HSCT (n=2004) and (3) allo-HSCT as a second line treatment and beyond (n=3405). Overall, there is a steady increase in numbers of allo-HSCT over the years. Upfront allo-HSCT use increased up to year 2000, followed by a decrease thereafter and represented 12% of allo-HSCTs performed in 2012. Tandem auto-allo-HSCT peaked around year 2004 and contributed to 19% of allo-HSCTs in 2012. Allo-HSCT as salvage after one or two or three autografts was steadily increasing over the last years and represented 69% of allo-HSCTs in 2012. Remarkable heterogeneity in using allo-HSCT was observed among the different European countries. The 5-year survival probabilities from time of allo-HSCT for the three groups after year 2004 were 42%, 54% and 32%, respectively. These results show that the use of allo-HSCT is increasing in Europe, especially as second line treatment and beyond. There is an unmet need for well-designed prospective studies investigating allo-HSCT as salvage therapy for MM.

The European Society for Blood and Marrow Transplant Research data set was used to retrospectively analyze the outcomes of hypomethylating therapy (HMA) compared with those of conventional chemotherapy (CC) before hematopoietic stem cell transplantation (HSCT) in 209 patients with advanced myelodysplastic syndromes. Median follow-up was 22.1 months and the median age of the group was 57.6 years with 37% of the population older than > 60 years. The majority of patients (59%) received reduced-intensity conditioning and 34% and 27% had intermediate-2 and high international prognostic scoring system (IPSS) scores. At time of HSCT, 32% of patients did not achieve complete remission (CR) and 13% had primary refractory disease. On univariate analysis, outcomes at 3 years were not significantly different between HMA and CC for overall survival (OS), relapse-free survival (RFS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM): OS (42% versus 35%), RFS (29% versus 31%), CIR (45% versus 40%), and NRM (26% versus 28%). Comparing characteristics of the groups, there were more patients < 55 years old, more patients in CR (68% versus 32%), and fewer patients with primary refractory disease in the CC group than in the HMA group (10% versus 19%, P < .001). Patients with primary refractory disease had worse outcomes than those in CR with regard to OS (hazard ratio [HR], 2.42; 95% confidence interval [CI], 1.41 to 4.13; P = .001), RFS (HR, 2.27; 95% CI, 1.37 to 3.76; P = .001), and NRM (HR, 2.49; 95% CI, 1.18 to 5.26; P = .016). In addition, an adverse effect of IPSS-R cytogenetic risk group was evident for RFS. In summary, outcomes after HSCT are similar for patients receiving HMA compared with those receiving CC, despite the higher proportion of patients with primary refractory disease in the HMA group.

BACKGROUND:Allogeneic hematopoietic stem cell transplantation (HSCT) is potentially curative in a variety of hematological malignancies. Graft-vs.-host disease (GvHD) remains a life-threatening complication. Standard treatment is high-dose (HD) corticosteroids. Steroid-refractory (SR) GvHD is associated with poor prognosis. At present, second-line treatment is ill-defined and includes a number of agents. Novel insights into the pathophysiology of acute GvHD (aGvHD) highlight the relevant role of the host inflammatory response governed by several kinase families, including Janus kinases (JAK)1/2. Ruxolitinib, a JAK1/2 inhibitor approved for intermediate-2/high-risk myelofibrosis, was recently employed in SR-GvHD with encouraging overall response rates. Clinical experience however remains limited. CASE PRESENTATION:A 51-year-old male with refractory anemia with excess blast type-2 underwent a myeloablative allogeneic HSCT from a 9/10 HLA-matched unrelated donor after conditioning with busulfan and cyclophosphamide. GvHD prophylaxis consisted of cyclosporine, methotrexate, and thymoglobulin. CD34(+) cells/kg infused were 8.69 × 10(6) kg. On day 29, the patient developed overall grade IV aGvHD with biopsy proven stage IV gastrointestinal (GI) GvHD refractory to HD corticosteroids. Patient conditions rapidly deteriorated and became critical despite the addition of mycophenolate mofetil and budesonide. On day 33, Ruxolitinib was started, and on day 39 the patient clinical conditions gradually improved. Complete resolution of aGvHD was also confirmed by histology on day 54. CONCLUSIONS:At 5 months from HSCT, the patient is well and in continuous hematological complete remission without flare of GvHD. Ruxolitinib was discontinued on day 156. Ruxolitinib is feasible and effective in SR-aGvHD though large prospective clinical trials are warranted.

Multiple myeloma (MM) is the leading indication for autologous stem cell transplantation (ASCT) worldwide. The safety and efficacy of reducing hospital stay for MM patients undergoing ASCT have been widely explored, and different outpatient models have been proposed. However, there is no agreement on the criteria for selecting patients eligible for this strategy as well as the standards for their clinical management. On the basis of this rationale, the Italian Group for Stem Cell Transplantation (GITMO) endorsed a project to develop guidelines for the management of outpatient ASCT in MM, using evidence-based knowledge and consensus-formation techniques. An expert panel convened to discuss the currently available data on the practice of outpatient ASCT management and formulated recommendations according to the supporting evidence. Evidence gaps were filled with consensus-based statements. Three main topics were addressed: (1) the identification of criteria for selecting MM patients eligible for outpatient ASCT management; (2) the definition of standard procedures for performing outpatient ASCT (model, supportive care and monitoring during the aplastic phase); (3) the definition of the standard criteria and procedures for re-hospitalization during the aplastic phase at home. Herein, we report the summary and the results of the discussion and the consensus.

Despite a remarkable reduction in the past decades, cytomegalovirus (CMV) disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients remains a feared complication, still associated with significant morbidity and mortality. Today, first line treatment of CMV infection/reactivation is still based on dated antiviral compounds Ganciclovir (GCV), Foscarnet (FOS) and Cidofovir (CDF) with their burdensome weight of side effects. Maribavir (MBV), Letermovir (LMV) and Brincidofovir (BDF) are three new promising anti-CMV drugs without myelosuppressive properties or renal toxic effects that are under investigation in randomized phase II and III trials. Adoptive T-cell therapy (ATCT) in CMV infection possesses a strong rationale, demonstrated by several proof of concept studies; its feasibility is currently under investigation by clinical trials. ATCT from third-party and naïve donors could meet the needs of HSCT recipients of seronegative donors and cord blood grafts. In selected patients such as recipients of T-cell depleted grafts, ATCT, based on CMV-specific host T-cells reconstitution kinetics, would be of value in the prophylactic and/or preemptive CMV treatment. Vaccine-immunotherapy has the difficult task to reduce the incidence of CMV reactivation/infection in highly immunocompromised HSCT patients. Newer notions on CMV biology may represent the base to flush out the Troll of transplantation.