Faculty Bibliography

We report the clinical outcomes of 83 patients with acute lymphoblastic leukemia (median age, 46 years; range, 18-75 years) treated at our institution between 1999 and 2011. Treatment refers to clinical trials open for accrual at the time of diagnosis or to institutional guidelines. Upfront allografting was considered for younger high-risk patients. Seventy-eight of 83 (94%) patients achieved complete remission after induction, although 53% of them eventually relapsed. Forty of 70 patients younger than 61 years underwent allografting. The median follow-up was 7.4 years (range, 0.2-15.0 years). Overall, the 5-year overall survival (OS) and event-free survival (EFS) were 40% and 39%, respectively. In patients undergoing transplantation, OS and EFS at 5 years were both 53%, whereas in a nontransplantation setting, both OS and EFS were 35% at 5 years (P = .044 for both OS and EFS). By multivariate analysis, the independent predictors of OS and EFS were age and leukocytosis in the overall population and allografting in young patients.

The European Society for Blood and Marrow Transplantation Chronic Malignancies Working Party held a preceptorship meeting in Turin, Italy on 25-26 September 2014, to discuss the role of stem cell transplantation (SCT) in the treatment of multiple myeloma and other plasma cell disorders. Scientists and clinicians working in the field gathered to discuss a variety of topics including the results of recent clinical trials, basic research, the concept of minimal residual disease, and immune modulation. As individual presentations revealed, important advances have occurred in our understanding of the pathophysiology of myeloma and the role that SCT, along with other forms of immunotherapy, plays in treating it. Each presentation stimulated discussion and exchange of ideas among the attendants. We decided to summarize and, importantly, to update the meeting proceedings in this review to share stimulating discussions and ideas on potentially novel treatment strategies among clinicians.

INTRODUCTION/BACKGROUND:Second-line, salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (AUTO-SCT) is the standard of care for patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL). Approximately 50% of patients relapse after AUTO-SCT and their prognosis is generally poor. Brentuximab Vedotin (BV) has demonstrated efficacy in this setting and allogeneic (ALLO)-SCT represents an option with curative potential in this subgroup of patients. AREAS COVERED/METHODS:A systematic review has been conducted to explore the actual knowledge on ALLO-SCT, BV and newer agents in R/R HL. EXPERT OPINION/CONCLUSIONS:The introduction of BV in clinical practice has significantly improved the management of post-AUTO-SCT relapses and the drug can induce durable remissions in a subset of R/R HL. Allografting select patients has been used to improve clinical outcomes and recent case series have begun to explore BV as a potential 'bridge' to allo-SCT, even though the optimal timing of ALLO-SCT after BV response remains undetermined. However, reduced tumor burden at the time of ALLO-SCT is a key factor to decrease relapse risk. Based on the unique composition of the tumor, more recently new agents such as PD-1 inhibitors have been developed. The potential role of PD-1 inhibitors with ALLO-SCT remains to be explored.

In contrast to the upfront setting in which the role of high dose therapy with autologous hematopoietic cell transplantation (HCT) as consolidation of a 1st remission in patients with multiple myeloma (MM) is well established, the role of high dose therapy with autologous or allogeneic HCT has not been extensively studied in MM patients relapsing after primary therapy. The International Myeloma Working Group together with the Blood and Marrow Transplant Clinical Trials Network (BMT-CTN), the American Society of Blood and Marrow Transplantation (ASBMT), and the European Society of Blood and Marrow Transplantation (EBMT) convened a meeting of MM experts to: 1. Summarize current knowledge regarding the role of autologous or allogeneic HCT in MM patients progressing after primary therapy; 2. Propose guidelines for the use of salvage HCT in MM; 3. Identify knowledge gaps; 4 Propose a research agenda and 5. Develop a collaborative initiative to move the research agenda forward. After reviewing the available data, the expert committee came to the following consensus statement for salvage autologous HCT: 1. In transplant eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high dose therapy with HCT as part of salvage therapy should be considered standard; 2. High dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of more than 18 months; 3. High dose therapy and autologous HCT can be used as a bridging strategy to allogeneic HCT; 4. The role of post salvage HCT maintenance needs to be explored in the context of well designed prospective trials that should include new agents such as monoclonal antibodies, immune-modulating agents and oral proteasome inhibitors; 5. Autologous HCT consolidation should be explored as a strategy to develop novel conditioning regimens or post HCT strategies in patients with short (less than 18 months remissions) after primary therapy; 6. Prospective randomized trials need to be performed to define the role of salvage autologous HCT in patients with MM relapsing after primary therapy comparing to "best non HCT" therapy. The expert committee also underscored the importance of collecting enough hematopoietic stem cells to perform two transplants early in the course of the disease. In regards to allogeneic HCT the expert committee agreed on the following consensus statements: 1. Allogeneic HCT should be considered appropriate therapy for any eligible patient with early relapse (less than 24 months) after primary therapy that included an autologous HCT and/or high risk features (i.e cytogenetics, extramedullary disease, plasma cell leukemia or high LDH); 2. Allogeneic HCT should be performed in the context of a clinical trial if possible; 3. The role of post allogeneic HCT maintenance therapy needs to be explored in the context of well designed prospective trials; 4. Prospective randomized trials need to be performed to define the role salvage allogeneic HCT in patients with MM relapsing after primary therapy.

BACKGROUND:The standard busulfan-cyclophosphamide myeloablative conditioning regimen is associated with substantial non-relapse mortality in patients older than 40 years with acute myeloid leukaemia who are undergoing allogeneic stem-cell transplantation. Because the combination of busulfan plus fludarabine has been proposed to reduce non-relapse mortality, we aimed to compare this treatment with busulfan plus cyclophosphamide as a preparative regimen in these patients. METHODS:We did an open-label, multicentre, randomised, phase 3 trial for patients with acute myeloid leukaemia at 25 hospital transplant centres in Italy and one in Israel. Eligible patients were aged 40-65 years, had an Eastern Cooperative Oncology Group performance status less than 3, and were in complete remission. Patients were randomly assigned 1:1 to receive intravenous busulfan plus cyclophosphamide or busulfan plus fludarabine. Treatment allocations were not masked to investigators or patients. Randomisation was done centrally via a dedicated web-based system using remote data entry, with patients stratified by donor type and complete remission status. Patients allocated to busulfan plus cyclophosphamide received intravenous busulfan 0·8 mg/kg four times per day during 2 h infusions for four consecutive days (16 doses from days -9 through -6; total dose 12·8 mg/kg) and cyclophosphamide at 60 mg/kg per day for two consecutive days (on days -4 and -3; total dose 120 mg/kg). Patients allocated to busulfan plus fludarabine received the same dose of intravenous busulfan (from days -6 through -3) and fludarabine at 40 mg/m(2) per day for four consecutive days (from days -6 through -3; total dose 160 mg/m(2)). The primary endpoint was 1-year non-relapse mortality, which was assessed on an intention-to-treat basis; safety outcomes were assessed in the per-protocol population. This trial has been completed and is registered with ClinicalTrials.gov, number NCT01191957. FINDINGS/RESULTS:Between Jan 3, 2008, and Dec 20, 2012, we enrolled and randomly assigned 252 patients to receive busulfan plus cyclophosphamide (n=125) or busulfan plus fludarabine (n=127). Median follow-up was 27·5 months (IQR 9·8-44·3). 1-year non-relapse mortality was 17·2% (95% CI 11·6-25·4) in the busulfan plus cyclophosphamide group and 7·9% (4·3-14·3) in the busulfan plus fludarabine group (Gray's test p=0·026). The most frequently reported grade 3 or higher adverse events were gastrointestinal events (28 [23%] of 121 patients in the busulfan plus cyclophosphamide group and 26 [21%] of 124 patients in the busulfan plus fludarabine group) and infections (21 [17%] patients in the busulfan plus cyclophosphamide group and 13 [10%] patients in the busulfan plus fludarabine group had at least one such event). INTERPRETATION/CONCLUSIONS:In older patients with acute myeloid leukaemia, the myeloablative busulfan plus fludarabine conditioning regimen is associated with lower transplant-related mortality than busulfan plus cyclophosphamide, but retains potent antileukaemic activity. Accordingly, this regimen should be regarded as standard of care during the planning of allogeneic transplants for such patients. FUNDING/BACKGROUND:Agenzia Italiana del Farmaco.

The European Myeloma Network provides recommendations for the management of the most common complications of multiple myeloma. Whole body low-dose computed tomography is more sensitive than conventional radiography in depicting osteolytic disease and thus we recommend it as the novel standard for the detection of lytic lesions in myeloma (grade 1A). Myeloma patients with adequate renal function and bone disease at diagnosis should be treated with zoledronic acid or pamidronate (grade 1A). Symptomatic patients without lytic lesions on conventional radiography can be treated with zoledronic acid (grade 1B), but its advantage is not clear for patients with no bone involvement on computed tomography or magnetic resonance imaging. In asymptomatic myeloma, bisphosphonates are not recommended (grade 1A). Zoledronic acid should be given continuously, but it is not clear if patients who achieve at least a very good partial response benefit from its continuous use (grade 1B). Treatment with erythropoietic-stimulating agents may be initiated in patients with persistent symptomatic anemia (hemoglobin <10g/dL) in whom other causes of anemia have been excluded (grade 1B). Erythropoietic agents should be stopped after 6-8 weeks if no adequate hemoglobin response is achieved. For renal impairment, bortezomib-based regimens are the current standard of care (grade 1A). For the management of treatment-induced peripheral neuropathy, drug modification is needed (grade 1C). Vaccination against influenza is recommended; vaccination against streptococcus pneumonia and hemophilus influenza is appropriate, but efficacy is not guaranteed due to suboptimal immune response (grade 1C). Prophylactic aciclovir (or valacyclovir) is recommended for patients receiving proteasome inhibitors, autologous or allogeneic transplantation (grade 1A).

The results of allogeneic stem cell transplantation (allo-SCT) in chronic myelomonocytic leukaemia (CMML) are usually reported together with other categories of myelodysplastic syndrome. We analysed transplantation outcome in 513 patients with CMML, with a median age of 53 years reported to the European Group for Blood and Marrow Transplantation. Conditioning was standard (n = 249) or reduced-intensity (n = 226). Donors were human leucocyte antigen-related (n = 285) or unrelated (n = 228). Disease status at transplantation was complete remission (CR) in 122 patients, no CR in 344, and unknown in 47. Engraftment was successful in 95%. Grades 2-4 acute graft-versus-host disease (GvHD) occurred in 33% of the patients and chronic GvHD was reported in 24%. The 4-year cumulative incidence of non-relapse mortality was 41% and 32% for relapse, resulting in a 4-year estimated relapse-free and overall survival (OS) of 27% and 33%, respectively. Patients transplanted in CR had lower probability for non-relapse death (P = 0·002) and longer relapse-free and OS (P = 0·001 and P = 0·005, respectively). In multivariate analysis the only significant prognostic factor for survival was the presence of CR at transplantation (P = 0·005). Allo-SCT remains a curative treatment option for patients with CMML and should preferably be performed early after diagnosis or after establishing the best possible remission status.

Pretransplant values of serum ferritin, albumin, and peripheral blood counts were previously suggested to provide prognostic information about hematopoietic cell transplantation (HCT) outcomes. Whether these "biomarkers" have prognostic value independent of each other and the HCT-comorbidity index (HCT-CI) is unknown. We analyzed data from 3917 allogeneic HCT recipients at multiple sites in the United States and Italy using multivariate models including each biomarker and the HCT-CI. Data from all sites were then randomly divided into a training set (n = 2352) to develop weights for the relevant biomarkers to be added to the HCT-CI scores and a validation set (n = 1407) to validate an augmented HCT-CI compared with the original index. Multivariate analysis with data from one site showed that ferritin, albumin, and platelets-not neutrophils or hemoglobin-were independently associated with increased nonrelapse mortality (NRM) and decreased overall survival. Findings were validated in data from the other sites. Subsequently, in a training set from all sites, ferritin >2500 mg/dL (hazard ratio [HR], 1.69); albumin 3 to 3.5 g/dL (HR, 1.61) and <3.0 g/dL (HR, 2.27); and platelets 50 to <100,000 (HR, 1.28), 20 to <50,000 (HR, 1.29), and <20,000 (HR, 1.55) were statistically significantly associated with NRM. Weights were assigned to these laboratory values following the same equation used to design the original index. In the validation set, the addition of the biomarkers to the original index to develop an augmented HCT-CI resulted in a statistically significant increase in a higher c-statistic estimate for prediction of NRM (P = .0007). Ferritin, albumin, and platelet counts are important prognostic markers that further refine the discriminative power of the HCT-CI for transplant outcomes.

Several studies provided evidence of a consistent antileukemic effect induced by cytomegalovirus (CMV) replication in acute myeloid leukemia (AML) patients receiving allogeneic hematopoietic stem cell transplantation (HSCT), however the use of antithymocyte globulin (ATG) as graft-versus-host disease prophylaxis, may potentially abrogate the protective effect of CMV infection. To address this issue, we retrospectively analyzed the risk of relapse in a cohort of 101 patients with AML who received grafts from an unrelated donor after a conditioning regimen including ATG. The cumulative incidence of CMV reactivation, evaluated by RT qPCR, was 59% at 12 months, and 93% of CMV reactivations occurred within the first 100 days post HSCT. The 5-year cumulative incidence of relapse in patients with CMV reactivation was 29% compared with 37% for patients without CMV reactivation, and the only factor associated with a reduced 5-year cumulative incidence of relapse was the disease status at HSCT (P < 0.001). In the multivariable model adverse cytogenetics (HR 2.42, 95% CI 1.02-5.72; P = 0.044) and acute GVHD (HR 3.36, 95% CI 1.32-8.54; P =  0.011) were independent risk factors for reducing overall survival (OS), while the presence of chronic GVHD was associated with a better OS (HR 0.37, 95% CI 0.15-0.89; P = 0.027). CMV replication was not an independent risk factor for OS (HR 1.06, 95% CI 0.07-15.75; P = 0.965). In Conclusion, the results of present study suggest that relapse prevention in patients with AML receiving T-cell depleted HSCT using ATG do not benefit from CMV reactivation.

Robust T cell function recovery has been shown to be crucial in determining allogeneic hematopoietic stem cell transplantation (HSCT) outcome, and there is growing evidence that the thymus plays a central role in regulating this process. We performed a long-term analysis of the role of thymic activity recovery in a population of pediatric patients undergoing allogeneic HSCT by signal joint T cell receptor excision circle (sjTREC) quantification. In this study, characterized by a long-term follow-up (median, 72 months), we found patients with higher levels of sjTRECs before transplantation had a statistically significant reduced risk of death compared with patients with lower values (relative risk, .31; 95% confidence interval, .30 to .32; P = .02), showing this different outcome was mainly related to a reduction of relapse incidence (14% versus 43%, P = .02). Unlike previous reports, we observed no correlation between sjTREC levels and lymphocyte recovery. Moreover, we confirmed that only graft-versus-host disease influenced thymic activity after transplantation. In conclusion, our results suggest an association between pretransplantation thymic activity and the long-term outcome of pediatric patients undergoing HSCT, mainly through a reduction of relapse opportunities.