Impact of patient: donor HLA disparity on reduced-intensity-conditioned allogeneic stem cell transplants from HLA mismatched unrelated donors for AML: from the ALWP of the EBMT.

Patients with acute myeloid leukaemia (AML) who lack a matched sibling or unrelated donor commonly undergo transplantation from a donor matched at 9/10 HLA-A, -B, -C, -DRB1, -DQB1 alleles, and it is unclear if a specific locus mismatch is preferable to any other. We therefore studied 937 patients with AML in complete remission transplanted using a reduced intensity conditioning regimen from an unrelated donor mismatched at a single allele. In a multivariate analysis, patient age, adverse karyotype and patient cytomegalovirus (CMV) seropositivity were correlated with decreased leukaemia free survival (LFS) and overall survival (OS). There was no significant difference in LFS or OS between patients transplanted from donors mismatched at HLA-A, -B, -C or -DRB1 in comparison to a HLA-DQB1 mismatched transplant. In a multivariate analysis, patients transplanted with a HLA-A mismatched donor had higher rates of acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM) than patients transplanted with a HLA-DQB1 mismatched donor. Patient CMV seropositivity was associated with an increase in NRM and acute GVHD and reduced LFS and OS, regardless of donor CMV status. For CMV seropositive patients lacking a fully matched donor, alternative GVHD and CMV prophylaxis strategies should be considered.

European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia.

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

Worldwide Network for Blood and Marrow Transplantation (WBMT) recommendations for establishing a hematopoietic stem cell transplantation program in countries with limited resources (Part II): Clinical, technical and socio-economic considerations.

The development of hematopoietic stem cell transplantation (HSCT) programs can face significant challenges in most developing countries because such endeavors must compete with other government health care priorities, including the delivery of basic services. While this is may be a limiting factor, these countries should prioritize development of the needed expertise to offer state of the art treatments including transplantation, by providing financial, technological, legal, ethical and other needed support. This would prove beneficial in providing successful programs customized to the needs of their population, and potentially provide long-term cost-savings by circumventing the need for their citizens to seek care abroad. Costs of establishing HSCT program and the costs of the HSCT procedure itself can be substantial barriers in developing countries. Additionally, socioeconomic factors intrinsic to specific countries can influence access to HSCT, patient eligibility for HSCT and timely utilization of HSCT center capabilities. This report describes recommendations from the Worldwide Network for Blood and Marrow Transplantation (WBMT) for establishing HSCT programs with a specific focus on developing countries, and identifies challenges and opportunities for providing this specialized procedure in the resource constrained setting.

Trends in patient outcome over the past two decades following allogeneic stem cell transplantation for acute myeloid leukaemia: an ALWP/EBMT analysis.

BACKGROUND: Outcomes for patients with acute myeloid leukaemia (AML) undergoing allogeneic stem cell transplantation (allo-SCT) have significantly improved in recent years. OBJECTIVES: To assess the incremental improvement of transplanted AML patients in the last two decades. METHODS: Patients included in this analysis were adult AML patients who underwent allo-SCT from an HLA-matched sibling donor (MSD) or HLA-matched unrelated donor (MUD) in first remission. Patient outcomes were assessed between three cohorts according to the year of transplant (1993-2002, 2003-2007 and 2008-2012). RESULTS: The analysis comprised a total of 20 187 patients of whom 4763 were transplanted between 1993 and 2002, 5835 in 2003 and 2007, and 9589 in 2008 and 2012. In multivariate analysis, leukaemia-free survival (LFS) rates were significantly improved in more recently transplanted patients compared to patients transplanted in 1993-2002 [Hazard ratio (HR) = 0.84, confidence interval (CI) 95%, 0.77-0.92; P = 0.003], a benefit which also extended to improved overall survival (OS; HR = 0.8, CI 95%, 0.73-0.89; P < 0.0001), and decreased nonrelapse mortality (NRM) rates (HR = 0.65, CI 95%, 0.56-0.75; P < 0.0001). Subset analysis revealed that in MSD, the rates of LFS, NRM and OS significantly improved in patients in the more recent cohort with similar results also seen in MUD. Finally, the incidence of acute graft-versus-host disease (GVHD) was significantly reduced leading to improved GVHD-free/relapse-free survival (GRFS) rates in more recently transplanted patients. CONCLUSION: Outcome of allo-SCT for AML patients has markedly improved in the last two decades owing to decreased nonrelapse mortality and improved rates of leukaemia-free survival resulting in significantly longer survival.

The relation between dyadic coping and relationship satisfaction in couples dealing with haematological cancer.

Couples' ability to cope with cancer is significantly associated with how satisfied they are with their relationship. However, little evidence specific to haemato-oncological patients exists. The objective of this study was to examine how dyadic coping (DC) affects relationship satisfaction among couples facing haematological cancer. Furthermore, we tested complex interactions between distress, disease-related and socio-demographic factors. In a multicentre study, 327 patients (haemato-oncological cancer; mean age: 57 years, 63% male) and their partners responded to surveys examining their relationship satisfaction, DC and distress. The Actor-Partner-Interdependence-Model (APIM) and moderator analyses were used to assess interactions between these concepts. In the APIM, positive DC was significantly related to greater levels of relationship satisfaction, and negative DC was related to lower levels of relationship satisfaction (all p < .001). The partners' distress was significantly related to lower levels of relationship satisfaction of the partners (p < .05). Furthermore, distress, age and relationship duration had significant moderating effects on the association between DC and relationship satisfaction (p < .05). Our results enable describing patient and partner as an interactional unit in which positive DC supports a satisfying relationship. They imply that strengthening positive DC in a couple facing haematological cancer can contribute to them having a well-functioning and sustaining relationship.

Factors associated with non-participation and dropout among cancer patients in a cluster-randomised controlled trial.

We investigated the impact of demographic and disease related factors on non-participation and dropout in a cluster-randomised behavioural trial in cancer patients with measurements taken between hospitalisation and 6 months thereafter. The percentages of non-participation and dropout were documented at each time point. Factors considered to be potentially related with non-participation and dropout were as follows: age, sex, marital status, education, income, employment status, tumour site and stage of disease. Of 1,338 eligible patients, 24% declined participation at baseline. Non-participation was higher in older patients (Odds Ratio [OR] 2.1, CI: 0.6-0.9) and those with advanced disease (OR 2.0, CI: 0.1-1.3). Dropout by 6 months was 25%. Dropout was more frequent with increased age (OR 2.8, CI: 0.8-1.2), advanced disease (OR 3.0, CI: 1.0-1.2), being married (OR 2.4, CI 0.7-1.1) and less frequent with university education (OR 0.4, CI -1.3 to -0.8) and middle income (OR 0.4, CI -0.9 to -0.7). When planning clinical trials, it is important to be aware of patient groups at high risk of non-participation or dropout, for example older patients or those with advanced disease. Trial designs should consider their special needs to increase their rate of participation.

Alloreactivity: the Janus-face of hematopoietic stem cell transplantation.

Differences in major and minor histocompatibility antigens between donor and recipient trigger powerful graft-versus-host reactions after allogeneic hematopoietic stem cell transplantation (HSCT). The clinical effects of alloreactivity present a Janus-face: detrimental graft-versus-host disease increases non-relapse mortality, beneficial graft-versus-malignancy may cure the recipient. The ultimate consequences on long-term outcome remain a matter of debate. We hypothesized that increasing donor-recipient antigen matching would decrease the negative effects, while preserving antitumor alloreactivity. We analyzed retrospectively a predefined cohort of 32 838 such patients and compared it to 59 692 patients with autologous HSCT as reference group. We found a significant and systematic decrease in non-relapse mortality with decreasing phenotypic and genotypic antigen disparity, paralleled by a stepwise increase in overall and relapse-free survival (Spearman correlation coefficients of cumulative excess event rates at 5 years 0.964; P<0.00; respectively 0.976; P<0.00). We observed this systematic stepwise effect in all main disease and disease-stage categories. The results suggest that detrimental effects of alloreactivity are additive with each step of mismatching; the beneficial effects remain preserved. Hence, if there is a choice, the best match should be donor of choice. The data support an intensified search for predictive genomic and environmental factors of 'no-graft-versus-host disease'.

Latin America: the next region for haematopoietic transplant progress.

Haematopoietic cell transplant activity in the 28 countries comprising Latin America is poorly defined. We conducted a voluntary survey of members of the Latin American Bone Marrow Transplantation Group regarding transplant activity 2009-2012. Collated responses were compared with data of transplant rates from the Worldwide Network for Blood and Marrow Transplantation for other geographic regions. Several socio-economic variables were analysed to determine correlations with transplant rates. In total, 94 teams from 12 countries reported 11 519 transplants including 7033 autotransplants and 4486 allotransplants. Annual activity increased from 2517 transplants in 2009 to 3263 in 2012, a 30% increase. Median transplants rate (transplant per million inhabitants) in 2012 was 64 (autotransplants, median 40; allotransplants, median 24). This rate is substantially lower than that in North America and European regions (482 and 378) but higher than that in the Eastern Mediterranean and Asia Pacific regions (30 and 45). However, the Latin America transplant rate is 5-8-fold lower than that in America and Europe, suggesting a need to increase transplant availability. Transplant team density in Latin America (teams per million population; 1.8) is 3-4-fold lower than that in North America (6.2) or Europe (7.6). Within Latin America, there is substantial diversity in transplant rates by country partially explained by diverse socio-economic variables including per capita gross national income, health expenditure and physician density. These data should help inform future health-care policy in Latin America.

Long-term survival of patients with CLL after allogeneic transplantation: a report from the European Society for Blood and Marrow Transplantation.

Even with the availability of targeted drugs, allogeneic hematopoietic cell transplantation (allo-HCT) is the only therapy with curative potential for patients with CLL. Cure can be assessed by comparing long-term survival of patients to the matched general population. Using data from 2589 patients who received allo-HCT between 2000 and 2010, we used landmark analyses and methods from relative survival analysis to calculate excess mortality compared with an age-, sex- and calendar year-matched general population. Estimated event-free survival, overall survival and non-relapse mortality (NRM) 10 years after allo-HCT were 28% (95% confidence interval (CI), 25-31), 35% (95% CI, 32-38) and 40% (95% CI, 37-42), respectively. Patients who passed the 5-year landmark event-free survival (N=394) had a 79% probability (95% CI, 73-85) of surviving the subsequent 5 years without an event. Relapse and NRM contributed equally to treatment failure. Five-year mortality for 45- and 65-year-old reference patients who were event-free at the 5-year landmark was 8% and 47% compared with 3% and 14% in the matched general population, respectively. The prospect of long-term disease-free survival remains an argument to consider allo-HCT for young patients with high-risk CLL, and programs to understand and prevent late causes of failure for long-term survivors are warranted, especially for older patients.

The EBMT-ELN working group recommendations on the prophylaxis and treatment of GvHD: a change-control analysis.

In 2013, recommendations for a standardized practice in the prophylaxis and treatment of GvHD were adopted and published by the European Society for Blood and Marrow Transplantation and the European LeukemiaNet. One year later, all 341 European Society for Blood and Marrow Transplantation centres performing allogeneic haematopoietic stem cell transplantation were contacted for a change-control analysis and asked to fill in a questionnaire; 111 centres (33%) responded. Of these, 83% had been aware of the recommendations. Paediatric centres (P=0.004), centres with shorter programme duration (P=0.049), not JACIE (the Joint Accreditation Committee of the International Society for Cellular Therapy and the European Society for Blood and Marrow Transplantation)-accredited centres (P=0.010) and centres from middle-income countries (P=0.033) were more likely to be unaware of the recommendations. Thirty-eight per cent of the centres regarded the recommendations as relevant guidelines affecting their policies, 61% as interesting information. Thirty per cent had decided to make changes in their institutional protocols based on the recommendations. More than 80% were willing to use the recommendations for a control arm in randomized studies. This survey shows that the published recommendations had some, though insufficient, impact on the strategies and methods of allogeneic haematopoietic stem cell transplantation applied by the centres. It also identified some of the weaknesses to be addressed when releasing recommendations in the future.

Allogeneic hematopoietic cell transplantation for multiple myeloma in Europe: trends and outcomes over 25 years. A study by the EBMT Chronic Malignancies Working Party.

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.

Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey.

Data on 68 146 hematopoietic stem cell transplants (HSCTs) (53% autologous and 47% allogeneic) gathered by 1566 teams from 77 countries and reported through their regional transplant organizations were analyzed by main indication, donor type and stem cell source for the year 2012. With transplant rates ranging from 0.1 to 1001 per 10 million inhabitants, more HSCTs were registered from unrelated 16 433 donors than related 15 493 donors. Grafts were collected from peripheral blood (66%), bone marrow (24%; mainly non-malignant disorders) and cord blood (10%). Compared with 2006, an increase of 46% total (57% allogeneic and 38% autologous) was observed. Growth was due to an increase in reporting teams (18%) and median transplant activity/team (from 38 to 48 HSCTs/team). An increase of 167% was noted in mismatched/haploidentical family HSCT. A Strengths, Weaknesses, Opportunities, Threats (SWOT) analysis revealed the global perspective of WBMT to be its major strength and identified potential to be the key professional body for patients and authorities. The limited data collection remains its major weakness and threat. In conclusion, global HSCT grows over the years without plateauing (allogeneic>autologous) and at different rates in the four World Health Organization regions. Major increases were observed in allogeneic, haploidentical HSCT and, to a lesser extent, in cord blood transplantation.

Allogeneic hematopoietic cell transplantation as curative therapy for non-transformed follicular lymphomas.

Allogeneic hematopoietic cell transplantation (HCT) offers the chance of cure for patients with non-transformed follicular lymphoma (FL), but is associated with the risk of non-relapse mortality (NRM). The aim of this study was to identify subgroups of FL patients who benefit from HCT. The European Society for Blood and Marrow Transplantation (EBMT) Minimum-Essential-A Data of 146 consecutive patients who received HCT for FL between 1998 and 2008 were extracted from the database of the German Registry 'DRST'. Diagnosis of FL was verified by contact with the reference pathologists. Estimated 1-, 2- and 5-year overall survivals (OS) were 67%, 60% and 53%, respectively. Day 100 NRM was 15%. Thirteen out of 33 patients (40%) with treatment-refractory disease (RD) at the time of transplantation survived long term. Univariate statistical analysis suggested limited chronic GvHD, donor age ⩽42 years and TBI-based conditioning in treatment refractory patients to correlate with favorable OS. Independent prognostic factors for OS were treatment-sensitive disease and limited chronic GvHD for the whole cohort, and additionally TBI-based conditioning for the treatment refractory subgroup. In contrast, patient age ⩾55 years had no impact on outcome. Thus, HCT for FL is associated with acceptable NRM, and offers a substantial chance of cure for patients with RD or advanced age. Donors ⩽42 years should be preferred if available.

Efficacy and safety of deferasirox in non-thalassemic patients with elevated ferritin levels after allogeneic hematopoietic stem cell transplantation.

Elevated serum ferritin contributes to treatment-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The multicenter DE02 trial assessed the safety, efficacy and impact of deferasirox on iron homeostasis after allogeneic HSCT. Deferasirox was administered at a starting dose of 10 mg/kg per day to 76 recipients of allogeneic HSCT, with subsequent dose adjustments based on efficacy and safety. Deferasirox was initiated at a median of 168 days after HSCT, with 84% of patients still on immunosuppression. Baseline serum ferritin declined from 2045 to 957 ng/mL. Deferasirox induced a negative iron balance in 84% of patients. Hemoglobin increased in the first 3 months, and trough serum cyclosporine levels were stable. Median exposure was 330 days, with a median compliance rate of >80%. The most common investigator-reported drug-related adverse events (AEs) were increased blood creatinine (26.5%), nausea (9.0%) and abdominal discomfort (8.3%). Fifty-four (71.1%) patients experienced drug-related AEs, which occasionally resulted in discontinuation (gastrointestinal (n=6), skin (n=3), elevated transaminases (n=1) and creatinine (n=1)). The incidence of AEs appeared to be dose related, with 7.5 mg/kg per day being the best-tolerated dose. Low-dose deferasirox is an effective chelation therapy after allogeneic HSCT, with a manageable safety profile, even in patients receiving cyclosporine.

Long-term follow-up of the AML97 study for patients aged 60 years and above with acute myeloid leukaemia: a study of the East German Haematology and Oncology Study Group (OSHO).

INTRODUCTION: Treatment of patients (pts) with acute myelogenous leukaemia (AML) above 60 years remains a challenge. We report long-term follow-up of the AML97 study, where pts were registered at diagnosis and received treatment dependent on their comorbidities: dose-intense cytarabine (AraC) and anthracycline in the curative arm, and low-dose chemotherapy in the palliative arm or best supportive care. MATERIALS AND METHODS: A total of 618 pts were enrolled in this protocol (curative 471, palliative 115 and supportive 32). In the curative arm, complete remission (CR) was obtained in 66.8 % of pts and the estimated probability of being alive at 2 years was 0.30 (±0.02 SE). In multivariate analysis, gender (p = 0.005), performance status (p = 0.04) and cytogenetics (p = 0.002) were significant factors for CR. With a median follow-up of 10 (range 0.1-11.8) years, the estimated probability of being event-free after 2 and 5 years according to cytogenetics was 0.48 ± 0.11 and 0.48 ± 0.11 for favourable, 0.20 ± 0.03 and 0.09 ± 0.03 for normal, 0.18 ± 0.06 and 0.10 ± 0.05 for other standard risk and 0.10 ± 0.03 and 0.05 ± 0.02 for unfavourable karyotypes, respectively. The median survival time for pts treated with palliative chemotherapy was 54 and 11 days with best supportive care only. CONCLUSION: In conclusion, treatment of older AML pts with dose-intense AraC is feasible in the majority of pts and induces high rates of CR. Nevertheless, except for favourable karyotype, OS and event-free survival remain low. These results need to be viewed in relation to the new modalities including stem cell transplantation following non-myeloablative conditioning, epigenetic and molecular therapies.

Impact of conditioning with TBI in adult patients with T-cell ALL who receive a myeloablative allogeneic stem cell transplantation: a report from the acute leukemia working party of EBMT.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a therapeutic option for adult patients with T-cell ALL (T-ALL). Meanwhile, few allo-SCT data specific to adult T-ALL have been described thus far. Specifically, the optimal myeloablative conditioning regimen is unknown. In this retrospective study, 601 patients were included. Patients received allo-SCT in CR1, CR2, CR >2 or in advanced disease in 69%, 15%, 2% and 14% of cases, respectively. With an overall follow-up of 58 months, 523 patients received a TBI-based regimen, whereas 78 patients received a chemotherapy-based regimen including IV busulfan-cyclophosphamide (IV Bu-Cy) (n=46). Unlike patients aged ⩾35 years, patients aged <35 years who received a TBI-based regimen displayed an improved outcome compared with patients who received a chemotherapy-based regimen (5-year leukemia-free survival (LFS) of 50% for TBI versus 18% for chemo-only regimen or IV Bu-Cy regimens, P=10(-5) and 10(-4), respectively). In multivariate analysis, use of TBI was associated with an improved LFS (hazard ratio (HR)=0.55 (0.34-0.86), P=0.01) and overall survival (HR=0.54 (0.34-0.87), P=0.01) in patients aged <35 years. In conclusion, younger adult patients with T-ALL entitled to receive a myeloablative allo-SCT may benefit from TBI-based regimens.

Second allogeneic transplantation for relapse of malignant disease: retrospective analysis of outcome and predictive factors by the EBMT.

In patients treated with allogeneic stem cell transplantation (SCT) for malignant disease who suffer from a relapse after the transplantation, the role of second allogeneic SCT is often uncertain. In a retrospective analysis, 2632 second allogeneic transplantations carried out for a relapse after the first transplantation were analyzed to define indications and identify predictive factors. Fifteen percent of the patients remained relapse-free until 5 years after the second SCT. Patients with CML had a better survival than patients with other diseases. In a multivariate analysis, factors associated with better survival were low disease burden, longer remission duration after the first transplantation, longer interval between the transplantations, younger age, absence of grade II-IV acute GvHD or chronic GvHD after the first transplantation, and later year of transplantation. The European Society for Blood and Marrow Transplantation risk score predicted the outcome. Using the same donor as in the first transplantation vs another donor had no predictive value for survival. Sibling donor was a favorable predictive factor. In conclusion, second allogeneic SCT offers a reasonable option especially for young patients with a long remission after the first transplantation and a low disease burden. The present findings do not support the usefulness of changing the donor for the second transplantation.

Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group.

The aim of this work is to produce recommendations on the management of allogeneic stem cell transplantation (allo-SCT) in primary myelofibrosis (PMF). A comprehensive systematic review of articles released from 1999 to 2015 (January) was used as a source of scientific evidence. Recommendations were produced using a Delphi process involving a panel of 23 experts appointed by the European LeukemiaNet and European Blood and Marrow Transplantation Group. Key questions included patient selection, donor selection, pre-transplant management, conditioning regimen, post-transplant management, prevention and management of relapse after transplant. Patients with intermediate-2- or high-risk disease and age <70 years should be considered as candidates for allo-SCT. Patients with intermediate-1-risk disease and age <65 years should be considered as candidates if they present with either refractory, transfusion-dependent anemia, or a percentage of blasts in peripheral blood (PB) >2%, or adverse cytogenetics. Pre-transplant splenectomy should be decided on a case by case basis. Patients with intermediate-2- or high-risk disease lacking an human leukocyte antigen (HLA)-matched sibling or unrelated donor, should be enrolled in a protocol using HLA non-identical donors. PB was considered the most appropriate source of hematopoietic stem cells for HLA-matched sibling and unrelated donor transplants. The optimal intensity of the conditioning regimen still needs to be defined. Strategies such as discontinuation of immune-suppressive drugs, donor lymphocyte infusion or both were deemed appropriate to avoid clinical relapse. In conclusion, we provided consensus-based recommendations aimed to optimize allo-SCT in PMF. Unmet clinical needs were highlighted.