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Summary: Allogeneic haematopoietic‐cell transplantation (allo‐HCT) is a potentially curative therapy for high‐risk myelodysplastic syndrome (MDS). Reduced‐intensity conditioning (RIC) is usually associated with lower non‐relapse mortality (NRM), higher relapse rate and similar overall‐survival (OS) as myeloablative‐conditioning (MAC). Fludarabine/treosulfan (FT) is a reduced‐toxicity regimen with intense anti‐leukaemia activity and a favourable toxicity profile. We investigated post‐transplant outcomes in 1722 MDS patients following allo‐HCT with FT (n = 367), RIC (n = 687) or MAC (n = 668). FT and RIC recipients were older than MAC recipients, median age 59, 59 and 51 years, respectively (P < 0·001) but other disease characteristics were similar. The median follow‐up was 64 months (1–171). Five‐year relapse rates were 25% (21–30), 38% (34–42) and 25% (22–29), after FT, RIC and MAC, respectively, (P < 0·001). NRM was 30% (25–35), 27% (23–30) and 34% (31–38, P = 0·008), respectively. Five‐year OS was 50% (44–55), 43% (38–47), and 43% (39–47), respectively (P = 0·03). In multivariate analysis, FT was associated with a lower risk of relapse (HR 0·55, P < 0·001) and better OS (HR 0·72, P = 0·01). MAC was associated with higher NRM (HR 1·44, P = 0·001). In conclusion, FT is associated with similar low relapse rates as MAC and similar low NRM as RIC, resulting in improved OS. FT may be the preferred regimen for allo‐HCT in MDS. [ABSTRACT FROM AUTHOR]

Background: In autologous stem cell transplant (ASCT)‐eligible myeloma patients, prolonged induction does not necessarily improve the depth of response. Method: We analyzed 1222 ASCT patients who were classified based on (a) the interval between induction and stem cell collection, (b) the type of induction regimen: BID (Bortezomib, IMiDs, and Dexamethasone), Bortezomib‐based, or CTD (Cyclophosphamide, Thalidomide, and Dexamethasone), and (c) the time to best response (Early ie, best response within 4 or 5 months, depending on the regimen vs Late; Good ie, VGPR or better vs Poor). Results: The length of induction treatment required to achieve a Good response did not affect PFS (P =.65) or OS (P =.61) post‐ASCT. The three types of regimen resulted in similar outcomes: median PFS 31, 27.7 and 30.8 months (P =.31), and median OS 81.7, 92.7, and 77.4 months, respectively (P =.83). On multivariate analysis, neither the type nor the duration of the induction regimen affected OS and PFS, except for Early Good Responders who had a better PFS compared to Early Poor Responders (HR = 1.21, P‐value =.02). However, achieving a Good response at induction was associated with a better response (≥VGPR) post‐transplant. Conclusion: The kinetics of response did not affect outcomes. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to compare the effect of the intensity of conditioning approaches used in allogeneic transplantation in myeloma—reduced intensity conditioning (RIC), non‐myeloablative (NMA), myeloablative conditioning (MAC) or Auto‐AlloHCT—on outcomes in patients who had had a prior autologous transplant. Methods: A retrospective analysis of the EBMT database (1991‐2012) was performed. Results: A total of 344 patients aged between 40 and 60 years at the time of alloHCT were identified: 169 RIC, 69 NMA, 65 MAC and 41 Auto‐Allo transplants. At a median follow‐up of 54 months, the probabilities of overall survival (OS) at 5 years were 39% (95% CI 31%‐47%), 45% (95% CI 32%‐57%), 19% (95% CI 6%‐32%) and 34% (95% CI 17%‐51%), respectively. Status at allogeneic HCT other than CR or PR conferred a 70% higher risk of death and a 40% higher risk of relapse. OS was markedly lower in the MAC group (P =.004). MAC alloHCT was associated with a higher risk of death than RIC alloHCT until 2002 (HR = 4.1, P <.001) but not after 2002 (HR = 1.2, P =.276). Conclusion: From 1991 to 2002, MAC was associated with poorer OS. Between 2003 and 2012, there were no significant differences in outcomes based on these different approaches. [ABSTRACT FROM AUTHOR]

The article examines diseases characteristics as well as treating centre attitudes concerning the therapy and outcome of patients having aplastic anaemia and lymphoma. The evaluation was peformed by Severe Aplastic Anaemia Working Party of the European Society of Blood and Bone Marrow Transplantation.

Summary: Dyskeratosis congenita (DC) is a genetic multisystem disorder with frequent involvement of the bone marrow. Haematopoietic stem cell transplantation (HSCT) is the only definitive cure to restore haematopoiesis, even though it cannot correct other organ dysfunctions. We collected data on the outcome of HSCT in the largest cohort of DC (n = 94) patients ever studied. Overall survival (OS) and event‐free survival (EFS) at 3 years after HSCT were 66% and 62%, respectively. Multivariate analysis showed better outcomes in patients aged less than 20 years and in patients transplanted from a matched, rather than a mismatched, donor. OS and EFS curves tended to decline over time. Early lethal events were infections, whereas organ damage and secondary malignancies appeared afterwards, even a decade after HSCT. A non‐myeloablative conditioning regimen appeared to be most advisable. Organ impairment present before HSCT seemed to favour the development of chronic graft‐versus‐host disease and T‐B immune deficiency appeared to enhance pulmonary fibrosis. According to the present data, HSCT in DC is indicated in cases of progressive marrow failure, whereas in patients with pre‐existing organ damage, this should be carefully evaluated. Further efforts to investigate treatment alternatives to HSCT should be encouraged. [ABSTRACT FROM AUTHOR]

The 'landmark' and 'Simon and Makuch' non-parametric estimators of the survival function are commonly used to contrast the survival experience of time-dependent treatment groups in applications such as stem cell transplant versus chemotherapy in leukemia. However, the theoretical survival functions corresponding to the second approach were not clearly defined in the literature, and the use of the 'Simon and Makuch' estimator was criticized in the biostatistical community. Here, we review the 'landmark' approach, showing that it focuses on the average survival of patients conditional on being failure free and on the treatment status assessed at the landmark time. We argue that the 'Simon and Makuch' approach represents counterfactual survival probabilities where treatment status is forced to be fixed: the patient is thought as under chemotherapy without possibility to switch treatment or as under transplant since the beginning of the follow-up. We argue that the 'Simon and Makuch' estimator leads to valid estimates only under the Markov assumption, which is however less likely to occur in practical applications. This motivates the development of a novel approach based on time rescaling, which leads to suitable estimates of the counterfactual probabilities in a semi-Markov process. The method is also extended to deal with a fixed landmark time of interest. [ABSTRACT FROM AUTHOR]

In multi-state models, it has been the tradition to model all transition intensities on one time scale, usually the time since entry into the study ('clock-forward' approach). The effect of time since an intermediate event has been accommodated either by changing the time scale to time since entry to the new state ('clock-back' approach) or by including the time at entry to the new state as a covariate. In this paper, we argue that the choice of time scale for the various transitions in a multi-state model should be dealt with as an empirical question, as also the question of whether a single time scale is sufficient. We illustrate that these questions are best addressed by using parametric models for the transition rates, as opposed to the traditional Cox-model-based approaches. Specific advantages are that dependence of failure rates on multiple time scales can be made explicit and described in informative graphical displays. Using a single common time scale for all transitions greatly facilitates computations of probabilities of being in a particular state at a given time, because the machinery from the theory of Markov chains can be applied. However, a realistic model for transition rates is preferable, especially when the focus is not on prediction of final outcomes from start but on the analysis of instantaneous risk or on dynamic prediction. We illustrate the various approaches using a data set from stem cell transplant in leukemia and provide supplementary online material in R. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This randomized phase III clinical trial explored the efficacy of DaunoXome (DNX) versus Daunorubicin (DNR) in acute myeloid leukaemia (AML) patients aged >60 years. Three hundred and one AML patients were randomized to receive DNR (45 mg/m2 days 1–3) or DNX (80 mg/m2 days 1–3) plus cytarabine (AraC; 100 mg/m2 days 1–7). Patients in complete remission (CR) received a course of the same drugs as consolidation and then were randomized for maintenance with AraC+ all trans retinoic acid or no further treatment. Among 153 patients in the DNR arm, 78 (51·0%) achieved CR, 55 (35·9%) were resistant and 20 (13·1%) died during induction. Among 148 patients in the DNX arm, 73 (49·3%) achieved CR, 47 (31·8%) were resistant and 28 (18·9%) died during induction. Univariate analysis showed no difference as to induction results. After CR, DNX showed a higher incidence of early deaths (12·5% vs. 2·6% at 6 months, P = 0·053) but a lower incidence of relapse beyond 6 months (59% vs. 78% at 24 months, P = 0·064), with a cross in overall survival (OS) and disease-free survival (DFS) curves and a later advantage for DNX arm after 12 months from diagnosis. DNX seems to improve OS and DFS in the long-term follow-up, because of a reduction in late relapses. [ABSTRACT FROM AUTHOR]

We compared antithymocyte globulin (ATG) with alemtuzumab in 73 patients with multiple myeloma, who underwent reduced conditioning with melphalan/fludarabine, followed by allogeneic stem cell transplantation from human leucocyte antigen-matched or -mismatched unrelated donors. The ATG group had more prior high-dose chemotherapies (P < 0·001), while bone marrow was used more as the stem cell source in the alemtuzumab group (P < 0·001). Alemtuzumab resulted in faster engraftment of leucocytes (P = 0·03) and platelets (P = 0·02) and in a lower incidence of acute graftversushost disease (GvHD) grades II–IV (24% vs. 47%,P = 0·06). More cytomegalovirus (CMV) seropositive patients in the alemtuzumab group experienced CMV reactivation (100% vs. 47%,P = 0·001). The cumulative incidence of treatment-related mortality at 2 years was 26% [95% confidence interval (CI) = 12–37%] for ATG vs. 28% (95% CI = 15–55%) for alemtuzumab,P = 0·7. There was no significant difference in the estimated 2-year overall and progression-free survival between ATG and alemtuzumab: 54% (95% CI: 39–75%) vs. 45% (95% CI: 28–73%) and 30% (95% CI: 16–55%) vs. 36% (95% CI: 20–62%) respectively. In multivariate analysis, treatment with alemtuzumab had a higher risk for relapse (hazard ratio: 2·37;P = 0·05) while killer immunoglobulin-like receptor (KIR)-ligand mismatch was protective for relapse (P < 0·0001). We conclude that alemtuzumab produced less acute GvHD, but higher probability of relapse. The data implicated a major role of KIR-ligand mismatched transplantation in multiple myeloma. [ABSTRACT FROM AUTHOR]

Myeloproliferative Neoplasm (MPN), unclassifiable (MPN-U) is a heterogeneous disease with regards to both clinical phenotype and disease course. Patients may initially be asymptomatic or present with leucocytosis or thrombocytosis, anaemia, progressive splenomegaly, constitutional symptom, thromboses or accelerated/blastic phase disease. Treatment strategies are variable and there are no widely accepted consensus management guidelines for MNU-U. Allogeneic Haematopoietic Cell Transplantation (allo-HCT) remains the only curative strategy yet outcomes, to date, are not well defined. We hereby report on the largest retrospective study of patients with MPN-U undergoing allo-HCT, highlighting the potentially curative role and providing clinicians with robust engraftment, GvHD and outcome data to facilitate patient discussion., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

The best approach for allogeneic haematopoietic stem cell transplantations (alloHCT) in patients with chronic lymphocytic leukaemia (CLL) is unknown. We therefore analysed the impact of procedure- and centre-related factors on 5-year event-free survival (EFS) in a large retrospective study. Data of 684 CLL patients who received a first alloHCT between 2000 and 2011 were analysed by multivariable Cox proportional hazards models with a frailty component to investigate unexplained centre heterogeneity. Five-year EFS of the whole cohort was 37% (95% confidence interval [CI], 34-42%). Larger numbers of CLL alloHCTs (hazard ratio [HR] 0·96, P = 0·002), certification of quality management (HR 0·7, P = 0·045) and a higher gross national income per capita (HR 0·4, P = 0·04) improved EFS. In vivo T-cell depletion (TCD) with alemtuzumab compared to no TCD (HR 1·5, P = 0·03), and a female donor compared to a male donor for a male patient (HR 1·4, P = 0·02) had a negative impact on EFS, but not non-myeloablative versus more intensive conditioning. After correcting for patient-, procedure- and centre-characteristics, significant variation in centre outcomes persisted. In conclusion, further research on the impact of centre and procedural characteristics is warranted. Non-myeloablative conditioning appears to be the preferable approach for patients with CLL., (© 2017 John Wiley & Sons Ltd.)