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AbstractCytokine release syndrome (CRS) occurs frequently after haplo-identical allogeneic stem cell transplantation (alloSCT) with post-transplant cyclophosphamide (PTCy), increasing nonrelapse mortality (NRM) and decreasing survival. Data on CRS in HLA-matched alloSCT are limited and effects of specific HLA-mismatches on CRS development unknown. We hypothesized that in HLA-matched alloSCT increasing degrees of HLA-mismatching influence CRS incidence, NRM and survival. Retrospective analysis of 126 HLA-matched PTCy-alloSCT patients showed that higher degrees of HLA-mismatching significantly increased CRS incidence (26%, 75% and 90% CRS with 12/12, 10/10 and 9/10 matched donors, respectively). Maximum temperature during CRS increased with higher HLA-mismatch. Specific associations between HLA-mismatches and CRS could be determined. Grade 2 CRS and CRS-induced grade 3 fever were associated with significantly increased NRM (p < 0.001 and p = 0.003, respectively) and inferior survival (p < 0.001 and p = 0.005, respectively). NRM was mainly caused by disease conditions that may be considered CRS-induced inflammatory responses (encephalopathy, cryptogenic organizing pneumonia and multi-organ failure). [ABSTRACT FROM AUTHOR]

Abstract: In recent years, multi-state models have been studied widely in survival analysis. Despite their clear advantages, their use in biomedical and other applications has been rather limited so far. An important reason for this is the lack of flexible and user-friendly software for multi-state models. This paper introduces a package in R, called ‘mstate’, for each of the steps of the analysis of multi-state models. It can be applied to non- and semi-parametric models. The package contains functions to facilitate data preparation and flexible estimation of different types of covariate effects in the context of Cox regression models, functions to estimate patient-specific transition intensities, dynamic prediction probabilities and their associated standard errors (both Greenwood and Aalen-type). Competing risks models can also be analyzed by means of mstate, as they are a special type of multi-state models. The package is available from the R homepage http://cran.r-project.org. We give a self-contained account of the underlying mathematical theory, including a new asymptotic result for the cumulative hazard function and new recursive formulas for the calculation of the estimated standard errors of the estimated transition probabilities, and we illustrate the use of the key functions of the mstate package by the analysis of a reversible multi-state model describing survival of liver cirrhosis patients. [ABSTRACT FROM AUTHOR]

Abstract: Snellius’s Fundamenta Arithmetica et Geometrica (1615) is much more than a Latin translation of Ludolph van Ceulen’s Arithmetische en Geometrische Fondamenten. Willebrord Snellius both adapted and commented on the Dutch original in his Fundamenta, and thus his Latin version can be read as a dialogue between representatives of two different approaches to mathematics in the early modern period: Snellius’s humanist approach and Van Ceulen’s practitioner’s approach. This article considers the relationship between the Dutch and Latin versions of the text and, in particular, puts some of their statements on the use of numbers in geometry under the microscope. In addition, Snellius’s use of the Fundamenta as an instrument to further his career is explained. Uittreksel: Snellius’Fundamenta Arithmetica et Geometrica (1615) is veel meer dan de Latijnse vertaling van Ludolph van Ceulens Arithmetische en Geometrische Fondamenten. Omdat Willebrord Snellius de Nederlandse versie aanpaste en becommentarieerde in de Fundamenta, kan deze Latijnse editie gelezen worden als een dialoog tussen twee verschillende benaderingen van wiskunde in de vroeg-moderne tijd: Snellius’ humanistische aanpak en Van Ceulens rekenmeestersaanpak. In het bijzonder legt dit artikel sommige van hun uitspraken over het gebruik van getallen in de meetkunde onder de loep. Bovendien wordt Snellius’ gebruik van de Fundamenta als een instrument om zijn carrière te bevorderen uitgelegd. [ABSTRACT FROM AUTHOR]

Background: We recently reported results of the prospective, open‐label HOVON‐100 trial in 334 adult patients with acute lymphoblastic leukemia (ALL) randomized to first‐line treatment with or without clofarabine (CLO). No improvement of event‐free survival (EFS) was observed, while a higher proportion of patients receiving CLO obtained minimal residual disease (MRD) negativity. Aim: In order to investigate the effects of CLO in more depth, two multi‐state models were developed to identify why CLO did not show a long‐term survival benefit despite more MRD‐negativity. Methods: The first model evaluated the effect of CLO on going off‐protocol (not due to refractory disease/relapse, completion or death) as a proxy of severe treatment‐related toxicity, while the second model evaluated the effect of CLO on obtaining MRD negativity. The subsequent impact of these intermediate events on death or relapsed/refractory disease was assessed in both models. Results: Overall, patients receiving CLO went off‐protocol more frequently than control patients (35/168 [21%] vs. 18/166 [11%], p = 0.019; HR 2.00 [1.13–3.52], p = 0.02), especially during maintenance (13/44 [30%] vs. 6/56 [11%]; HR 2.85 [95%CI 1.08–7.50], p = 0.035). Going off‐protocol was, however, not associated with more relapse or death. Patients in the CLO arm showed a trend towards an increased rate of MRD‐negativity compared with control patients (HR MRD‐negativity: 1.35 [0.95–1.91], p = 0.10), which did not translate into a significant survival benefit. Conclusion: We conclude that the intermediate states, i.e., going off‐protocol and MRD‐negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL. [ABSTRACT FROM AUTHOR]

Benchmarking is commonly used in many healthcare settings to monitor clinical performance, with the aim of increasing cost-effectiveness and safe care of patients. The funnel plot is a popular tool in visualizing the performance of a healthcare center in relation to other centers and to a target, taking into account statistical uncertainty. In this paper, we develop a methodology for constructing funnel plots for survival data. The method takes into account censoring and can deal with differences in censoring distributions across centers. Practical issues in implementing the methodology are discussed, particularly in the setting of benchmarking clinical outcomes for hematopoietic stem cell transplantation. A simulation study is performed to assess the performance of the funnel plots under several scenarios. Our methodology is illustrated using data from the European Society for Blood and Marrow Transplantation benchmarking project. [ABSTRACT FROM AUTHOR]

This article examines the occurrence of liver complications in patients with myelofibrosis who undergo allogeneic hematopoietic stem cell transplantation (HSCT). The study found that liver adverse events (AEs) were more common than expected, with 64% of patients experiencing liver AEs within the first 100 days after HSCT. The most common liver AEs were caused by the conditioning regimen. Risk factors for liver toxicity included worse performance status, higher comorbidity index, and higher prognostic scoring system score. The study also found that hyperbilirubinemia and hepatic graft-versus-host disease were associated with increased mortality. The text emphasizes the importance of monitoring liver complications in HSCT patients and suggests using imaging and biopsies to determine the cause and guide treatment. The study included various factors in the analysis and was approved by the appropriate ethics committee. [Extracted from the article]

In the last decade, the number of older patients undergoing allogeneic Hematopoietic Cell Transplantation (alloHCT) has increased substantially. Analyzing the long-term outcomes of these patients poses new methodological challenges since their population mortality (the risk of mortality that they would have faced in the absence of their disease and treatment) is non-negligible. Interpreting all non-relapse mortality (NRM) as treatment-related mortality cannot be justified in this older population. An additional problem in the analysis of the causes of death is that individual adjudication as to treatment-related complications is often impossible. Although more common in transplant recipients, both cardiac deaths and cancer also occur frequently in the general population in this age group. For these reasons, we propose to extend the analysis of standard outcomes with statistical methods to estimate the size of population- and treatment-related mortality in heterogeneous populations. We analyzed the outcomes of two large cohorts of patients whose data had been collected by the European Society for Blood and Marrow Transplantation: (1) myelodysplastic syndromes or secondary acute myeloid leukemia (n=6434, median age 56 years), and (2) chronic lymphocytic leukemia (n=2589, median age 55 years). We focused on patients who had survived for two years after alloHCT without relapse or progression. We used integrated methods from relative survival and multi-state models to estimate what proportion of mortality can be attributed to disease relapse and what to the expected general population mortality. A key assumption was that the risk of mortality of the patient cohorts, apart from that associated with the disease and its treatment, was similar to that of the age-, sex-, calendar year- and country-matched general population. The remaining mortality, excess non-relapse mortality, can then be interpreted as closely approximating to treatment-related mortality, where 'treatment' refers both to treatment prior to transplantation and to alloHCT and its sequelae. The figures illustrate the probabilities of these events for the MDS cohort. This non-parametric model was then extended to a Cox model where we also assessed the impact of age and other risk factors on the different components of mortality. Combining relative survival and multi-state models gives more insight into the different causes of mortality and the impact of age and other risk factors on them. We show that for older patients, a substantial part of NRM is actually attributable to population mortality, information which should hopefully lead to more informed discussions regarding the risk of alloHCT and improvement of long-term care. [ABSTRACT FROM AUTHOR]

• The DIPSS was not predictive of survival in myelofibrosis secondary to essential thrombocythemia or polycythemia vera after stem cell transplantation. • The MYSEC-PM predicted survival and showed improved prognostic ability. • Although performance of the MYSEC-PM was still moderate, risk stratification may be improved by incorporating clinical, mutational, and transplant-related factors. We aimed to validate the MYelofibrosis SECondary to PV and ET prognostic model (MYSEC-PM) in 159 patients with myelofibrosis secondary to polycythemia vera (PV) and essential thrombocythemia (ET) from the European Society for Blood and Marrow Transplantation registry undergoing transplantation from matched siblings or unrelated donors. Furthermore, we aimed to test its prognostic performance in comparison with the Dynamic International Prognostic Scoring System (DIPSS). Score performance was analyzed using the concordance index (C): the probability that a patient who experienced an event had a higher risk score than a patient who did not (C >.5 suggesting predictive ability). Median follow-up of the total cohort was 41 months (range, 34 to 54), 45 months in post-PV and 38 months in post-ET myelofibrosis. Survival at 1, 2, and 4 years was 70% (95% CI, 63% to 77%), 61% (95% CI, 53% to 69%), and 52% (95% CI, 43% to 61%) for the total cohort; 70% (95% CI, 59% to 80%), 61% (95% CI, 49% to 73%), and 51% (95% CI, 38% to 64%) for post-PV; and 71% (95% CI, 61% to 81%), 61% (95% CI, 50% to 72%), and 54% (95% CI, 42% to 66%) for post-ET myelofibrosis (P =.78). Overall, the DIPSS was not significantly predictive of outcome (P =.28). With respect to the MYSEC-PM, overall survival at 4 years was 69% for the low-risk, 55% for the intermediate 1-risk, 47% for the intermediate 2-risk, and 22% (0% to 45%) for the high-risk groups. The prognostic model was predictive of survival overall (P =.05), whereas groups with intermediate 2 and high risk showed no significant difference (P =.44). Assessment of prognostic utility yielded a C-index of.575 (95% CI,.502 to.648) for the DIPSS, whereas assessment of the MYSEC-PM resulted in a C-statistics of.636 (95% CI,.563 to.708), indicating improvement in prediction of post-transplant survival using the new MYSEC-PM. In addition, transplantations from an unrelated donor in comparison with an HLA-identical sibling showed worse outcome (P =.04), and transplant recipients seropositive for cytomegalovirus in comparison with seronegative recipients (P =.01) showed worse survival. In conclusion, incorporating transplant-specific and clinical and mutational information together with the MYSEC-PM may enhance risk stratification. [ABSTRACT FROM AUTHOR]

When analysing patient survival, one is often interested in cause of death. Little is known about the presence of population mortality in advanced melanoma patients. The aim of this study was to assess population mortality after different response states in advanced melanoma patients in the Netherlands, and analyse the contribution of disease and population mortality for different age groups. We selected patients diagnosed between 2013 and 2019 with unresectable IIIC or stage IV melanoma, registered in the Dutch Melanoma Treatment Registry. A multi-state model with response states integrating population mortality was fitted. One-year landmark analyses were performed to assess outcomes after each response state. Overall, 5119 patients were selected. Five-year probabilities of melanoma-related mortality in patients alive in complete response at one year after diagnosis increased with age, and was 17.2% (95% confidence interval: 13.0–21.4) for patients aged <65 years and 28.7% (95% confidence interval: 24.3–33.1) in patients aged ≥80 years. Population mortality only played a large role for older patients (75 years and above) alive at 1 year after diagnosis with a partial or complete response. Even though survival outcomes of advanced melanoma patients have improved over the last decade, the vast majority of patients still die due to melanoma-related mortality. • Melanoma-related mortality after tumour responses has not been studied so far. • Using multi-state models, the prognostic impact of response states was assessed. • Melanoma-related mortality dominates population mortality in advanced melanoma. • Population mortality plays a role in patients ≥75 years who respond to therapy. [ABSTRACT FROM AUTHOR]

Patients with leukemia who receive a T cell-depleted allogeneic stem cell graft followed by postponed donor lymphocyte infusion (DLI) can experience graft-versus-leukemia (GVL) reactivity, with a lower risk of graft-versus-host disease (GVHD). Here, we have investigated the magnitude, diversity, and specificity of alloreactive CD8 T cells in patients who developed GVL reactivity after DLI in the absence or presence of GVHD. We observed a lower magnitude and diversity of CD8 T cells for minor histocompatibility antigens (MiHAs) in patients with selective GVL reactivity without GVHD. Furthermore, we demonstrated that MiHA-specific T cell clones from patients with selective GVL reactivity showed lower reactivity against nonhematopoietic cells, even when pretreated with inflammatory cytokines. Expression analysis of MiHA-encoding genes showed that similar types of antigens were recognized in both patient groups, but in patients who developed GVHD, T cell reactivity was skewed to target broadly expressed MiHAs. As an inflammatory environment can render nonhematopoietic cells susceptible to T cell recognition, prevention of such circumstances favors induction of selective GVL reactivity without development of GVHD. [ABSTRACT FROM AUTHOR]

In this retrospective analysis we evaluated the outcome of 313 patients aged ≥ 70 years in the registry of the European Group for Blood and Marrow Transplantation with myelodysplastic syndrome (MDS; n = 221) and secondary acute myeloid leukemia (n = 92) who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from related (n = 79) or unrelated (n = 234) donors. Median age at HSCT was 72 years (range, 70 to 78). Conditioning regimen was nonmyeloablative (n = 54), reduced intensity (n = 207), or standard intensity (n = 52). Allogeneic HSCT for MDS patients ≥ 70 years was increasingly performed over time. Although during 2000 to 2004 only 16 patients received HSCT, during 2011 to 2013 the number of transplantations increased to 181. The cumulative incidence of nonrelapse mortality at 1 year and relapse at 3 years was 32% and 28%, respectively, with a 3-year overall survival rate of 34%. Good performance, determined by Karnofsky performance status, and recipients' seronegativity for cytomegalovirus was associated with 3-year estimated overall survival rates of 43% ( P  = .01) and 46% ( P  = .002), respectively. Conditioning intensity did not impact survival. After careful patient selection, allogeneic HSCT can be offered to patients older than 70 years with MDS. [ABSTRACT FROM AUTHOR]

In older patients with breast cancer, the risk of dying from other causes than breast cancer strongly increases after the age of 70. The aim of this study was to assess contributions of breast cancer mortality versus other-cause mortality after locoregional or distant recurrence in a population-based cohort of older patients analysed by multi-state models. Surgically treated patients ≥70 years diagnosed with stage I-III breast cancer in 2003–2009 were selected from the Netherlands Cancer Registry. A novel multi-state model with locoregional and distant recurrence that incorporates relative survival was fitted. Other-cause and breast cancer mortality were indicated as population and excess mortality. Overall, 18,419 patients were included. Ten-year cumulative incidences of locoregional and distant recurrence were 2.8% (95%CI 2.6–3.1%) and 12.5% (95%CI 11.9–13.1%). Other-cause mortality increased from 23.9% (95%CI 23.7–24.2%) in patients 70–74 years to 73.8% (95%CI 72.2–75.4%) in those ≥80 years. Ten-year probabilities of locoregional or distant recurrence with subsequent breast cancer death were 0.4–1.3% and 10.2–14.6%, respectively. For patients with a distant recurrence in the first two years after diagnosis, breast cancer death probabilities were 95.3% (95%CI 94.2–96.4%), 93.1% (95%CI 91.6–94.6%), and 88.6% (95%CI 86.5–90.8%) in patients 70–74, 75–79, and ≥80 years. In older patients without recurrence, prognosis is driven by other-cause mortality. Although locoregional recurrence is a predictor for worse outcome, given its low incidence it contributes little to breast cancer mortality after diagnosis. For patients who develop a distant recurrence, breast cancer remains the dominant cause of death, even at old age. • Older patients with breast cancer often die from competing causes. • Competing mortality after recurrence has not been extensively studied so far. • Novel multi-state models were used including time after recurrence. • These models can be applied to different datasets as input for clinical decision tools. [ABSTRACT FROM AUTHOR]

In studies analyzing competing time-to-event outcomes, interest often lies in both estimating the effects of baseline covariates on the cause-specific hazards and predicting cumulative incidence functions. When missing values occur in these baseline covariates, they may be discarded as part of a complete-case analysis or multiply imputed. In the latter case, the imputations may be performed either compatibly with a substantive model pre-specified as a cause-specific Cox model [substantive model compatible fully conditional specification (SMC-FCS)], or approximately so [multivariate imputation by chained equations (MICE)]. In a large simulation study, we assessed the performance of these three different methods in terms of estimating cause-specific regression coefficients and predicting cumulative incidence functions. Concerning regression coefficients, results provide further support for use of SMC-FCS over MICE, particularly when covariate effects are large and the baseline hazards of the competing events are substantially different. Complete-case analysis also shows adequate performance in settings where missingness is not outcome dependent. With regard to cumulative incidence prediction, SMC-FCS and MICE are performed more similarly, as also evidenced in the illustrative analysis of competing outcomes following a hematopoietic stem cell transplantation. The findings are discussed alongside recommendations for practising statisticians. [ABSTRACT FROM AUTHOR]

Multi-state models provide an extension of the usual survival/event-history analysis setting. In the medical domain, multi-state models give the possibility of further investigating intermediate events such as relapse and remission. In this work, a further extension is proposed using relative survival, where mortality due to population causes (i.e. non-disease-related mortality) is evaluated. The objective is to split all mortality in disease and non-disease-related mortality, with and without intermediate events, in datasets where cause of death is not recorded or is uncertain. To this end, population mortality tables are integrated into the estimation process, while using the basic relative survival idea that the overall mortality hazard can be written as a sum of a population and an excess part. Hence, we propose an upgraded non-parametric approach to estimation, where population mortality is taken into account. Precise definitions and suitable estimators are given for both the transition hazards and probabilities. Variance estimating techniques and confidence intervals are introduced and the behaviour of the new method is investigated through simulations. The newly developed methodology is illustrated by the analysis of a cohort of patients followed after an allogeneic hematopoietic stem cell transplantation. The work has been implemented in the R package mstate. [ABSTRACT FROM AUTHOR]

Clofarabine is an active antileukemic drug for subgroups of patients with acute myeloid leukemia (AML). Multi‐state models can provide additional insights to supplement the original intention‐to‐treat analysis of randomized controlled trials (RCT). We re‐analyzed the HOVON102/SAKK30/09 phase III RCT for newly diagnosed AML patients, which randomized between standard induction chemotherapy with or without clofarabine. Using multi‐state models, we evaluated the effects of induction chemotherapy outcomes (complete remission [CR], measurable residual disease [MRD]), and post‐remission therapy with allogeneic stem cell transplantation [alloSCT] on relapse and death. Through the latter a consistent reduction in the hazard of relapse in the clofarabine arm compared to the standard arm was found, which occurred irrespective of MRD status or post‐remission treatment with alloSCT, demonstrating a strong and persistent antileukemic effect of clofarabine. During the time period between achieving CR and possible post‐remission treatment with alloSCT, non‐relapse mortality was higher in patients receiving clofarabine. An overall net benefit of treatment with clofarabine was identified using the composite endpoint current leukemia‐free survival (CLFS). In conclusion, these results enforce and extend the earlier reported beneficial effect of clofarabine in AML and show that multi‐state models further detail the effect of treatment on competing and series of events. [ABSTRACT FROM AUTHOR]

Simple Summary: The survival of advanced melanoma patients has improved significantly over the last decade due to the introduction of new systemic therapies. It is unknown whether survival outcomes of advanced melanoma patients differ between melanoma centers in the Netherlands. This research aimed to assess center variation in treatments and 2-year survival probabilities of advanced melanoma patients diagnosed between 2013 and 2017 in the Netherlands. Significant center variation in 2-year survival probabilities of patients diagnosed in 2014–2015 was observed after correcting for case-mix and treatment with new systemic therapies. The different use of new systemic therapies partially explained the observed variation. From 2016 onwards, no significant difference in 2-year survival was observed between centers. This study shows the added value of quality monitoring with a national registry that enables the study of variation between centers. Background: To assure a high quality of care for patients treated in Dutch melanoma centers, hospital variation in treatment patterns and outcomes is evaluated in the Dutch Melanoma Treatment Registry. The aim of this study was to assess center variation in treatments and 2-year survival probabilities of patients diagnosed between 2013 and 2017 in the Netherlands. Methods: We selected patients diagnosed between 2013 and 2017 with unresectable IIIC or stage IV melanoma, registered in the Dutch Melanoma Treatment Registry. Centers' performance on 2-year survival was evaluated using Empirical Bayes estimates calculated in a random effects model. Treatment patterns of the centers with the lowest and highest estimates for 2-year survival were compared. Results: For patients diagnosed between 2014 and 2015, significant center variation in 2-year survival probabilities was observed even after correcting for case-mix and treatment with new systemic therapies. The different use of new systemic therapies partially explained the observed variation. From 2016 onwards, no significant difference in 2-year survival was observed between centers. Conclusion: Our data suggest that between 2014 and 2015, after correcting for patient case-mix, significant variation in 2-year survival probabilities between Dutch melanoma centers existed. The use of new systemic therapies could partially explain this variation. In 2013 and between 2016 and 2017, no significant variation between centers existed. [ABSTRACT FROM AUTHOR]

Mucosal melanoma (MM) is rare and has a poor prognosis. Since 2011, new effective treatments are available for advanced melanoma. It is unclear whether patients with mucosal melanoma equally benefit from these new treatments compared with patients with cutaneous melanoma (CM). Patients with advanced MM and CM diagnosed between 2013 and 2017 were included from a nationwide population-based registry – the Dutch Melanoma Treatment Registry. Overall survival (OS) was estimated with the Kaplan-Meier method (also for a propensity score-matched cohort). A Cox model was used to analyse the association of possible prognostic factors with OS. In total, 120 patients with MM and 2960 patients with CM were included. Median OS was 8.7 months and 14.5 months, respectively. Patients with MM were older (median age 70 versus 65 years) and more often female (60% versus 41%), compared with CM. In total, 77% and 2% of the MM patients were treated with first-line immunotherapy and targeted therapy, respectively, compared with 49% and 33% of the CM patients. In contrast to CM, OS for MM did not improve for patients diagnosed in 2015–2017, compared with 2013–2014. ECOG performance score ≥1 (HR = 1.99 [1.26–3.15; p = 0.003]) and elevated LDH level (HR = 1.63 [0.96–2.76]; p = 0.069) in MM were associated with worse survival. Within the era of immune and targeted therapies, prognosis for patients with advanced MM has not improved as much as for CM. Collaboration is necessary to enlarge sample size for research to improve immunotherapeutic strategies and identify targetable mutations. • Survival of advanced mucosal melanoma (MM) was worse than cutaneous melanoma (CM). • Prognosis of advanced MM has not improved as much as CM despite novel therapies. • ECOG PS of ≥1 and elevated LDH were the most important prognostic factors. • The prognosis of different types of MM appeared to be similar. • NRAS and KIT were the most common mutations in MM. [ABSTRACT FROM AUTHOR]

Purpose: The optimal dose intensity for conditioning prior to allogeneic hematopoietic stem cell transplantation (alloHSCT) for chronic lymphocytic leukemia (CLL) is unknown. Methods: We retrospectively compared outcomes of patients who received a first alloHCST after non-myeloablative (NMA) and reduced intensity conditioning (RIC). Data of 432 patients with a median age of 55 years were included, of which 86 patients underwent NMA and 346 RIC. Results: The median follow-up after alloHSCT was 4.3 years. Compared to the RIC group, more NMA patients had purine-analog-sensitive disease, were in complete remission and received matched related donor transplantation. After RIC, the probabilities for 5-year OS, EFS, CIR, and NRM were 46%, 38%, 28%, and 35% and after NMA the respective probabilities were 52%, 43%, 25%, and 32%. In multivariate analysis, remission status prior to conditioning but not RIC versus NMA conditioning had a significant impact on CIR, EFS, and OS. Conclusion: Presumed higher anti-leukemic activity of RIC versus NMA conditioning did not translate into better outcomes after alloHSCT, but better remission status prior to conditioning did. Effective pathway inhibitor-based salvage therapies combined with NMA conditioning might thus represent the most attractive contemporary approach for alloHSCT for patients with CLL. [ABSTRACT FROM AUTHOR]

Summary: Myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukaemia (CMML) can progress to secondary acute myeloid leukaemia (sAML). We compared the outcome of 4214 sAML patients who received allogeneic haematopoietic stem cell transplantation (allo‐HSCT) from an unrelated (62%) or human leucocyte antigen (HLA)‐identical sibling donor (38%) according the underlying disease: MDS (n = 3541), CMML (n = 251) or MPN (n = 422). After a median follow up of 46·5 months, the estimated 3‐year progression‐free (PFS) and overall survival (OS) for the entire group was 36% (34–37%) and 41% (40–43%), respectively. The cumulative incidence of relapse and non‐relapse mortality (NRM) was 37% (35–39%) and 27% (26–29%), respectively. In a multivariable analysis for OS, besides age (P < 0·001), unrelated donor (P = 0·011), cytomegalovirus ± constellation (P = 0·007), Karnofsky index ≤ 80 (P < 0·001), remission status (P < 0·001), peripheral blood as stem cell source (P = 0·009), sAML from MPN (P = 0·003) remained a significant factor in comparison to sAML from MDS, while worse outcome of sAML from CMML did not reach statistical significance (P = 0·06). This large registry study demonstrates a major impact of the underlying disease on outcome of sAML after allo‐HSCT. [ABSTRACT FROM AUTHOR]

Highlights • We performed a retrospective review of 56 myelofibrosis patients transplanted from mismatched family donors. • Neutrophil engraftment at a median of 20days was observed in 82%. • Low rates of acute GVHD grades II to IV were observed in 28% (16% to 40%) and grades III to IV in 9% (2% to 16%). • Chronic GVHD at 1 year was found in 45% (32% to 58%). • Overall survival at 2years was 56% (41% to 70%). Abstract This analysis included 56 myelofibrosis (MF) patients transplanted from family mismatched donor between 2009 and 2015 enrolled in the European Society for Blood and Marrow Transplantation database. The median age was 57years (range, 38 to 72); 75% had primary MF and 25% had secondary MF. JAK2 V617F was mutated in 61%. Donors were HLA mismatched at 2 or more loci. Stem cells were sourced from bone marrow in 66% and peripheral blood in 34%. The median CD34+ cell dose was 4.8 × 106/kg (range, 1.7 to 22.9; n = 43). Conditioning was predominantly myeloablative in 70% and reduced intensity in the remainder. Regimens were heterogeneous with thiotepa, busulfan, fludarabine, and post-transplant cyclophosphamide used in 59%. The incidence of neutrophil engraftment by 28days was 82% (range, 70% to 93%), at a median of 21days (range, 19 to 23). At 2years the cumulative incidence of primary graft failure was 9% (95% CI 1% to 16%) and secondary graft failure was 13% (95% CI 4% to 22%). The cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV was 28% (95% CI 16% to 40%) and 9% (95% CI 2% to 17%) at 100days. The cumulative incidence of chronic GVHD at 1 year was 45% (95% CI 32% to 58%), but the cumulative incidence of death without chronic GVHD by 1 year was 20% (95% CI 10% to 31%). With a median follow-up of 32 months, the 1- and 2-year overall survival was 61% (95% CI 48% to 74%) and 56% (95% CI 41% to 70%), respectively. The 1- and 2- year progression-free survival was 58% (95% CI 45% to 71%) and 43% (95% CI 28% to 58%), respectively, with a 2-year cumulative incidence of relapse of 19% (95% CI 7% to 31%). The 2-year nonrelapse mortality was 38% (95% CI 24% to 51%). This retrospective study of MF allo-SCT using family mismatched donors demonstrated feasibility of the approach, timely neutrophil engraftment in over 80% of cases, and acceptable overall and progression-free survival rates with relapse rates not dissimilar to the unrelated donor setting. However, strategies to minimize the risk of graft failure and the relatively high nonrelapse mortality need to be used, ideally in a multicenter prospective fashion. [ABSTRACT FROM AUTHOR]

Background: Patients with prolonged neutropenia caused by chemotherapy or underlying marrow disorders are at risk of invasive bacterial and fungal infections. New treatment options alongside targeted antimicrobial therapy that might improve outcomes include granulocyte transfusions (GTX). To inform the research agenda, a prospective observational cohort study was performed in the Netherlands and United Kingdom. The aim was to describe the incidence, characteristics, and outcomes of patients developing invasive infections and assess patients fulfilling criteria for GTX.Study Design and Methods: All patients receiving myeloablative chemotherapy and anticipated to develop 7 or more days of neutropenia (<0.5 × 109 /L) were eligible and followed for the development of invasive infections according to a defined algorithm and mortality up to 100 days. Secondary outcomes were types of infection and eligibility for GTX.Results: A total of 471 patients enrolled at six hematology-oncology departments were followed for 569 neutropenic episodes. Overall, 32.5% of patients developed invasive infections during their first episode. Significant baseline risk factors for developing infections were high comorbidity scores (WHO performance status ≥ 2, hazard ratio [HR], 2.6 [1.7-3.9]; and hematopoietic cell transplantation-comorbidity index score ≥ 2 HR 1.3 [0.9-1.8]). Infections were bacterial (59.4%) and fungal (22.3%). Despite 34 patients (6.3% of all episodes) appearing to meet criteria to receive GTX, only nine patients received granulocytes. The HR for death was 5.8 (2.5-13.0) for patients with invasive infections.Conclusion: This study documents that invasive infections are associated with significant mortality. There is a need for new strategies to prevent and treat infections, which may include better understanding of use GTX. [ABSTRACT FROM AUTHOR]

The article presents a study which examined the short-term efficacy and safety of antithymocyte globulin treatment (ATG) in elderly patients with acquired aplastic anaemia. Also cited are the combined horse-derived ATG and ciclosporin (CSA) as standard first-line immunosuppressive therapy (IST) for the disease, and the results showing that age should not be an absolute contraindication for using ATG and CSA to treat older patients with acquired aplastic anaemia.