Molecular disparity of HLA-DPB1 is associated with the development of subsequent solid cancer after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: An increased incidence of subsequent solid cancers (SSCs) has been reported in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and SSC is associated with inferior mortality and morbidity. Previous studies showed that the incidence of SSC is significantly higher in those who underwent allo-HSCT from HLA-mismatched donors, suggesting that persistent alloimmunity may predispose patients to SSCs. It was recently reported that, in a cohort of patients who received allo-HSCT from an unrelated donor matched at HLA-A, -B, -C, -DRB1/3/4/5, and -DQB1 loci, HLA-DPB1 alloimmunity determined by high mismatched eplets (MEs) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) score (PS), was associated with relapse protection and increased risk of acute graft-versus-host disease (GVHD). METHODS: In the present study, the impact of HLA-DPB1 alloimmunity assessed by molecular mismatch algorithms on the development of SSCs in a cohort of 1514 patients who underwent allo-HSCT for hematologic malignancies was further investigated. ME load at the HLA-DPB1 locus was measured using the HLAMatchmaker module incorporated in HLA Fusion software, and the PS for mismatched HLA-DPB1 was calculated using the HSCT module from the PIRCHE online matching service. RESULTS: In multivariable analysis after adjusting for baseline risk factors, higher ME, PS-I, and PS-II in the GVH direction, but not in the HVG direction, were associated with an increased risk of SSCs (ME: subdistribution hazard ratio [SHR] 1.58, p = .01; PS-I: SHR 1.59, p = .009; PS-II: SHR 1.71, p = .003). In contrast, nonpermissive HLA-DPB1 mismatches defined by the conventional T-cell epitope algorithm were not predictive of the risk of SSCs. Moreover, posttransplant cyclophosphamide-based GVHD prophylaxis was associated with a reduced risk of subsequent solid cancer (SHR 0.34, p = .021). CONCLUSIONS: These results indicate for the first time that increased GVH alloreactivity could contribute to the development of SSCs in allo-HSCT survivors.

Development and validation of a patient-reported outcome measure to assess symptom burden after chimeric antigen receptor T-cell therapy.

This cross-sectional study aimed to develop and validate a patient-reported outcomes (PROs) assessment tool to assess symptom burden and daily functioning in patients after chimeric antigen receptor (CAR) T-cell therapy, the MD Anderson Symptom Inventory (MDASI-CAR). The items were generated based on literature review, content elicitation interviews with patients, and clinician's review. The patients completed the MDASI core and module, single-item quality-of-life (QoL) measure and Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29). The psychometric validation analysis was based on the acceptability after item reduction process. The final 10 MDASI-CAR module items included tremors, fever/chills, headache, balance, dizziness, attention, difficulty speaking, coughing, sexual dysfunction, and diarrhoea with high internal consistency (Cronbach's alpha: MDASI Core, 0.865; MDASI Interference, 0.915; CAR-T module, 0.746). The MDASI-CAR has excellent known-group validity that was demonstrated by differentiate patients based on patient's performance status (Cohen's d for MDASI core = -1.008, interference = -0.771, module = -0.835). Criterion validity was demonstrated by the significant correlations between the MDASI-CAR composite score, the single QoL item and the relevant domains on PROMIS-29 (all p < 0.05). This study established the MDASI-CAR module as a reliable and valid PRO tool for monitoring symptom burden after CAR T-cell therapy in patients with haematological malignancies. The findings need to be validated with a longitudinal design.

Is There Still a Role for Transplant for Patients with Mantle Cell Lymphoma (MCL) in the Era of CAR-T Cell Therapy?

OPINION STATEMENT: For years, upfront autologous hematopoietic cell transplant (auto-HCT) has been the standard of care for younger and physically fit mantle cell lymphoma (MCL) patients after chemoimmunotherapy (CIT) induction. Bruton's tyrosine kinase (BTK) inhibitors have proven to be excellent salvage therapies, but their durability remains a question, especially in high-risk (HR) MCL. Allogeneic HCT (allo-HCT) was the only option for long-term remission and possibly cure for MCL relapse after auto-HCT and sometime as upfront consolidation for a young patient with HR MCL (debatable). We have seen a paradigm shift since the FDA approval in July 2020 of the brexucabtagene autoleucel chimeric antigen receptor T (CAR-T) cell therapy for relapsed and refractory (R/R) MCL with an preliminary evidence suggesting CAR-T may overcome known biological risk factors in MCL. Given its safety profile and excellent efficacy, the role of CAR-T among other approved therapies and HCT may need to be better defined. Based on the current evidence, auto-HCT remains a standard frontline consolidation therapy. CAR-T therapy is a preferred option for patients with relapsed/refractory (R/R) MCL, particularly those who failed BTK inhibitors. In certain high-risk MCL patients (such as high ki 67, TP53 alterations, complex karyotype, blastoid morphology, early relapse after initial diagnosis), CAR-T cell therapy may be considered before BTK inhibitors (preferably on a clinical trial). The role of allo-HCT is unclear in the CAR-T era, but remains a viable option for eligible patients who have no access or who have failed CAR-T therapy. Our review discusses current standards and the shifting paradigms in the indications for HCT and the role of CAR-T cell therapy for MCL. Prospective studies tailored based on risk factors are needed to better define the optimal sequences of HCT and cellular therapy and other approved novel therapies.

Chimeric antigen receptor T-cell therapy toxicities.

Cancer immunotherapy has greatly advanced in recent years, with chimeric antigen receptor (CAR) T cells emerging as an innovative technology that harnesses the immune system to fight malignant diseases. These genetically engineered T-cells have shown encouraging results for B-cell lymphoid malignancies and are now being explored for other cancer types. However, this novel adoptive cell therapy is associated with a new spectrum of immune-mediated adverse events and toxicities. As CAR T cells recognize and engage tumour cells, cytokines are secreted and activate other immune cells, frequently leading to rapid development of cytokine release syndrome, which can result in acute deterioration of the patient's clinical condition. In many patients, cytokine release syndrome is mild and easy to manage, but others experience persistent fevers accompanied by hypotension and hypoxia, which require management with immune-modulatory agents. Another deleterious effect of cytokines released by effector cells is immune effector cell-associated neurotoxicity syndrome. This syndrome, caused by a disruption of the blood-brain barrier as a consequence of the immune process, can result in rapid deterioration in cognitive function. This is often associated with subtle changes in handwriting, often progressing to loss of memory and concentration and reduced ability to name objects or follow commands. In some cases, the neurological state is further compromised by seizures and in rare instances with fulminant life-threatening cerebral oedema. In this review, we discuss these toxicities, as well as other CAR T-cell-related immune phenomenon, and address their clinical manifestations, grading, and management options.

Cytogenetics and Blast Count Determine Transplant Outcomes in Patients with Active Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) patients not in remission and beyond first or second complete remission are considered allogeneic stem cell transplant (SCT) candidates. We present 361 patients who underwent SCT from matched related or unrelated donors between 2005 and 2013. The purpose was to identify a subgroup of patients with active disease at the time of transplant that benefit. Cox proportional hazards regression analysis was used for univariate and multivariate analyses to predict overall survival (OS). Variables considered were age, sex, SWOG cytogenetic risk group, bone marrow (BM) and peripheral blood (PB) blast percentage, regimen intensity, and type of AML. At a median of 26 months after transplantation, OS, progression-free survival (PFS), non-relapse mortality, and relapse rates were 26, 24, 23, and 48%, respectively. In a univariate analysis, risk cytogenetics (p < 0.001) and BM blasts >4% (p = 0.006) or any blasts in PB (p < 0.001) indicated worse OS. In a multivariate analysis, patients with <5% BM blasts or absence of circulating blasts and good or intermediate risk cytogenetics had significantly superior OS (46%), PFS (44%), and disease progression at 3 years. Based on these findings, patients not in remission with good or intermediate risk cytogenetics and low blast counts should be considered for SCT.

Endothelial Activation and Stress Index (EASIX) at Admission Predicts Fluid Overload in Recipients of Allogeneic Stem Cell Transplantation.

Fluid overload (FO) grade ≥2 (more than 10% weight gain from baseline) has recently been recognized as an important toxicity associated with a high rate of nonrelapse mortality in recipients of allogeneic hematopoietic cell transplantation (AHCT). The causes for FO remain unclear. We hypothesized that endothelial damage, possibly due to treatments received prior to AHCT, may be associated with this toxicity and sought to determine whether the Endothelial Activation and Stress Index (EASIX) (defined as lactate dehydrogenase [U/L]â€ˆ× creatinine [mg/dL]/platelets [109 cells/L]) correlates with grade ≥2 FO in 2 cohorts of recipients of AHCT at our institution. We tested our hypothesis in a cohort of 145 consecutive recipients (study cohort) of AHCT transplant from HLA-haploidentical donors and validated the findings in a cohort of 449 (validation cohort) recipients of AHCT from HLA-matched donors who underwent transplantation between 2010 and 2015. Predictors of grade ≥2 FO were evaluated using competing risks regression in univariate analysis and classification and regression tree (CART) analysis in multivariate analysis. The cumulative incidence of grade ≥2 FO was estimated considering death as a competing risk. EASIX scores were evaluated based on log2-transformed values. Optimal predictive EASIX cutoff values were determined based on receiver operating characteristics curve analysis. Grade ≥2 FO occurred in 21% and 6% of the study and validation cohorts, respectively, with the majority of these cases being diagnosed before the day of AHCT. Median log2 EASIX score at admission was 2.4 (interquartile range [IQR], 1.3, 3.7) and 2.5 (IQR, 1.4, 3.9) in the 2 respective cohorts. In univariate analysis, high EASIX at admission was a significant predictor of grade ≥2 FO in the study (cutoff: 4.4, hazard ratio [HR] = 4.8, P < .001) and in the validation (cutoff: 4.3, HR = 4.8, P < .001) cohorts. The significant effect of EASIX persisted in multivariate CART analysis in the study (HR = 6.3, P < .001) and the validation (HR = 28, P = .002) cohorts. Additional predictors in multivariate analysis included body weight below 80 kg in recipients older than 55 years (HR = 4.5, P < .001) in the study cohort and diabetes (HR = 34, P = .001) and age >60 years (HR = 9.6, P = .04) in the validation cohort. At admission, the prevalence of EASIX score of >4.3 (18% versus 17%, P = .9) was not different between the diabetics and nondiabetics. EASIX score at admission is a significant predictor of grade ≥2 FO in recipients of AHCT from HLA-haploidentical or HLA-matched donors. Independently of EASIX, older patients with low weight were associated with increased risk of grade ≥2 FO for recipients of HLA-haploidentical transplants. For the HLA-matched cohort, diabetes and older age were associated with increased FO risk. These findings require validation in external cohorts.

Chimeric Antigen Receptor Therapy: How Are We Driving in Solid Tumors?

Immune effector cell (IEC) therapy is emerging as a promising approach in the field of cancer immunotherapy. Clinical IEC trials, predominantly using chimeric antigen receptor (CAR) T cells, have shown excellent responses in CD19+ B cell malignancies and multiple myeloma. In solid tumors, preclinical data are encouraging, but clinical data are in their infancy, and there are challenges in using CAR T therapy in this setting, including (1) on-target off-tumor toxicity, (2) optimal target identification, (3) effective trafficking into bulky tumor tissue, and (4) resistance to tumor immune evasion mechanisms. Novel techniques and modifications are being explored in both the preclinical and clinical settings, aiming to improve treatment efficacy and address the aforementioned obstacles to successful CAR T therapy in solid tumors. Here we review these challenges in a clinically oriented approach and summarize published clinical trials using CAR T therapy in a variety of solid tumors.

Haploidentical transplants for patients with relapse after the first allograft.

Relapse after allogeneic hematopoietic stem-cell transplantation (AHSCT) is associated with very poor outcomes. A second transplant offers the possibility of long-term disease control. We analyzed outcomes with haploidentical donors for second allograft at our institution. All consecutive patients with hematological malignancies (N = 29) who relapsed after AHSCT and underwent a haploidentical transplant (haploSCT) as second transplant between February 2009 and October 2018 were included. Median age was 36 years (interquartile range (IQR) 24-60); 83% of patients had high/very high disease risk index; 61% of AML/MDS patients had high-risk cytogenetics; and only 24% were in complete remission at transplant. With a median follow-up of 46.9 months, the 3-year relapse, non-relapse mortality (NRM), progression-free survival (PFS) and overall survival (OS) were 30%, 39%, 31% and 40%, respectively. In multivariable analysis (MVA), comorbidity index (HCT-CI) and detectable donor-specific anti-HLA antibodies (DSA) prior to second transplant were significantly associated with worse outcomes. Patients with HCT-CI <3 and without DSA had 3-year PFS and OS of 53% and 60.3%, respectively. Our findings suggest that haploSCT as second AHSCT is feasible and potentially curative. Lower HCT-CI and no DSA were associated with lower NRM and improved survival. Haploidentical grafts might be a preferred donor source for second AHSCT as these are high-risk patients who frequently need to proceed urgently to transplant.

Comparison of Outcomes of Allogeneic Hematopoietic Cell Transplantation for Multiple Myeloma Using Three Different Conditioning Regimens.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for patients with multiple myeloma, as it provides a graft-versus-myeloma effect alongside a myeloma-free graft. Although reduced-intensity conditioning regimens decrease nonrelapse mortality (NRM), there is a paucity of data with regard to the ideal conditioning regimen in myeloma. We conducted a retrospective comparison of 3 different preparative regimens used for allo-HCT for multiple myeloma at our institution in recent clinical trials: busulfan/fludarabine (BuFlu), fludarabine/melphalan 100 mg/m2 (FM100), and fludarabine/melphalan 140 mg/m2 (FM140). NRM, progression-free survival (PFS) at 3 years, and overall survival (OS) at 3 years were the primary endpoints. Secondary endpoints included time to engraftment, and the incidence of grades II through IV acute graft-versus-host disease and chronic graft-versus-host disease. A total of 73 patients received allo-HCT with these regimens. NRM at 3 years was seen in 3 (21%), 5 (28%), and 6 (24%) patients in the BuFlu, FM100, and FM140 groups, respectively. Three-year PFS in the BuFlu, FM100, and FM140 groups was 16% (hazard ratio [HR], 1.2; 95% confidence interval [CI], 0.6 to 2.1), 26% (HR, 0.6; 95% CI, 0.3 to 1.2), and 11% (reference), respectively. Three-year OS in the BuFlu, FM100, and FM140 groups was 39% (HR, 1.1; 95% CI, 0.5 to 2.2), 43% (HR, 0.7; 95% CI, 0.3 to 1.4), and 32% (reference), respectively. High-risk cytogenetics and relapsed disease prior to allo-HCT were found to be independent predictors of inferior OS on multivariate analysis, with a HR of 2.1 (P = .02) and 2.6 (P = .004), respectively. In contrast, the preparative regimen did not emerge as a predictor of PFS or OS. Durable clinical remission can be achieved in 11% to 25% of patients with multiple myeloma with the use of allo-HCT without any significant difference in the safety or efficacy of the conditioning regimen. High-risk cytogenetics and relapsed disease prior to transplant were associated with inferior PFS and OS.

Haploidentical transplantation for acute myeloid leukemia patients with minimal/measurable residual disease at transplantation.

There have been conflicting results regarding the impact of minimal/measurable disease at transplant on acute myeloid leukemia (AML) outcomes after haploidentical transplantation (haplo-SCT). We assessed the impact of pre-transplant disease status on post-transplant outcomes of 143 patients treated with haplo-SCT using fludarabine-melphalan (FM) conditioning and post-transplant cyclophosphamide (PTCy). With a median follow-up of 29 months, the two-year PFS for all patients was 41%. Compared to patients in complete remission (CR) at transplant, those with active disease (n = 29) and CR with incomplete count recovery (CRi) (n = 39) had worse PFS. They had hazard ratios (HR) of 3.5 (95% CI: 2.05-6.1; P < .001) and 2.3 (95% CI: 1.3-3.9; P = .002), respectively. Among patients who were in CR at transplant, there were no differences in PFS between those who had minimal residual disease (MRD) positive (n = 24), and MRD negative (n = 41) (HR 1.85, 95%CI: 0.9-4.0; P = .1). In multivariable analysis for patients in CR, only age was predictive for outcomes, while MRD status at transplant did not influence the treatment outcomes. Our findings suggest that haplo-SCT with FM conditioning regimen and PTCy-based GVHD prophylaxis has a protective effect, and may potentially abrogate the inferior outcomes of MRD positivity for patients with AML. Patients with positive MRD may benefit from proceeding urgently to a haplo-SCT, as this does not appear to negatively impact transplant outcomes.

Four-year follow-up of a single arm, phase II clinical trial of ibrutinib with rituximab (IR) in patients with relapsed/refractory mantle cell lymphoma (MCL).

Ibrutinib has shown significant activity in patients with relapsed or refractory mantle cell lymphoma (RR-MCL). We report the long-term outcome and safety profile of a single-centre, single arm, open-label, phase 2 study of RR-MCL treated with IR. Overall, the median follow-up time was 47 months (range 1-52 months), median duration on treatment was 16 months (range 1-53 months) and median number of treatment cycles was 17 (range 1-56). Twenty-nine patients (58%) achieved complete remission and of these, 12 patients continue on study. Thirty-eight patients discontinued treatment, 14 due to disease progression (2 transformed). Patients with blastoid morphology, high risk MCL International Prognostic Index score and high Ki67% had inferior survival. The commonest grade 1-2 toxicities were fatigue, diarrhoea, nausea, arthralgias and myalgias. None had long term toxicities. Median progression-free survival was 43 months. Eighteen patients (36%) died (14 deaths were MCL-related). The median overall survival has not been reached. Treatment with IR can provide durable remissions in a subset of patients with RR-MCL, especially those with low Ki67%. The possible benefit of adding other therapies in combination with IR in RR-MCL is under exploration.

Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for High-Risk Acute Lymphoblastic Leukemia.

Haploidentical transplantation performed with post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has been associated with favorable outcomes for patients with acute myeloid leukemia and lymphomas. However, it remains unclear if such approach is effective for patients with acute lymphoblastic leukemia (ALL). We analyzed outcomes of 109 consecutively treated ALL patients 18 years of age and older at 5 institutions. The median age was 32 years and the median follow-up for survivors was 13 months. Thirty-two patients were in first complete remission (CR1), while the rest were beyond CR1. Neutrophil engraftment occurred in 95% of the patients. The cumulative incidences of grades II to IV and III and IV acute GVHD at day 100 after transplantation were 32% and 11%, respectively, whereas chronic GVHD, nonrelapse mortality, relapse rate, and disease-free survival (DFS) at 1 year after transplantation were 32%, 21%, 27%, and 51%, respectively. Patients in CR1 had 52% DFS at 3 years. These results suggest that haploidentical transplants performed with PTCy-based GVHD prophylaxis provide a very suitable alternative to HLA-matched transplantations for patients with ALL.

A randomized phase II study of standard-dose versus high-dose rituximab with BEAM in autologous stem cell transplantation for relapsed aggressive B-cell non-hodgkin lymphomas: long term results.

High-dose rituximab (HD-R) combined with carmustine, cytarabine, etoposide and melphalan (BEAM) and autologous stem cell transplant (ASCT) was effective and tolerable in a single-arm prospective study of relapsed aggressive B-cell non-Hodgkin lymphoma (R-NHL). We performed a randomized phase 2 study comparing HD-R versus standard-dose rituximab (SD-R) in R-NHL. Ninety-three patients were randomized to HD-R (1000 mg/m2 ) (n = 42) or SD-R (375 mg/m2 ) (n = 51) administered on post-transplant days +1 and +8, using a Bayesian adaptive algorithm. The 2 treatment arms were balanced in regards to patient demographic and clinical characteristics. At a median follow-up of 7·92 years, the 5-year disease-free survival (DFS) and overall survival (OS) were 40% and 48%, respectively. We found no statistically significant differences between HD-R and SD-R in 5-year DFS (36% vs. 43%; P = 0·205) and OS (43% vs. 52%; P = 0·392). In multivariate analyses, only disease status before ASCT [residual disease versus complete remission (CR)] (hazard ratio [HR] 1·79, 95% confidence interval [CI]: 1·08-2·95) and number of prior treatments received (>2 vs. ≤2 lines of treatment) (HR 1·89, 95% CI: 1·13-3·18) were associated with worse DFS and OS. Patients who had SCT while in CR or who received ≤2 lines of treatment prior to SCT had better 5-year OS (57% vs. 35%; P = 0·02 and 54% vs. 30%, P = 0·001, respectively) in both arms. No differences in engraftments or adverse events were noted in the 2 arms. When combined with BEAM and ASCT in relapsed aggressive B-cell NHL, HD-R provided no DFS or OS advantage over SD-R. In patients who have been exposed to rituximab in the frontline or salvage setting, the addition of rituximab in the peri-transplant setting remains controversial.

Outcome of Patients with Multiple Myeloma and CKS1B Gene Amplification after Autologous Hematopoietic Stem Cell Transplantation.

The gain/amplification of the CKS1B gene on chromosome 1q21 region is associated with a poor outcome in patients with multiple myeloma (MM). However, there are limited data on the outcome of patients with CKS1B amplification after a single high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT). We retrospectively evaluated the outcome of patients with CKS1B amplification who received an auto-HCT between June 2012 and July 2014 at our institution. We identified 58 patients with MM and CKS1B gene amplification detected by fluorescent in situ hybridization (FISH). We compared their outcomes with a propensity score-matched control group of 58 patients without CKS1B amplification who were treated at approximately the same time. The primary objective was to compare the progression-free (PFS) and overall survival (OS) between the CKS1B and the control groups. Stratified log-rank test with the matched pairs as strata and double robust estimation under the Cox model were used to assess the effect of CKS1B gene amplification on PFS or OS in the matched cohort. Patients in the CKS1B and control groups were well matched for age, gender, disease status, year of auto-HCT, response to pretransplantation therapy, and baseline hemoglobin level. In both groups, 57% patients were in first remission and 43% had relapsed disease at auto-HCT. Twenty-seven (47%) patients with CKS1B amplification had concurrent monosomy 13 or 13q deletion; 6 (10%) by conventional cytogenetics only, 16 (28%) by FISH only, and 5 (9%) by both. Median follow-up after auto-HCT was 25.4 months. The median PFS of the CKS1B and the control groups were 15.0 months and 33.0 months (P = .002), respectively. The median OS have not been reached yet. The 2-year OS rates in the CKS1B and the control groups were 62% and 91% (P = .02), respectively. In conclusion, Patients with CKS1B amplification are more likely to have additional high-risk cytogenetic abnormalities and a shorter PFS and OS after an auto-HCT.

Incidence and patient survival of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms in the United States, 2001-12.

Descriptive epidemiological information on myeloproliferative neoplasms (MPNs) and myelodysplastic (MDS)/MPNs is largely derived from single institution and European population-based studies. Data obtained following adoption of the World Health Organization classification of haematopoietic neoplasms and JAK2 V617F mutation testing are sparse. Using population-based data, we comprehensively assessed subtype-specific MPN and MDS/MPN incidence rates (IRs), IR ratios (IRRs) and relative survival (RS) in the United States (2001-12). IRs were highest for polycythaemia vera (PV) (IR = 10·9) and essential thrombocythaemia (ET) (IR = 9·6). Except for ET and mastocytosis, overall IRs were significantly higher among males (IRRs = 1·4-2·3). All evaluable MPNs were associated with lower IRs among Hispanic whites than non-Hispanic whites (NHWs), with the exception of BCR-ABL1-positive chronic myeloid leukaemia (CML), chronic eosinophilic leukaemia (CEL) and juvenile myelomonocytic leukaemia. Except for CEL, Asians/Pacific Islanders had significantly lower MPN IRs than NHWs. ET, MPN-unclassifiable and CEL IRs were 18%, 19% and 60% higher, respectively, among blacks than NHWs. Five-year RS was more favourable for younger (<60 years) than older individuals and for women compared with men, except for PV at older ages. RS was highest (>90%) for younger PV and ET patients and lowest (<20%) for older chronic myelomonocytic leukaemia and atypical BCR-ABL1-negative CML patients. Varying MPN and MDS/MPN incidence patterns by subtype support distinct aetiologies and/or susceptible populations. Decreased survival rates as compared to that expected in the general population were associated with every MPN subtype, highlighting the need for new treatments, particularly among older individuals.