Summary 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 (2001-2012). 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.
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.
Background Population-based studies comprehensively describing incidence patterns of human papillomavirus (HPV)-related preinvasive and invasive neoplasms prior to widespread HPV vaccination are sparse. Methods We calculated age-adjusted incidence rates (IRs), IR ratios (IRRs), and annual percent changes (APC) in IRs for potentially HPV-related tumors diagnosed in the Surveillance, Epidemiology and End Results Program during 1978–2007. Results Overall IRs for preinvasive tumors were significantly higher than for invasive squamous cell tumors of cervix (IRR=3.42), vulva (IRR=1.87), and vagina (IRR=1.19) and significantly lower for adenomatous cervical tumors (IRR=0.43), and squamous cell tumors of penis (IRR=0.64), anus (males, IRR=0.53; females, IRR=0.14), and head and neck (H&N) (males, IRR=0.01; females, IRR=0.02). Incidence of preinvasive squamous tumors of cervix, vagina, and penis rose rapidly over time and decreased for invasive neoplasms. The most rapid increases occurred for preinvasive (males, APC=16.0; females, APC=7.3) and invasive anal tumors (males, APC=3.6; females, APC=2.3). IR patterns were generally similar among evaluable racial/ethnic groups, with the exception of H&N invasive tumor IRs which increased exclusively among white males. Conclusion Contrary to the opposing trends of preinvasive and invasive squamous tumors of cervix, vagina, and penis, preinvasive and invasive anal tumor IRs increased significantly over time by gender, age, and racial/ethnic groups. Successful HPV vaccination programs are needed to measurably reduce incidence of HPV-related neoplasms in the future, particularly for cancer sites with rising incidence rates for which effective screening modalities are limited.
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 incidence (CI) of grades II–IV and III–IV acute GVHD at day 100 post-transplant was 32% and 11%, while chronic GVHD, non-relapse mortality, relapse rate and disease-free survival (DFS) at 1 year post-transplant 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 an excellent alternative to HLA matched transplants for patients with ALL.
The Endothelial Activation and Stress Index (EASIX) score, defined as [(creatinine × lactate dehydrogenase [LDH])/platelets], is a marker of endothelial activation that has been validated in the allogeneic hematopoietic stem cell transplant setting. Endothelial activation is one of the mechanisms driving immune-mediated toxicities in patients treated with chimeric antigen receptor-T (CAR-T)-cell therapy. This study’s objective was to evaluate the association between EASIX and other laboratory parameters collected before lymphodepletion and the subsequent onset of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) those patients. Toxicity data were collected prospectively on 171 patients treated with axicabtagene ciloleucel (axi-cel) for large B-cell lymphoma (LBCL). CRS grades 2 to 4 were diagnosed in 81 (47%) patients and ICANS grades 2 to 4 in 84 (49%). EASIX combined with ferritin (EASIX-F) identified 3 risk groups with CRS grades 2 to 4 cumulative incidence of 74% (hazards ratio [HR], 4.8; 95% confidence interval [CI], 2.1-11; P < .001), 49% (HR, 2.3; 95% CI, 1.02-5; P = .04), and 23% (reference), respectively. EASIX combined with CRP and ferritin (EASIX-FC) identified 3 risk groups with an ICANS grade 2 to 4 cumulative incidence of 74% (HR, 3.6; 95% CI, 1.9-6.9; P < .001), 51% (HR, 2.1; 95% CI, 1.1-3.9; P = .025), and 29% (reference). Our results indicate that common laboratory parameters before lymphodepletion correlate with CAR-T–related toxicities and can help support clinical decisions, such as preemptive toxicity management, hospitalization length, and proper setting for CAR-T administration.
The optimal conditioning regimen for older patients with acute myeloid leukemia (AML) remains unclear. In this study, we compared outcomes of AML patients >60 years of age undergoing allogenic hematopoietic stem cell transplantation at our institution. All 404 consecutively treated patients received 1 of the following conditioning regimens: (1) fludarabine+melphalan 100 mg/m2 (FM100), (2) fludarabine+melphalan 140 mg/m2 (FM140), (3) fludarabine+IV busulfan AUC ≥ 5000/d × 4 d (Bu≥20000), and (4) fludarabine+IV busulfan AUC 4000/d × 4 d (Bu16000). A propensity score analysis (PSA) was used to compare outcomes between these 4 groups. Among the 4 conditioning regimens, the FM100 group had a significantly better long-term survival with 5-year progression-free survival of 49% vs 30%, 34%, and 23%, respectively. The benefit of the FM100 regimen resulted primarily from the lower nonrelapse mortality associated with this regimen, an effect more pronounced in patients with lower performance status. The PSA confirmed that FM100 was associated with better posttransplantation survival, whereas no significant differences were seen between the other regimen groups. In summary, older patients with AML benefited from a reduced-intensity conditioning regimen with lower melphalan doses (FM100), which was associated with better survival, even though it was primarily used in patients who could not receive a more intense conditioning regimen.
Background: Hematopoietic stem cell transplantation (HCT) conditioning regimens that can reduce relapse risk without increasing non-relapse mortality (NRM) are needed. We tested the safety of timed-sequential delivery of myeloablative dose of busulfan in older patients and younger patients with comorbidities. Methods: In this open label, non-stratified, randomized phase II clinical trial, patients with hematological malignancies up to 75 years of age were randomized 1:1 by a computer generated program in a block size of 4 to receive a total intravenous busulfan dose to achieve an area under the curve (AUC) of 16,000 μmol.min (16K) or 20,000 μmol.min (20K) based on pharmacokinetic analysis, with fludarabine 40 mg/m2 intravenously for four days (Bu-Flu). The investigators and the research nurses were blinded to the block size to conceal allocation. The primary endpoint was day 100 NRM analyzed by intention-to-treat. No interim analyses were planned and the accrual is complete. Findings: Forty-nine patients were randomized to the 16K arm and 48 to the 20K arm. Median age was 60 (range, 18-75) years. Over 50% had an HCT-Comorbidity Index (HCT-CI) ≥ 3, and 42% had a high or very high Disease Risk Index (DRI). Day 100 NRM was 4.1% (95% confidence interval [CI], 0%-9.7%) in the 16K arm and 6.3% (95% CI, 0%-13.2%) in the 20K arm (P= 0.65). In multivariate analysis, HCT-CI was an independent predictor of NRM (hazard ratio [HR], 2.12; 95% CI, 1.37-3.29; P=0.0008). Infection was the most common grade 3 to 5 toxicity that occurred equally in the 20K arm (n=25) and the 16K arm (n=24). Mucositis (n=10 versus n=3), idiopathic pneumonia syndrome (n=9 versus n=2), and culture-negative neutropenic fever (n=16 versus n=8) were more common in the 20K arm than in the 16K arm, respectively. Interpretation: Myeloablative doses of busulfan administered in a timed-sequential manner with fludarabine results in low NRM in older patients. Whether this approach can further reduce the risk of relapse requires additional studies.
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] £ creatinine [mg/dL]/ platelets [10 9 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 log 2 -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 log 2 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.
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