Aaron T. Gerds

Reduced-Intensity Hematopoietic Cell Transplantation for Patients with Primary Myelofibrosis: A Cohort Analysis from the Center for International Blood and Marrow Transplant Research

We evaluated outcomes and associated prognostic factors in 233 patients undergoing allogeneic hematopoietic cell transplantation (HCT) for primary myelofibrosis (MF) using reduced-intensity conditioning (RIC). The median age at RIC HCT was 55 yr. Donors were a matched sibling donor (MSD) in 34% of RIC HCTs, an HLA well-matched unrelated donor (URD) in 45%, and a partially matched/mismatched URD in 21%. Risk stratification according to the Dynamic International Prognostic Scoring System (DIPSS) was 12% low, 49% intermediate-1, 37% intermediate-2, and 1% high. The probability of survival at 5 yr was 47% (95% confidence interval [CI], 40% to 53%). In a multivariate analysis, donor type was the sole independent factor associated with survival. Adjusted probabilities of survival at 5-yr were 56% (95% CI, 44% to 67%) for MSD, 48% (95% CI, 37% to 58%) for well-matched URD, and 34% (95% CI, 21% to 47%) for partially matched/mismatched URD (P = .002). The relative risk (RR) for NRM was 3.92 (P = .006) for well-matched URD and 9.37 (P < .0001) for partially matched/mismatched URD. Trends toward increased NRM (RR, 1.7; P = .07) and inferior survival (RR, 1.37; P = .10) were observed in DIPSS intermediate-2/high-risk patients compared with DIPSS low/intermediate-1 risk patients. Our data indicate that RIC HCT is a potentially curative option for patients with MF, and that donor type is the most important factor influencing survival in these patients.

An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults.

Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are hematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes and myeloproliferative neoplasms. There are currently no standard treatment recommendations for most adult patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic end points and standardized response criteria for clinical trials. The dual dysplastic and proliferative features in these stem cell malignancies define their uniqueness and challenges. We propose response assessment guidelines to harmonize future clinical trials with the principal objective of establishing suitable treatment algorithms. An international panel comprising laboratory and clinical experts in MDS/MPN was established involving 3 independent academic MDS/MPN workshops (March 2013, December 2013, and June 2014). These recommendations are the result of this collaborative project sponsored by the MDS Foundation.

Incorporation of molecular data into the Revised International Prognostic Scoring System in treated patients with myelodysplastic syndromes

The Revised International Prognostic Scoring System (IPSS-R) was developed for untreated myelodysplastic syndrome (MDS) patients based on clinical data. We created and validated a new model that incorporates mutational data to improve the predictive capacity of the IPSS-R in treated MDS patients. Clinical and mutational data from treated MDS patients diagnosed between January 2000 and January 2012 were used to develop the new prognostic system. A total of 508 patients were divided into training (n=333) and validation (n=175) cohorts. Independent significant prognostic factors for survival included age, IPSS-R, EZH2, SF3B1 and TP53. Weighted coefficients for each factor were used to build the new linear predictive model, which produced four prognostic groups: low, intermediate-1, intermediate-2 and high with a median overall survival of 37.4, 23.2, 19.9 and 12.2 months, respectively, P<0.001. Significant improvement in the C-index of the new model (0.73) was observed compared with the IPSS-R (0.69). The new model predicted outcome both in a separate validation cohort and in another cohort of patients with paired samples at different time points during their disease course. The addition of mutational data to the IPSS-R makes it dynamic and enhances its predictive ability in treated MDS patients regardless of their initial or subsequent therapies.

Scoring System Prognostic of Outcome in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome

PURPOSE To develop a system prognostic of outcome in those undergoing allogeneic hematopoietic cell transplantation (allo HCT) for myelodysplastic syndrome (MDS). PATIENTS AND METHODS We examined 2,133 patients with MDS undergoing HLA-matched (n = 1,728) or -mismatched (n = 405) allo HCT from 2000 to 2012. We used a Cox multivariable model to identify factors prognostic of mortality in a training subset (n = 1,151) of the HLA-matched cohort. A weighted score using these factors was assigned to the remaining patients undergoing HLA-matched allo HCT (validation cohort; n = 577) as well as to patients undergoing HLA-mismatched allo HCT. RESULTS Blood blasts greater than 3% (hazard ratio [HR], 1.41; 95% CI, 1.08 to 1.85), platelets 50 × 10(9)/L or less at transplantation (HR, 1.37; 95% CI, 1.18 to 1.61), Karnofsky performance status less than 90% (HR, 1.25; 95% CI, 1.06 to 1.28), comprehensive cytogenetic risk score of poor or very poor (HR, 1.43; 95% CI, 1.14 to 1.80), and age 30 to 49 years (HR, 1.60; 95% CI, 1.09 to 2.35) were associated with increased hazard of death and assigned 1 point in the scoring system. Monosomal karyotype (HR, 2.01; 95% CI, 1.65 to 2.45) and age 50 years or older (HR, 1.93; 95% CI, 1.36 to 2.83) were assigned 2 points. The 3-year overall survival after transplantation in patients with low (0 to 1 points), intermediate (2 to 3), high (4 to 5) and very high (≥ 6) scores was 71% (95% CI, 58% to 85%), 49% (95% CI, 42% to 56%), 41% (95% CI, 31% to 51%), and 25% (95% CI, 4% to 46%), respectively (P < .001). Increasing score was predictive of increased relapse (P < .001) and treatment-related mortality (P < .001) in the HLA-matched set and relapse (P < .001) in the HLA-mismatched cohort. CONCLUSION The proposed system is prognostic of outcome in patients undergoing HLA-matched and -mismatched allo HCT for MDS.

Development and Validation of a Novel Acute Myeloid Leukemia–Composite Model to Estimate Risks of Mortality

Importance To our knowledge, this multicenter analysis is the first to test and validate (1) the prognostic impact of comorbidities on 1-year mortality after initial therapy of acute myeloid leukemia (AML) and (2) a novel, risk-stratifying composite model incorporating comorbidities, age, and cytogenetic and molecular risks. Objective To accurately estimate risks of mortality by developing and validating a composite model that combines the most significant patient-specific and AML-specific features. Design, Setting, and Participants This is a retrospective cohort study. A series of comorbidities, including those already incorporated into the hematopoietic cell transplantation–comorbidity index (HCT-CI), were evaluated. Patients were randomly divided into a training set (n = 733) and a validation set (n = 367). In the training set, covariates associated with 1-year overall mortality at a significance level of P < .10 constructed a multivariate Cox proportional hazards model in which the impact of each covariate was adjusted for that of all others. Then, the adjusted hazard ratios were used as weights. Performances of models were compared using C statistics for continuous outcomes and area under the curve (AUC) for binary outcomes. Exposures Initial therapy for AML. Main Outcomes and Measures Death within 1 year after initial therapy for AML. Results A total of 1100 patients, ages 20 to 89 years, were treated for AML between January 1, 2008, and December 31, 2012, at 5 academic institutions specialized in treating AML; 605 (55%) were male, and 495 (45%) were female. In the validation set, the original HCT-CI had better C statistic and AUC estimates compared with the AML comorbidity index for prediction of 1-year mortality. Augmenting the original HCT-CI with 3 independently significant comorbidities, hypoalbuminemia, thrombocytopenia, and high lactate dehydrogenase level, yielded a better C statistic of 0.66 and AUC of 0.69 for 1-year mortality. A composite model comprising augmented HCT-CI, age, and cytogenetic/molecular risks had even better predictive estimates of 0.72 and 0.76, respectively. Conclusions and Relevance In this cohort study, comorbidities influenced 1-year survival of patients with AML, and comorbidities are best captured by an augmented HCT-CI. The augmented HCT-CI, age, and cytogenetic/molecular risks could be combined into an AML composite model that could guide treatment decision-making and trial design in AML. Studying physical, cognitive, and social health might further clarify the prognostic role of aging. Targeting comorbidities with interventions alongside specific AML therapy might improve survival.

Allogeneic Hematopoietic Cell Transplantation for Adult Chronic Myelomonocytic Leukemia

Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for patients with chronic myelomonocytic leukemia (CMML); however, few data exist regarding prognostic factors and transplantation outcomes. We performed this retrospective study to identify prognostic factors for post-transplantation outcomes. The CMML-specific prognostic scoring system (CPSS) has been validated in subjects receiving nontransplantation therapy and was included in our study. From 2001 to 2012, 209 adult subjects who received HCT for CMML were reported to the Center for International Blood and Marrow Transplant Research. The median age at transplantation was 57 years (range, 23 to 74). Median follow-up was 51 months (range, 3 to 122). On multivariate analyses, CPSS scores, Karnofsky performance status (KPS), and graft source were significant predictors of survival (P = .004, P = .01, P = .01, respectively). Higher CPSS scores were not associated with disease-free survival, relapse, or transplantation-related mortality. In a restricted analysis of subjects with relapse after HCT, those with intermediate-2/high risk had a nearly 2-fold increased risk of death after relapse compared to those with low/intermediate-1 CPSS scores. Respective 1-year, 3-year, and 5-year survival rates for low/intermediate-1 risk subjects were 61% (95% confidence interval [CI], 52% to 72%), 48% (95% CI, 37% to 59%), and 44% (95% CI, 33% to 55%), and for intermediate-2/high risk subjects were 38% (95% CI, 28% to 49%), 32% (95% CI, 21% to 42%), and 19% (95% CI, 8% to 29%). We conclude that higher CPSS score at time of transplantation, lower KPS, and a bone marrow graft are associated with inferior survival after HCT. Further investigation of CMML disease-related biology may provide insights into other risk factors predictive of post-transplantation outcomes.

Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: A randomized clinical trial

Importance Myelofibrosis is a hematologic malignancy characterized by splenomegaly and debilitating symptoms. Thrombocytopenia is a poor prognostic feature and limits use of Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) inhibitor ruxolitinib. Objective To compare the efficacy and safety of JAK2 inhibitor pacritinib with that of best available therapy (BAT), including ruxolitinib, in patients with myelofibrosis and thrombocytopenia. Design, Setting, and Participants For this phase 3 randomized international multicenter study—the PERSIST-2 study—of pacritinib vs BAT, 311 patients with myelofibrosis and platelet count 100 × 109/L or less were recruited for analysis. Crossover from BAT was allowed after week 24 or for progression of splenomegaly. Interventions Patients were randomized 1:1:1 to pacritinib 400 mg once daily, pacritinib 200 mg twice daily, or BAT. Main Outcomes and Measures Coprimary end points were rates of patients achieving 35% or more spleen volume reduction (SVR) and 50% or more reduction in total symptom score (TSS) at week 24. Efficacy analyses were performed on the intention-to-treat efficacy population, comprising all patients with a randomization date allowing for week 24 data. Results Overall, 311 patients (mean [SD] age, 63.70 [9.08] years; 171 men [55%] and 140 women [45%]) were included in the study; 149 patients (48%) had prior ruxolitinib. The most common BAT was ruxolitinib (44 patients [45%]); 19 patients (19%) received watchful-waiting only. The intention-to-treat efficacy population included 75 patients randomized to pacritinib once daily; 74, pacritinib twice daily, and 72, BAT. Pacritinib (arms combined) was more effective than BAT for 35% or more SVR (27 patients [18%] vs 2 patients [3%]; P = .001) and had a nonsignificantly greater rate of 50% or more reduction in TSS (37 patients [25%] vs 10 patients [14%]; P = .08). Pacritinib twice daily led to significant improvements in both end points over BAT (≥35% SVR: 16 patients [22%] vs 2 patients [3%]; P = .001; ≥50% reduction in TSS: 24 patients [32%] vs 10 patients [14%]; P = .01). Clinical improvement in hemoglobin and reduction in transfusion burden were greatest with pacritinib twice daily. For pacritinib once daily, pacritinib twice daily, and BAT, the most common (>10%) grade 3 or 4 adverse events were thrombocytopenia (32 patients [31%], 34 patients [32%], 18 patients [18%]), and anemia (28 patients [27%], 23 patients [22%], 14 patients [14%]). In the pacritinib once daily, twice daily, and BAT arms, discontinuation owing to adverse events occurred in 15 patients (14%), 10 patients (9%), and 4 patients (4%). Conclusions and Relevance In patients with myelofibrosis and thrombocytopenia, including those with prior anti-JAK therapy, pacritinib twice daily was more effective than BAT, including ruxolitinib, for reducing splenomegaly and symptoms. Trial Registration clinicaltrials.gov Identifier: NCT02055781

The relationship between eligibility criteria and adverse events in randomized controlled trials of hematologic malignancies

To minimize adverse events (AEs) unrelated to drugs and maximize the likelihood of drug approvals, eligibility criteria for randomized controlled trials (RCTs) may be overly restrictive. The purpose of this study was to determine if RCTs in hematologic malignancies exclude patients irrespective of known toxicities or observed AEs. MEDLINE was searched from 1/2010 to 1/2015 for RCTs published in high-impact journals. Of 97 trials, 33% were conducted in leukemia, 28% in lymphoma, 34% in multiple myeloma and 5% in myelodysplastic syndromes or myelofibrosis. Expected toxicities at thresholds of ⩾10%, ⩾5% and <5% were not correlated with cardiac, hepatic or renal eligibility criteria (logistic regression). To explore this lack of correlation we tested the concordance of expected toxicities and eligibility criteria using a modified version of McNemar’s test: at each threshold, hepatic, renal and cardiac expected toxicities were significantly discordant with eligibility criteria. Hepatic and renal eligibility criteria were also not correlated with observed AEs, P=0.69 and P=0.77, respectively, but a significant correlation was detected between cardiac eligibility criteria and observed AEs, P=0.02. Thus, the analyzed RCTs excluding patients with organ dysfunction do not reflect expected toxicities, based on prescription drug labels/prior experience, or reported AEs on the trials.

Adding molecular data to prognostic models can improve predictive power in treated patients with myelodysplastic syndromes

Adding molecular data to prognostic models can improve predictive power in treated patients with myelodysplastic syndromes

Prognostic significance of pre-transplant quality of life in allogeneic hematopoietic cell transplantation recipients

Quality of life (QOL) is an important outcome for hematopoietic cell transplantation (HCT) recipients. Whether pre-HCT QOL adds prognostic information to patient and disease related risk factors has not been well described. We investigated the association of pre-HCT QOL with relapse, non-relapse mortality (NRM), and overall mortality after allogeneic HCT. From 2003 to 2012, the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale instrument was administered before transplantation to 409 first allogeneic HCT recipients. We examined the association of the three outcomes with (1) individual QOL domains, (2) trial outcome index (TOI) and (3) total score. In multivariable models with individual domains, functional well-being (hazard ratio (HR) 0.95, P=0.025) and additional concerns (HR 1.39, P=0.002) were associated with reduced risk of relapse, no domain was associated with NRM, and better physical well-being was associated with reduced risk of overall mortality (HR 0.97, P=0.04). TOI was not associated with relapse or NRM but was associated with reduced risk of overall mortality (HR 0.93, P=0.05). Total score was not associated with any of the three outcomes. HCT-comorbidity index score was prognostic for greater risk of relapse and mortality but not NRM. QOL assessments, particularly physical functioning and functional well-being, may provide independent prognostic information beyond standard clinical measures in allogeneic HCT recipients.