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Background : Older adults are under-represented in cancer clinical trials. However, it remains unclear which types of trials under-enroll aging patients. We aimed to identify associations between trial characteristics and disparate enrollment of older adults onto trials sponsored by the Alliance for Clinical Trials in Oncology (Alliance). Methods : Actual age ≥ 65 percentage and trial data were extracted from the Alliance closed study list. Each trial, based on its cancer type and years of enrollment, was assigned an expected age ≥ 65 percentage extracted from the Surveillance, Epidemiology, and End Results (SEER) US population-based database. Enrollment disparity difference (EDD), the difference between the expected age ≥ 65 percentage and the actual age ≥ 65 percentage, was calculated for each trial. Linear regression determined trial variables associated with larger EDDs and variables with an overall association p -value <0.20 were included in a multivariable fixed-effects linear model. Results : The median age of 66,708 patients across 237 trials was 60 years (range 18–102). The average actual age ≥ 65 percentage enrolled per trial was lower than each trial's expected age ≥ 65 percentage average (39% vs. 58%; EDD 19, 95% CI 17.1–21.3%, p < 0.0001). In multivariable analyses, non-genitourinary (GU) cancer types (p < 0.001), trimodality+ trials (estimate 8.78, 95%CI 2.21–15.34, p = 0.009), and phase 2 trials (estimate 4.43 95% CI -0.06-8.91; p = 0.05) were all associated with larger EDDs. Conclusions : Disparate enrollment of older adults is not equal across cancer trials. Future strategies to improve older adult inclusion should focus on trial types associated with the highest disparate enrollment. [ABSTRACT FROM AUTHOR]

Palbociclib is a widely used treatment for advanced breast cancer in older adults. However, the existing evidence regarding its safety and tolerability in this age group is inconsistent and limited to retrospective subgroup or pooled analyses. We conducted a prospective single-arm multicenter phase 2 study to evaluate the safety and tolerability of palbociclib in participants aged 70 years or older with advanced hormone receptor-positive breast cancer. Participants were given palbociclib in combination with their physician's choice of endocrine therapy (letrozole or fulvestrant). The primary endpoint was the incidence of grade 3+ adverse events (AEs) by six months. Secondary endpoints included AE-related dose delays, dose reductions, early discontinuations, and hospitalizations. Additionally, we compared these endpoints by age groups (70–74 and ≥ 75 years). Of the 90 participants (median age 74 years [70–87]) enrolled, 75.6% (95% confidence interval [CI], 65.4–84.0) had grade 3+ AEs by six months. The most frequent grade 3+ AEs were neutropenia (61%), fatigue (4%), and nausea (3%). Febrile neutropenia was uncommon (1.1%). Due to AEs, 36% had dose delays, 34% had dose reductions, 10% had early discontinuations, and 10% had hospitalizations. Compared to those aged 70–74 years, participants aged ≥75 years had higher rates of early discontinuations (5.9% vs 15.9%, a difference of 9.5% [95% CI 3.5%–22.5%]). Palbociclib has an overall favorable safety profile in adults aged ≥70 with advanced breast cancer. However, adults ≥75 years had a trend toward higher rates of AE-related early discontinuations compared to those 70–74 years. Further research is needed to evaluate tolerability and improve the delivery of palbociclib in older adults. ClinicalTrials.gov : NCT03633331 [ABSTRACT FROM AUTHOR]

Context: Preliminary trials report that Scrambler Therapy, a form of electroanalgesia, may improve discomfort from chemotherapy-induced peripheral neuropathy (CIPN).Objective: The objective of this phase II, randomized controlled trial was to evaluate the efficacy of Scrambler therapy vs. transcutaneous electrical nerve stimulation (TENS) in treating CIPN.Methods: Fifty patients were accrued for the first half of this two-part, crossover trial consisting of a 2-week treatment period with either Scrambler or TENS, followed by an 8-week observation period, and then crossover treatment. Twenty-two patients proceeded to the crossover phase. The primary means of assessment was patient-reported outcomes, including symptom severity scales and Global Impression of Change questionnaires. Symptoms were assessed daily during the treatment period and weekly during an 8-week observation period.Results: A 50% or greater reduction in primary symptom (pain or tingling) score on the last day of treatment was achieved by 6 of 10 Scrambler-treated patients (60%) and 3 of 12 TENS-treated patients (25%) after crossover (P = 0.11). By day 4 of treatment, the two arms diverged with respect to mean change in primary symptom score; this effect was largely carried through to the end of the two-week treatment period. Similarly, Scrambler therapy appeared better than TENS when assessed by Global Impression of Change for neuropathy, pain, and overall quality of life.Conclusions: Similar findings from the initial randomization and crossover phases of this study support further evaluation of the efficacy of Scrambler therapy in alleviating CIPN symptoms. Evaluation in a larger, randomized controlled trial with standardized treatment is warranted. [ABSTRACT FROM AUTHOR]

Optimal treatment for older adults with stage III non-small cell lung cancer (NSCLC) remains unclear. Here we hypothesized that sequential chemoradiation therapy (sCRT) is better tolerated than concurrent (cCRT) but confers acceptable efficacy. We evaluated these strategies in older adults utilizing Alliance for Clinical Trials in Oncology data. Pooled analyses from 6 first-line stage III NSCLC CRT trials (Cancer and Leukemia Group B 8433, 8831, 9130, 30106, 30407, 39801) were used to compare toxicity and survival outcomes with cCRT versus sCRT in patients age ≥ 65 years. Grade 3–5 adverse events (AEs), progression-free and overall survival (PFS; OS) are reported with adjustment for covariates. Four hundred older adults, of whom 106 (26.5%) had received sCRT and 294 (73.5%) had received cCRT, comprised the cohorts. Virtually all had an Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1 (99%). More grade 3–5 AEs were observed at any time-point with cCRT than sCRT (94.2% versus 86.8%; 95% confidence interval for difference in proportions, 1.3%, 15.5%) and this finding remained after adjusting for length of study treatment (P = 0.018). Comparable PFS and OS were observed with sCRT versus cCRT (median: 8.0 versus 9.2 months; median: 11.9 versus 13.4 months, respectively) even after adjustment for age, sex, ECOG PS, body mass index, pretreatment weight loss, stage, and cisplatin-based therapy (P = 0.604 and P = 0.906, respectively). These data show that sCRT was associated with less toxicity than cCRT with no associated statistically significant decrease in efficacy outcomes and that sCRT merits further study in this population. [ABSTRACT FROM AUTHOR]

Discrepancies between clinicians' assessment of chemotherapy-induced peripheral neuropathy (CIPN) and patient-reported outcomes (PRO) have been described, though the underlying reasons are unknown. Our objective was to identify potential patient-specific factors associated with under-describing of CIPN to clinicians in women with non-metastatic breast cancer treated with paclitaxel. Patients enrolled in an observational study (n = 60) completed weekly CIPN PRO using the EORTC CIPN20. Clinician-documented CIPN using the NCI CTCAE were abstracted from the electronic medical record and paired with CIPN20 data at weeks 7 and 10. Patients were classified as under-describers if their CIPN20 was above the 80th percentile of the CIPN20 distribution for that CTCAE grade from an independent clinical trial (N08CA). Demographics, Assessment of Survivor Concerns (ASC), Trust in Oncologist Scale (TiOS), and health literacy assessment were collected post-treatment via survey. Repeated measures cumulative logistic regression models were used to identify factors associated with under-describing CIPN. Forty-two women completed the survey (response rate 70%). Three and 9 patients were categorized as under-describers at weeks 7 and 10, respectively. Women who were not working (OR = 9.00, 95%CI 1.06–76.15), had lower income (OR = 7.04, 95%CI 1.5–32.99), and displayed higher trust in their oncologist's competence (OR = 1.29, 95%CI 1.03–1.62 for a 0.1-unit increase in score) were more likely to under-describe CIPN symptoms. This preliminary study identified non-working status, low income and trust in oncologist's competence as potential factors influencing under-description of CIPN to the clinical team. Further work is needed to clarify these relationships and test additional factors. • This pilot study examined factors associated with under-describing of neuropathy. • Patient-reported and clinician-documented neuropathy severity were compared. • Non-working status and low income were associated with neuropathy under-describing. • Trust in oncologist's competence was associated with neuropathy under-describing. • Recording patient-clinician interactions would confirm under-describing behavior. [ABSTRACT FROM AUTHOR]

To demonstrate feasibility of performing geriatric assessment (GA) in the National Clinical Trials Network (NCTN) and to explore the utility of GA to characterize treatment tolerance. We conducted a multisite companion study (CALGB 361006) to CALGB 11001, a phase 2 trial of adults ≥60 years old with newly diagnosed FLT3- mutated AML, testing the efficacy of adding sorafenib to intensive chemotherapy. On 361006, a GA was administered prior to induction and prior to post-remission therapy. The GA is divided into items requiring administration by a health care professional (HCP) and patient self-administered questionnaires. Feasibility outcomes were recruitment rate, time to GA completion, difficulty with GA administration, percent of patients requiring assistance, and satisfaction. Change in GA measures pre- and post-induction were compared using Wilcoxon signed rank test and McNemar's tests. The recruitment rate was 80% (N = 43, median age 68 years). Median completion time of the GA was 30 min; (10 and 21 min for HCP and patients, respectively). HCP reported no difficulty completing assessments (100%). Most patients completed questionnaires without assistance (77%), and were satisfied with the length (89%). Self-reported physical function, mental health, social activity and nutritional parameters worsened after induction. GA is feasible to administer in the setting of intensive induction for older adults with AML in the NCTN and provides evidence of the impact of induction therapy on physical and emotional health. [ABSTRACT FROM AUTHOR]

This pilot trial aimed to assess if cooling hands and feet with crushed ice during receipt of paclitaxel helps prevent peripheral neuropathy. This prospective, randomized trial compared cryotherapy to standard care in patients initiating paclitaxel weekly x 12. For those on cryotherapy, hands and feet were cooled starting 15 min prior to and ending 15 min after each paclitaxel dose. EORTC QLQ-CIPN20 was completed at baseline, weekly x12, then monthly x6. Area under the curve (AUC) was calculated for subscale scores, adjusting for baseline, and compared between arms (Wilcoxon rank-sum test). Cross-study comparisons used data from 2 prior similarly-conducted neuropathy trials. Forty-six patients were accrued. Three withdrew and one was ineligible. Of the remaining 42 (21 cryotherapy, 21 control), 39 (19 cryotherapy, 20 control) were analyzable for AUC. Cryotherapy was well tolerated, but the AUC of the CIPN20 sensory scores over 12 weeks of paclitaxel was not found to differ between the study arms (mean difference 3.45, 95% CI -3.13 to 10.02, p = 0.26). However, the control arm of the current trial experienced less neuropathy than did the placebo arms of two previous similar trials. When our cryotherapy arm was compared to the combined control arms from all three trials, the cryotherapy arm had less neuropathy (Wilcoxon Rank-Sum p = 0.01). While there was no difference in CIPN20 scores identified between the 2 study arms in the current phase II trial, further investigation is needed given that the control arm experienced less neuropathy than was expected. • There was no less paclitaxel-induced neuropathy in cryotherapy recipients. • There was unexpectedly little neuropathy in those who did not get cryotherapy. • A large phase III trial would be needed to definitively assess cryotherapy. [ABSTRACT FROM AUTHOR]

Relapse remains the major cause of death in older patients transplanted for acute myeloid leukemia (AML) in first complete remission or for patients with advanced myelodysplastic syndrome (MDS) at any age. Conventional myeloablative conditioning followed by allogeneic blood or marrow transplantation is associated with significantly less relapse compared with reduced-intensity conditioning when performed in younger patients with AML or MDS, but the toxicity of this approach in older patients is prohibitive. We hypothesized that pharmacokinetic targeting to optimize busulfan (BU) exposure, combined with the administration of azacitidine (AZA) post-transplant would mitigate the risk of relapse while reducing nonrelapse mortality and ultimately improve progression-free survival (PFS). On this phase II multicenter study, 63 patients (40 unrelated donors and 23 matched related donors) received a uniform conditioning regimen consisting of fludarabine i.v. (days –7 to –3), BU targeted to a daily area under the curve (AUC) of 4000 μM/min (days –6 to –3) after the administration of a 25-mg/m2 i.v. test dose on 1 day between days –14 to –9, and antithymocyte globulin (days –6, –5, and –4 (2 doses for matched related donors and 3 for matched unrelated donors only). Beginning on days +42 to +90, all patients were planned to receive up to 6 monthly cycles of AZA at 32 mg/m2 subcutaneously for 5 days. The median age was 62 years (range, 44 to 74); 13 had AML and 50 had MDS; 87% of patients were within 20% of the target AUC based on a validation sample. Forty-one patients (65%) started AZA at a median of 61 days (range, 43 to 91) post-transplant, and 17 patients (41%) completed all 6 cycles of AZA. The cumulative incidence of nonrelapse mortality at 2 years was 33.4% (95% confidence interval [CI], 22%-45%). The cumulative incidence of relapse was 25% (95% CI, 15%-37%) at 2 years. With a median follow-up of 58.9 months, the estimated PFS probability at 2 years and 5 years after transplantation was 41.2% (80% CI, 33.9%-49.9%) and 26.9% (80% CI, 20.4%-35.5%), respectively, for the entire group with a median PFS of 15.8 months (95% CI, 6.7 to 28.3). The probability of overall survival at 2 and 5 years was 45.7% (95% CI, 34.9%-59.9%) and 31.2% (95% CI, 21.3% to 45.8%), respectively, for the entire group with a median overall survival of 19.2 months (95% CI, 8.7 to 37.5). In summary, we demonstrated the feasibility of a novel reduced-intensity conditioning regimen with test dose BU targeted to an AUC of 4000 μM/min. The feasibility of AZA in this setting appears to be limited if applied to an unselected population of older hematopoietic stem cell transplantation recipients. (ClinicalTrials.gov Identifier: NCT01168219.) [ABSTRACT FROM AUTHOR]

Attribution of adverse events (AEs) is critical to oncology drug development and the regulatory process. However, processes for determining the causality of AEs are often sub-optimal, unreliable, and inefficient. Thus, we conducted a toxicity-attribution workshop in Silver Springs MD to develop guidance for improving attribution of AEs in oncology clinical trials. Attribution stakeholder experts from regulatory agencies, sponsors and contract research organizations, clinical trial principal investigators, pre-clinical translational scientists, and research staff involved in capturing attribution information participated. We also included patients treated in oncology clinical trials and academic researchers with expertise in attribution. We identified numerous challenges with AE attribution, including the non-informative nature of and burdens associated with the 5-tier system of attribution, increased complexity of trial logistics, costs and time associated with AE attribution data collection, lack of training in attribution for early-career investigators, insufficient baseline assessments, and lack of consistency in the reporting of treatment-related and treatment-emergent AEs in publications and clinical scientific reports. We developed recommendations to improve attribution: we propose transitioning from the present 5-tier system to a 2-3 tier system for attribution, more complete baseline information on patients' clinical status at trial entry, and mechanisms for more rapid sharing of AE information during trials. Oncology societies should develop recommendations and training in attribution of toxicities. We call for further harmonization and synchronization of recommendations regarding causality safety reporting between FDA, EMA and other regulatory agencies. Finally, we suggest that journals maintain or develop standardized requirements for reporting attribution in oncology clinical trials. [ABSTRACT FROM AUTHOR]

Objective This study sought to define the role of first-line platinum-based doublet chemotherapy in older patients with non-small cell lung cancer (NSCLC). Materials and Methods We analyzed three first-line NSCLC trials: CALGB 9730, CALGB 30203, and CALGB 30801, which tested carboplatin and paclitaxel; carboplatin and gemcitabine; and carboplatin with either pemetrexed or gemcitabine, respectively. Overall survival was the primary endpoint. Age-based comparisons with a cutpoint of 65 years were performed with Cox proportional hazards models with adjustments for sex, tumor histology, cancer stage, chemotherapy, and smoking history and after stratifying by performance score. Secondary endpoints were grade 3–5 adverse events, chemotherapy cycles completed, and whether toxicity prompted chemotherapy discontinuation. Results 730 patients were included; 337 (46%) were 65+ years of age. No statistically significant difference in survival was observed for older (≥65) versus younger patients (HR = 1.096; 95% CI = (0.94, 1.28); p  = 0.25). A trend emerged with increased odds of a grade 3–5 adverse event for patients ≥65 years versus <65 years (OR = 1.52; 95% CI = (0.99, 2.31); p  = 0.05). The proportion of completed chemotherapy cycles was marginally lower in older patients (difference = −5%; 95% CI = (−9, 0.2); p  = 0.06) for those ≥65 years versus <65 years, but no statistically significant difference occurred in the rate of chemotherapy discontinuation for toxicity (OR = 1.4; 95% CI = (0.85, 2.19); p  = 0.21) for patients ≥65 years versus <65 years. A cutpoint of 70 years yielded similar results. Conclusion These findings support carboplatin doublet-based chemotherapy in select older patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

Background and objectives Clustered competing risks data arise often in genetic studies, multicenter investigations, and matched-pairs studies. In the last two decades, major advances in competing risks theory had been made. Many new statistical methods need to be evaluated via simulation studies. Some mechanisms for simulating clustered competing risks data have been considered in the literature. However, most of them produce data where the strength of the dependence between individuals within a cluster is not clear. In this article, we aim to examine various techniques for generating bivariate competing risks data. Methods Theoretical framework for simulating dependent competing risks data using latent failure time approach, multistate models, and shared frailty models is described. The steps needed to implement each method are outlined. Properties of each technique are discussed and standard measures of association are provided in order to assess the degree of dependence in simulated paired competing risks data. Results and conclusions In addition to describing a variety of techniques to generate dependent competing risks data, the cross-hazard ratios from multiple scenarios for each method are computed. The cross-hazard ratios provide a means to compare the level of dependence of the generated data across methods. This acts as a guide for researchers to select an approach and the parameters needed to achieve the desired degree of dependence for their simulation studies. [ABSTRACT FROM AUTHOR]

Busulfan (Bu)-containing regimens are commonly used in myeloablative conditioning regimens before allogeneic hematopoietic cell transplantation (HCT). Yet, there is considerable variability on how Bu is administered related to frequency (4 times a day [Q6] or daily [Q24]) and combinations with other chemotherapeutic agents (cyclophosphamide [Cy] or fludarabine [Flu]). We performed a prospective cohort study of recipients of Bu-based conditioning according to contemporary practices to compare different approaches (BuCy Q6, n = 495; BuFlu Q24, n = 331; BuCy Q24, n = 96; BuFlu Q6, n = 91) in patients with myeloid malignancies between 2009 and 2011. BuFlu Q24 recipients were more likely to be older and tended to have worse performance status and a higher comorbid burden. The cumulative incidences of hepatic veno-occlusive disease ( P = .40), idiopathic pneumonia ( P = .50), and seizures ( P = .50) did not differ across groups. One-year HCT-related mortality ranged from 12% to 16% ( P = .80), 3-year relapse incidence ranged from 32% to 36% ( P = .80), and 3-year overall survival ranged from 51% to 58% ( P = .20) across groups. This study demonstrates that HCT conditioning regimens using i.v. Bu Q6 or Q24 alone or in combination with Cy or Flu have similar outcomes in the myeloablative setting for treatment of myeloid malignancies. [ABSTRACT FROM AUTHOR]

In this paper we propose a class of flexible weight functions for use in comparison of two cumulative incidence functions. The proposed weights allow the users to focus their comparison on an early or a late time period post treatment or to treat all time points with equal emphasis. These weight functions can be used to compare two cumulative incidence functions via their risk difference, their relative risk, or their odds ratio. The proposed method has been implemented in the R-CIFsmry package which is readily available for download and is easy to use as illustrated in the example. [ABSTRACT FROM AUTHOR]

The introduction of reduced-intensity conditioning (RIC) regimens made it possible to offer allogeneic hematopoietic cell transplantation (alloHCT) to older patients with myelodysplastic syndromes (MDS). However, the relative risks and benefits of alloHCT compared with novel nontransplant therapies continue to be the source of considerable uncertainty. We will perform a prospective biologic assignment trial to compare RIC alloHCT with nontransplant therapies based on donor availability. Primary outcome is 3-year overall survival. Secondary outcomes include leukemia-free survival, quality of life, and cost-effectiveness. Four hundred patients will be enrolled over roughly 3 years. Planned subgroup analyses will evaluate key biologic questions, such as the impact of age and response to hypomethylating agents on treatment effects. Findings from this study potentially may set a new standard of care for older MDS patients who are considered candidates for alloHCT. [ABSTRACT FROM AUTHOR]

Studies show that engaging patients in exercise and/or stress management techniques during hematopoietic cell transplantation (HCT) improves quality of life. The Blood and Marrow Transplant Clinical Trials Network tested the efficacy of training patients to engage in self-directed exercise and stress management during HCT. The study randomized 711 patients at 21 centers to receive 1 of 4 training interventions before HCT: a self-directed exercise program, a self-administered stress management program, both, or neither. Participants completed self-reported assessments at enrollment and up to 180 days after HCT. Randomization was stratified by center and transplant type. There were no differences in the primary endpoints of the Physical Component Summary and Mental Component Summary scales of the Medical Outcomes Study Short Form 36 at day +100 among the groups, based on an intention-to-treat analysis. There also were no differences in overall survival, days of hospitalization through day +100 post-HCT, or in other patient-reported outcomes, including treatment-related distress, sleep quality, pain, and nausea. Patients randomized to training in stress management reported more use of those techniques, but patients randomized to training in exercise did not report more physical activity. Although other studies have reported efficacy of more intensive interventions, brief training in an easy-to-disseminate format for either self-directed exercise or stress management was not effective in our trial. [ABSTRACT FROM AUTHOR]

Purpose: The objectives of this study were to evaluate the feasibility and efficacy of fractional CO2 laser therapy in gynecologic cancer survivors.Methods: This was a pilot, multi-institutional randomized sham-controlled trial of women with gynecologic cancers with dyspareunia and/or vaginal dryness. Participants were randomized to fractional CO2 laser treatment or sham laser treatment. The primary aim was to estimate the proportion of patients who had improvement in symptoms based on the Vaginal Assessment Scale (VAS). Secondary aims included changes in sexual function assessed using the Female Sexual Functioning Index (FSFI) and urinary symptoms assessed using the the Urinary Distress Inventory (UDI-6).Results: Eighteen women participated in the study, ten in the treatment arm and eight in the sham arm. The majority of participants had stage I (n = 11, 61.1 %) or II (n = 3, 16.7 %) endometrial cancer with adenocarcinoma histology (n = 9, 50 %). In total, 15 (83.3 %) of the participants completed all treatments and follow-up visit. There was no difference in the change in the median VAS score from baseline to follow-up. However, there was an improvement in change in the median total FSFI score with treatment compared with sham (Δ 6.5 vs -0.3, p = 0.02). The change in the median UDI-6 score was lower in the treatment arm (Δ -14.6 vs -2.1, p = 0.17), but this was not statistically significant. There were no reported serious adverse events.Conclusions: Fractional CO2 laser therapy is feasible in gynecologic cancer survivors, with preliminary evidence of safety. In addition, there was preliminary evidence of improvement in sexual function compared with sham treatment. Clinicaltrial.gov Identifier: NCT03372720 (OSU-17261; NCI-2017-02051). [ABSTRACT FROM AUTHOR]

Survival for children with relapsed T cell acute lymphoblastic leukemia (T-ALL) is poor when treated with chemotherapy alone, and outcomes after allogeneic hematopoietic cell transplantation (HCT) is not well described. Two hundred twenty-nine children with T-ALL in second complete remission (CR2) received an HCT after myeloablative conditioning between 2000 and 2011 and were reported to the Center for International Blood and Marrow Transplant Research. Median age was 10 years (range, 2 to 18). Donor source was umbilical cord blood (26%), matched sibling bone marrow (38%), or unrelated bone marrow/peripheral blood (36%). Acute (grades II to IV) and chronic graft-versus-host disease occurred in, respectively, 35% (95% confidence interval [CI], 27% to 45%) and 26% (95% CI, 20% to 33%) of patients. Transplant-related mortality at day 100 and 3-year relapse rates were 13% (95% CI, 9% to 18%) and 30% (95% CI, 24% to 37%), respectively. Three-year overall survival and disease-free survival rates were 48% (95% CI, 41% to 55%) and 46% (95% CI, 39% to 52%), respectively. In multivariate analysis, patients with bone marrow relapse, with or without concurrent extramedullary relapse before HCT, were most likely to relapse (hazard ratio, 3.94; P = .005) as compared with isolated extramedullary disease. In conclusion, HCT for pediatric T-ALL in CR2 demonstrates reasonable and durable outcomes, and consideration for HCT is warranted. [ABSTRACT FROM AUTHOR]

A second allogeneic hematopoietic cell transplantation (HCT) is the sole salvage option for individuals who develop graft failure after their first HCT. Data on outcomes after second HCT in patients with Fanconi anemia (FA) are scarce. Here we report outcomes after second allogeneic HCT for FA (n = 81). The indication for second HCT was graft failure after the first HCT. Transplantations were performed between 1990 and 2012. The timing of the second HCT predicted subsequent graft failure and survival. Graft failure was high when the second HCT was performed less than 3 months from the first. The 3-month probability of graft failure was 69% when the interval between the first HCT and second HCT was less than 3 months, compared with 23% when the interval was longer ( P < .001). Consequently, the 1-year survival rate was substantially lower when the interval between the first and second HCTs was less than 3 months compared with longer (23% vs 58%; P = .001). The corresponding 5-year probability of survival was 16% and 45%, respectively ( P = .006). Taken together, these data suggest that fewer than one-half of patients with FA undergoing a second HCT for graft failure are long-term survivors. There is an urgent need to develop strategies to reduce the rate of graft failure after first HCT. [ABSTRACT FROM AUTHOR]

Reduced-intensity conditioning/nonmyeloablative conditioning regimens are increasingly used in allogeneic hematopoietic cell transplantation (HCT). Reports have shown CD34+ dose to be important for transplantation outcome using myeloablative conditioning. The role of CD34+ dose of peripheral blood progenitor cells (PBPC) has not been previously analyzed in a large population undergoing reduced-intensity conditioning/nonmyeloablative HCT. We studied 1054 patients, ages 45 to 75 years, with acute myeloid leukemia or myelodysplastic syndrome who underwent transplantation between 2002 and 2011. Results of multivariate analysis showed that PBPC from HLA-matched siblings containing <4 × 106 CD34+/kg was associated with higher nonrelapse mortality (hazard ratio [HR], 2.03; P = .001), overall mortality (HR, 1.48; P = .008), and lower neutrophil (odds ratio [OR], .76; P = .03) and platelet (OR, .76; P = .03) recovery. PBPC from unrelated donors with CD34+ dose < 6 × 106 CD34+/kg was also associated with higher nonrelapse (HR, 1.38; P = .02) and overall mortality (HR, 1.20; P = .05). In contrast to reports after myeloablative HCT, CD34+ dose did not affect relapse or graft-versus-host disease with either donor type. An upper cell dose limit was not associated with adverse outcomes. These data suggest that PBPC CD34+ doses >4 × 106 CD34+/kg and >6 × 106 CD34+/kg are optimal for HLA-matched sibling and unrelated donor HCT, respectively. [ABSTRACT FROM AUTHOR]

Abstract: To identify favored choice of transplantation in patients with acute promyelocytic leukemia (APL) in second complete remission, we studied 294 patients with APL in second complete remission (CR2) receiving allogeneic (n = 232) or autologous (n = 62) hematopoietic cell transplantation (HCT) reported to the Center for International Blood and Marrow Transplantation Research (CIBMTR) from 1995 to 2006, including 155 with pre-HCT PML/RAR∝ status (49% of allogeneic and 66% of autologous). Patient characteristics and transplantation characteristics, including treatment-related mortality, overall survival (OS), and disease-free survival, were collected and analyzed for both univariate and multivariate outcomes. With median follow-up of 115 (allogeneic) and 72 months (autologous), 5-year disease-free survival (DFS) favored autologous with 63% (49% to 75%), compared with allogeneic at 50% (44% to 57%) (P = .10). OS was 75% (63% to 85%) versus 54% (48% to 61%) (P = .002), for autologous and allogeneic transplantation, respectively. Multivariate analysis showed significantly worse DFS after allogeneic HCT (hazard ratio [HR], 1.88; 95% confidence interval [CI], 1.16 to 3.06; P = .011) and age > 40 years (HR, 2.30; 95% CI, 1.44 to 3.67; P = .0005). OS was significantly worse after allogeneic HCT (HR, 2.66; 95% CI, 1.52 to 4.65; P = .0006); age > 40 (HR, 3.29; 95% CI, 1.95 to 5.54; P < .001), and first complete remission < 12 months (HR, 1.56; 95% CI, 1.07 to 2.26; P = .021). Positive pre-HCT PML-RAR∝ status in 17 of 114 allogeneic and 6 of 41 receiving autologous transplantation did not influence relapse, treatment failure, or survival in either group. The survival advantage for autografting was attributable to increased treatment-related mortality (TRM) in the allogeneic group of 30% compared to 2% in the autologous group, in addition to the added mortality associated with GVHD. We conclude that autologous HCT yields superior OS for APL in CR2. Long-term DFS in autologous recipients, even with minimal residual disease–positive grafts, remains an important subject for further study. [Copyright &y& Elsevier]

A recently developed two-step method provides an alternative to single-step methods in the analysis of cluster randomized trials (CRTs). This method, called the symbolic two-step method because it was developed within the symbolic data analysis framework, adjusts for patient-level factors when estimating and testing effects of center-level factors on both the average center-level outcome and its variation. Estimation/testing of center-level effects on center-outcome variation is the innovation of the method; identifying such effects may lead to practice changes to reduce such variation. We evaluated the performance of our method in challenging settings and recommend when this method is preferred over single-step methods. The method was compared to single-step multilevel linear models – one that permitted heterogeneous within-center variances and one that did not – via simulation. We applied each method to a CRT. After adjusting for patient-level factors in the setting of varying center sizes without any correlation between patient and center-level factors, the single-step models led to increased statistical power for center-level factors. In the presence of correlation, our method was more powerful. Applying these methods to model the center-mean outcome from the CRT led to similar conclusions; however, because the two-step method also models the within-center variability of that outcome we identified a factor predicting the within-center variance that was not possible with the single-step methods. We recommend single-step methods under the restrictive assumptions of no correlation between patient- and center-level factors and no center-level factor affecting center-outcome variation. Otherwise, we recommend the symbolic two-step method. • The symbolic two-step method provides an alternative to single-step multilevel linear models in design and analysis of CRTs. • The method adjusts for patient(pt)-level factors when testing center-level factors on center-mean outcome and its variation. • With varying center sizes without correlation between pt- and center-level factors, single-step models were more powerful. • In the presence of correlation between pt- and center-level factors, the two-step method was more powerful. [ABSTRACT FROM AUTHOR]

This multicenter study evaluated a treosulfan-based regimen in children and young adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplant (HCT). Forty patients with median age 11 years (range, 1 to 19) underwent allogeneic HCT for AML in first (n = 18), second (n = 11), and third or greater remission (n = 3) or MDS (n = 8) using bone marrow (n = 25), peripheral blood stem cells (n = 5), or cord blood (n = 9). The regimen consisted of body surface area (BSA)-based treosulfan 10 g/m 2 /day (BSA ≤ .5 m 2 ), 12 g/m 2 /day (BSA > .5 to 1.0 m 2 ), or 14 g/m 2 /day (BSA > 1.0 m 2 ) on days −6 to −4; fludarabine 30 mg/m 2 /day on days −6 to −2; and a single fraction of 200 cGy total body irradiation on day −1. Graft-versus-host disease (GVHD) prophylaxis included tacrolimus and methotrexate for marrow and peripheral blood stem cell and cyclosporine/mycophenolate mofetil for cord blood. One-year overall survival, disease-free survival, and nonrelapse mortality were 80%, 73%, and 3%, respectively. One-year relapse was 38% for AML and 13% for MDS. No serious organ toxicities were observed. All 37 assessable patients engrafted. Cumulative incidences of grades II to IV acute GVHD and chronic GVHD were 22% and 40%, respectively. BSA-based treosulfan dosing resulted in predictable area under the curve and maximum concentration, which is required for dosing without measuring individual pharmacokinetic parameters. Observed differences in pharmacokinetics did not impact disease control or regimen toxicity. This BSA-based treosulfan regimen resulted in excellent engraftment and disease-free survival and minimal toxicity and transplant-related mortality (3%) in children and young adults with AML and MDS. [ABSTRACT FROM AUTHOR]

Blood and Marrow Transplant Clinical Trials Network (BMT CTN) protocol 0902 evaluated whether exercise and stress management training before hematopoietic cell transplantation (HCT) improved physical and mental functioning after HCT. Neither overall survival nor other patient-reported transplantation outcomes were improved by the training intervention. In some animal studies of HCT, moderate-intensity exercise for 8 weeks before HCT has been associated with positive effects on hematopoietic progenitors, resulting in improved donor engraftment and improved survival. Accordingly, we performed a secondary analysis of data from BMT CTN 0902 to determine whether exercise engagement before HCT was associated with engraftment and survival. We found no significant associations between self-reported pre-HCT exercise levels and engraftment or survival. There was also no effect of pretransplantation exercise on either neutrophil or platelet engraftment. These findings do not support the observations in animal models but are limited by several shortcomings that do not refute the hypothesis that exercise before HCT may be beneficial. [ABSTRACT FROM AUTHOR]

This secondary analysis of a large, multicenter Blood and Marrow Transplant Clinical Trials Network randomized trial assessed whether patient-reported outcomes (PROs) and socioeconomic status (SES) before hematopoietic stem cell transplantation (HCT) are associated with each other and predictive of clinical outcomes, including time to hematopoietic recovery, acute graft-versus-host disease, hospitalization days, and overall survival (OS) among 646 allogeneic and autologous HCT recipients. Pretransplantation Cancer and Treatment Distress (CTXD), Pittsburgh Sleep Quality Index (PSQI), and mental and physical component scores of the Short-Form 36 were correlated with each other and with SES variables. PROs and SES variables were further evaluated as predictors of clinical outcomes, with the PSQI and CTXD evaluated as OS predictors ( P  < .01 considered significant given multiple testing). Lower attained education was associated with increased distress ( P  = .002), lower income was related to worse physical functioning ( P  = .005) and increased distress ( P  = .008), lack of employment before transplantation was associated with worse physical functioning ( P  < .01), and unmarried status was associated with worse sleep ( P  = .003). In this large heterogeneous cohort of HCT recipients, although PROs and SES variables were correlated at baseline, they were not associated with any clinical outcomes. Future research should focus on HCT recipients at greater psychosocial disadvantage. [ABSTRACT FROM AUTHOR]

Conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) identify high-risk multiple myeloma (HRM) populations characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM populations after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma identified by FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (<45 chromosomes excluding -Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 HRM patients (17.5%), induction with bortezomib and immunomodulatory agents (imids) was higher compared with non-HRM (56% versus 43%, P  < .001) with similar pretransplant complete response (CR) rates (14% versus 16%, P .1). At day 100 post-transplant, at least a very good partial response was 59% in HRM and 61% in non-HRM ( P  = .6). More HRM patients received post-transplant therapy with bortezomib and imids (26% versus 12%, P  = .004). Three-year post-transplant progression-free (PFS) and overall survival (OS) rates in HRM versus non-HRM were 37% versus 49% ( P  < .001) and 72% versus 85% ( P  < .001), respectively. At 3 years, PFS for HRM patients with and without post-transplant therapy was 46% (95% confidence interval [CI], 33 to 59) versus 14% (95% CI, 4 to 29) and in non-HRM patients with and without post-transplant therapy 55% (95% CI, 49 to 62) versus 39% (95% CI, 32 to 47); rates of OS for HRM patients with and without post-transplant therapy were 81% (95% CI, 70 to 90) versus 48% (95% CI, 30 to 65) compared with 88% (95% CI, 84 to 92) and 79% (95% CI, 73 to 85) in non-HRM patients with and without post-transplant therapy, respectively. Among patients receiving post-transplant therapy, there was no difference in OS between HRM and non-HRM ( P = .08). In addition to HRM, higher stage, less than a CR pretransplant, lack of post-transplant therapy, and African American race were associated with worse OS. In conclusion, we show HRM patients achieve similar day 100 post-transplant responses compared with non-HRM patients, but these responses are not sustained. Post-transplant therapy appeared to improve the poor outcomes of HRM. [ABSTRACT FROM AUTHOR]

Busulfan, cyclophosphamide, and etoposide (BuCyE) is a commonly used conditioning regimen for autologous stem cell transplantation (ASCT). This multicenter, phase II study examined the safety and efficacy of BuCyE with individually adjusted busulfan based on preconditioning pharmacokinetics. The study initially enrolled Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients ages 18 to 80 years but was amended due to high early treatment-related mortality (TRM) in patients > 65 years. BuCyE outcomes were compared with contemporaneous recipients of carmustine, etoposide, cytarabine, and melphalan (BEAM) from the Center for International Blood and Marrow Transplant Research. Two hundred seven subjects with HL (n = 66) or NHL (n = 141) were enrolled from 32 centers in North America, and 203 underwent ASCT. Day 100 TRM for all subjects (n = 203), patients > 65 years (n = 17), and patients ≤ 65 years (n = 186) were 4.5%, 23.5%, and 2.7%, respectively. The estimated rates of 2-year progression-free survival (PFS) were 33% for HL and 58%, 77%, and 43% for diffuse large B cell lymphoma (DLBCL; n = 63), mantle cell lymphoma (MCL; n = 29), and follicular lymphoma (FL; n = 23), respectively. The estimated rates of 2-year overall survival (OS) were 76% for HL and 65%, 89%, and 89% for DLBCL, MCL, and FL, respectively. In the matched analysis rates of 2-year TRM were 3.3% for BuCyE and 3.9% for BEAM, and there were no differences in outcomes for NHL. Patients with HL had lower rates of 2-year PFS with BuCyE, 33% (95% CI, 21% to 46%), than with BEAM, 59% (95% CI, 52% to 66%), with no differences in TRM or OS. BuCyE provided adequate disease control and safety in B cell NHL patients ≤ 65 years but produced worse PFS in HL patients when compared with BEAM. [ABSTRACT FROM AUTHOR]

Abstract: Autologous hematopoietic cell transplantation (AHCT) as initial therapy of patients with multiple myeloma (MM) improves survival. However, data to support this approach for relapsed/progressive disease after initial AHCT (AHCT1) are limited. Using Center for International Blood and Marrow Transplant Research data, we report the outcomes of 187 patients who underwent a second AHCT (AHCT2) for the treatment of relapsed/progressive MM. Planned tandem AHCT was excluded. Median age at AHCT2 was 59 years (range, 28 to 72), and median patient follow-up was 47 months (range, 3 to 97). Nonrelapse mortality after AHCT2 was 2% at 1 year and 4% at 3 years. Median interval from AHCT1 to relapse/progression was 18 months, and median interval between transplantations was 32 months. After AHCT2, the incidence of relapse/progression at 1 and 3 years was 51% and 82%, respectively. At 3 years after AHCT2, progression-free survival was 13%, and overall survival was 46%. In multivariate analyses, those relapsing ≥36 months after AHCT1 had superior progression-free (P = .045) and overall survival (P = .019). Patients who underwent AHCT2 after 2004 had superior survival (P = .026). AHCT2 is safe and feasible for disease progression after AHCT1. In this retrospective study, individuals relapsing ≥36 months from AHCT1 derived greater benefit from AHCT2 compared with those with a shorter disease-free interval. Storage of an adequate graft before AHCT1 will ensure that the option of a second autologous transplantation is retained for patients with relapsed/progressive MM. [Copyright &y& Elsevier]

We analyzed the outcomes of 248 (61% male) adult recipients of HLA-matched unrelated and HLA-mismatched related donor hematopoietic cell transplantation (HCT) for non-Hodgkin lymphoma (NHL) after reduced or lower intensity conditioning (RIC), reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1997 to 2004. Median age was 52 (range: 18-72 years); 31% had a Karnofsky performance score <90. Follicular NHL (43%) was the major histology. Incidence of grades II-IV acute graft-versus-host disease (aGVHD) was 43% at 100 days; and chronic GVHD (cGVHD) was 44% at 3 years. Treatment-related mortality (TRM) at 100 days was 24%. Three-year overall survival (OS) and progression-free survival (PFS) were 41% and 32%, respectively. In multivariate analysis, use of antithymocyte globulin (ATG) and HLA mismatch were associated with increased TRM. High-grade histology, ATG use, and chemotherapy resistance were associated with lower PFS. Older age, shorter interval from diagnosis to HCT, non–total body irridiation (TBI) conditioning regimens, ex vivo T cell depletion, and HLA-mismatched unrelated donors were associated with mortality. GVHD did not influence relapse or PFS. Older age, aggressive histology, and chemotherapy resistance correlated with poorer survival. For selected patients with NHL, lack of an available sibling donor should not be a barrier to allogeneic HCT. [ABSTRACT FROM AUTHOR]

We report the results of a phenotypic and functional analysis of immune reconstitution in HIV(+) patients treated with allogeneic hematopoietic stem cell transplant (allo-HSCT), in comparison with HIV(+) autologous transplant (auto-HSCT) recipients, HIV(-) auto-HSCT recipients and healthy controls (HCs). Blood samples were collected at days 56, 180 and 365 post-transplant from HIV(+) allo-ASCT recipients (n=17, BMT-CTN-0903/AMC-080 trial), HIV(+) auto-SCT recipients (n=36, BMT-CTN-0803/AMC-071 trial) and HIV(-) auto-SCT recipients (n=30, NCT00569309/OSU-07044 trial), and at 1 time point from 71 HCs. Five-color flow cytometry was performed on whole blood. Principal component analysis (PCA) examined global differences across 18 immune cell subsets between all subject cohorts. Wilcoxon rank-sum tests compared median absolute and proportionate cell counts. Feature importance score analysis (FIS) identified contributions of 100 immune cell populations to differences between HIV(+) cohorts and HCs. Functional responsiveness of HIV(+) allo-HSCT recipients' T cells to stimulation with CD3- and CD28-directed antibodies, NK cells to stimulation with IL-12+IL-18 and monocytes to stimulation with lipopolysaccharide (LPS) was assessed by mass cytometry on peripheral blood mononuclear cells (n=2) and compared to HCs (n=2). PCA showed that immunomes of HIV(+) allo-HSCT recipients and HIV(+) auto-HSCT recipients clustered together at all time points. HIV(-) auto-SCT recipients and HCs clustered together and away from the HIV(+) cohorts. FIS identified 13 cell subsets that defined the difference between HIV(+) allo-HSCT recipients (all visits) and HCs and 11 immune cell subsets that defined the difference between HIV(+) auto-HSCT recipients (all visits) and HCs; in each comparison, activated CD3+/HLA-DR+ T cells had the greatest impact on the difference between composite HIV(+) and HC immunomes. At 1 year, both HIV(+) transplant recipient cohorts had higher absolute numbers of activated T cells, effector T cells and CD8+ T cells than HCs and lower numbers of CD4+ T cells, naïve T cells, and activated NK cells compared to HCs (p<0.031). Mass cytometry analysis showed that IFNʏ production by CD8+ T cells was increased and there were expanded populations of CD4+/T-bet+ and CD8+/T-bet+ T cells co-expressing cytotoxic molecules granzyme B and perforin persisting in HIV(+) allo-HSCT recipients, but not in HCs at 1 year. NK cell function was preserved; monocytes showed enhanced production of TNFα upon stimulation with LPS in HIV(+) allo-HSCT recipients compared to HCs at 1 year post-HSCT. Chronic HIV infection confers pro-inflammatory immune characteristics on phenotypic and functional profiling of the cellular immunome of stem cell transplant recipients, irrespective of allogeneic or autologous stem cell donor source. [ABSTRACT FROM AUTHOR]