CPX-351 Pharmacokinetics and Safety in Adults with Hematologic Malignancies and Renal Function Impairment: Phase 1 Trial

This open-label phase 1 study (clinicaltrials.gov, NCT03555955) assessed CPX-351 pharmacokinetics (PK) and safety in patients with hematologic malignancies with normal or impaired renal function. Patients were enrolled into three cohorts based on their creatinine clearance (CrCl): ≥90 mL/min (Cohort 1, normal renal function, n = 7), 30 to n = 8), or n = 6). Patients received intravenous CPX-351 for initial induction; blood and urine samples were collected for PK analysis. The primary objective was to assess the PK parameters for cytarabine, daunorubicin, and their respective metabolites, arabinosyluracil (Ara-U) and daunorubicinol. Renal impairment did not significantly impact the cytarabine, daunorubicin, or daunorubicinol exposure, but it caused a slight increase in the Ara-U exposure. The CPX-351 side effect profile was similar in patients with impaired renal function compared to those with normal renal function. All the patients reported ≥1 treatment-emergent adverse event (TEAE), most commonly febrile neutropenia and nausea (57% each) and hyperglycemia (43%); no patients discontinued treatment due to TEAEs. These data suggest that CPX-351 dose adjustment is not required for patients with hematologic malignancies with moderate or severe renal impairment

AML-145: Multicenter 11-Year Experience of Outcomes After Intensive Versus Less-Intensive Therapy for Patients with Acute Myeloid Leukemia: Focus on Older and Medically Infirm Patients

Acute myeloid leukemia (AML) has a median survival of 6-12 months, with no major improvement over the last two decades. AML is a disease of elderly patients. Less-intensive induction therapies increasingly used in older patients, presuming they are more effective/better tolerated than intensive therapies. Compare survival, quality of life (QOL), and function between less-intensive versus intensive therapies. We studied a retrospective cohort (n=1,295) treated from 2008-2012 at six institutions, followed by a prospective observational cohort (n=692) treated from 2013-2017 at thirteen institutions. Both cohorts were ages 18-80 years. Survival estimates were obtained with the Kaplan-Meier method. We used an AML-composite model (AML-CM) assigning higher scores to increasing age, comorbidity burden, and adverse cytogenetics. Less- and more-intensive induction therapies were compared within distinct prognostic groups defined by AML-CM. We used a competing-risk Cox regression model to test the impact of allogeneic transplant (HCT). Prospective QOL and function were compared between less-intensive and intensive groups across time using logistic regression. 20% and 21% of patients received less-intensive therapies in the retrospective and prospective cohorts, respectively. In both cohorts, less-intensive therapies were used more often with increasing age, comorbidity burden, and cytogenetic/molecular risks, and also with Karnofsky Performance Status (KPS) ≤ 70%. Retrospective cohort patients with AML-CM scores of 4-6, 7-9, and ≥10, respectively, had significantly higher hazard ratios (HR) for death after less-intensive therapies, independent from receipt of HCT [in HCT-adjusted models, AML-CM=4-6: HR=1.82 (95% CI=1.25-2.63); =7-9: HR=1.67 (95% CI=1.22-2.27); >10: HR=1.32 (95% CI=0.99-1.72)]. Patients aged 70-79 years had similar results [HR=1.37 (95% CI=1.02-1.85), p=0.04]. Higher mortality risks were also seen in the prospective cohort after less-intensive therapies. In models adjusted for age, physician-assigned KPS and physician perceptions of chances of cure, mortality risks were similar between less-intensive and intensive therapies; QOL and function were also similar. We did not find that receiving less-intensive induction led to better survival, QOL, or function compared to intensive therapies, including in those aged 70-79 years or with high comorbidity burden. This challenges current practice and demonstrates the need for a randomized trial. This research was, in part, funded by a Patient-Centered Outcome Research Institute award (CE-1304-7451), in part, by a Research Scholar Grant from the American Cancer Society (RSG-13-084-01-CPHPS), and, in part, supported by an American Society for Hematology Bridge Award

Enasidenib vs conventional care in older patients with late-stage mutant-IDH2 relapsed/refractory AML: a randomized phase 3 trial

This open-label, randomized, phase 3 trial (NCT02577406) compared enasidenib, an oral IDH2 inhibitor, with conventional care regimens (CCR) in patients aged ≥60 years with late-stage, mutant-IDH2 acute myeloid leukemia (AML) relapsed/refractory (R/R) to 2 or 3 prior AML-directed therapies. Patients were first preselected to a CCR (azacitidine, intermediate-dose cytarabine, low-dose cytarabine, or supportive care), and then randomized (1:1) to enasidenib 100 mg/day or CCR. The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), time to treatment failure (TTF), overall response rate (ORR), hematologic improvement (HI), and transfusion independence (TI). Overall, 319 patients were randomized to enasidenib (n=158) or CCR (n=161). Median age was 71 years. Median (range) enasidenib exposure was 142 days (3-1270) and CCR was 36 days (1-1166). One enasidenib (0.6%) and 20 CCR (12%) patients received no randomized treatment, and 30% and 43%, respectively, received subsequent AML-directed therapies during follow-up. Median OS with enasidenib vs CCR was 6.5 vs 6.2 months (HR [hazard ratio] 0.86; P=.23); 1-year survival was 37.5% vs 26.1%. Enasidenib meaningfully improved EFS (median 4.9 months, vs 2.6 months with CCR; HR 0.68; P=.008), TTF (median 4.9 vs 1.9 months, HR 0.53;

An 8-year pragmatic observation evaluation of the benefits of allogeneic HCT in older and medically infirm AML patients

We designed a prospective, observational study enrolling patients presenting for treatment of AML at 13 institutions to analyze associations between hematopoietic cell transplantation (HCT) and survival, quality of life (QOL), function and geriatric health, in 6 groups: 1) the entire cohort, 2) ≥65 years old, 3) high comorbidity burden, 4) intermediate cytogenetic-risk, 5) adverse cytogenetic-risk, and 6) first complete remission with or without measurable residual disease. Patient health and preferences were assessed eight times across 2 years. Time-dependent regression models were used. Among 692 evaluable patients, 46% received HCT with 2-year survival of 58%. In unadjusted models, HCT was associated with reduced risks of mortality in the entire group and most of the subgroups. However, after accounting for covariates associated with increased mortality (age, comorbidity-burden, disease risks, frailty, impaired QOL, depression, and impaired function), the associations between HCT and longer survival disappeared in all groups. While function, social life, performance status, and depressive symptoms were better for those selected for HCT compared to those who were not, these health advantages were lost after receiving HCT. Recipients and non-recipients of HCT similarly ranked and expected cure as main goal of therapy, while physicians expected more cure for the formers. Accounting for health impairments negate survival benefits from HCT for AML, suggesting that the unadjusted observed benefit is due mostly to selection of the healthier candidates. Considering patients' overall expectations of cure but also the QOL burdens of HCT motivate the need for randomized trials to identify the best candidates for HCT

Limitations to Receiving Allogeneic Hematopoietic Cell Transplantation for Treatment of Acute Myeloid Leukemia: A Large Multi-Center Prospective Longitudinal Observational Study

Older pts with AML often have significant comorbidities and other geriatric health problems, and the effect of these on the probability of receiving HCT is unknown. We designed a prospective, longitudinal, observational study of adult pts with AML dating from first presentation at one of 13 centers. We examined the effects of different variables on the probability to 1) survive long enough to receive HCT and 2) to receive HCT if such survival occurred. We enrolled 695 pts (Table 1). Data on demographics, AML status, cytogenetic risks per European Leukemia Network (ELN), response, age, comorbidities per the HCT-comorbidity index (CI), function, frailty, geriatric assessment, cognition, Karnofsky performance status (KPS), QOL, social support, and depression were collected at enrollment and at 1, 3, 6, 9, 12, 18, and 24 months thereafter. We used competing risk Cox regression analyses, treating HCT as the event of interest and death without HCT as a competing risk, with staggered entry (left truncation) at time of consent. Associations between variables were assessed both at enrollment and over time. The overall rate of HCT at 9 months after enrollment was 43% (Figure 1) and 92% who received HCT did so by 9 months. In multivariate analyses, death without HCT (Table 2) was associated with augmented HCT-CI scores ≥5, age ≥50 years with those aged ≥70 years having the highest association, ELN intermediate or unfavorable risks, receiving low-intensity induction regimens, relapsed/refractory disease at enrollment, dependent status per ADL scores <14, and depression per PHQ-9. Among survivors (Table 3), low likelihood to receive HCT was associated with age ≥70 years, low ELN risk, low-intensity induction, poor KPS, and relapse after initial complete remission (CR); while pts with high-risk MDS, relapsed/refractory disease at enrollment, and CR after induction were more likely to receive HCT. Among pts aged ≥60 years, and after considering previous factors, impaired cognition and hearing had a lower likelihood to receive HCT. Increasing age, comorbidity burden, ELN risk, low-intensity initial AML induction regimen, depression, and functional dependence increase risks of early mortality without HCT. In those who survived long enough to potentially receive HCT, age up to 69 years and/or multiple comorbidities were not found to be barriers to HCT, likely reflecting the widespread use of reduced-intensity conditioning regimens. The adverse impact of impairments in psychological health and function on survival and of impairments of cognition, geriatric health, and performance status on receipt of HCT emphasize the need for interventions that target these health limitations in conjunction with AML treatment to improve outcomes. Finally, the benefit of intensive vs. less-intensive induction therapies should be addressed with a randomized trial

Limitations to Receiving Allogeneic Hematopoietic Cell Transplantation for Treatment of Acute Myeloid Leukemia: A Large Multi-Center Prospective Longitudinal Observational Study

Abstract Introduction: Acute myeloid leukemia (AML) is most frequently diagnosed in older patients (pts), whose median survival is less than 1 year. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment. However, older pts often have significant comorbidities and other geriatric health problems, and the effect of these on the probability of receiving HCT is unknown. To this end, we designed a prospective, multi-center, longitudinal, observational study dating from first presentation of adult pts with AML to be treated at one of 13 different referral centers that provide both AML treatment and HCT. We examined the effects of different variables (see methods) on the probability to 1) survive long enough to receive HCT and 2) to receive HCT if such survival occurred. Methods: We enrolled 695 pts (Table 1). Data on demographics, AML status, cytogenetic risks per European Leukemia Network (ELN), and response; age; comorbidities per the HCT-comorbidity index (CI); function including instrumental activities of daily living (IADL) and activities of daily living (ADL); frailty including walk test; geriatric assessment (GA) including cognition; Karnofsky performance status (KPS); QOL including the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT), Euro-QOL 5-Dimension scale (EQ-5D), ENRICHD Social Support Instrument, Social Activity Log, and Patient Health Questionnaire 9-item Depression Scale (PHQ-9) were collected at enrollment and at 1, 3, 6, 9, 12, 18, and 24 months thereafter. High-risk myelodysplastic syndromes (MDS) receiving AML-like therapy were included. We used competing risk Cox regression analyses, treating HCT as the event of interest and death without HCT as a competing risk, with staggered entry (left truncation) at time of consent. Associations between variables were assessed both at enrollment and over time. Results: The overall rate of HCT at 9 months after enrollment was 43% (Figure 1) and 92% of pts who received HCT did so by the 9 month mark. In multivariate analyses, death without HCT (Table 2) was associated with augmented HCT-CI scores ≥5 (HR:2.11, p<0.0001), age ≥50 years with those aged ≥70 years having the highest association (HR:2.71, p<0.0001), ELN intermediate (HR:2.43, p=0.0003) or unfavorable risks (HR:4.3, p<0.0001), receiving low-intensity induction regimens (HR:1.42, p=0.04), relapsed/refractory disease at enrollment (HR:2.04, p<0.0001), dependent status per ADL scores <14 (HR:1.59, p=0.005), and depression per PHQ-9 (HR:1.56, p=0.009). Among survivors (Table 3), low likelihood to receive HCT was associated with age ≥70 years (HR:0.40, p=0.0001), low ELN risk (HR:0.28, p<0.0001), low-intensity induction (HR:0.56, p=0.02), poor KPS (HR:0.49, p=0.0005), and relapse after initial complete remission (CR) (HR:0.41, p=0.001); while pts with high-risk MDS (HR:2.43, p<0.0001), relapsed/refractory disease at enrollment (HR:2.43, p<0.0001), and CR after induction (HR:4.59, p<0.0001) were more likely to receive HCT. Among pts aged ≥60 years, and after considering previous factors, impaired cognition (HR:0.45, p=0.007) and impaired hearing (HR:0.71, p=0.009) were associated with lower likelihood to receive HCT. Conclusions: In a prospective, observational, multi-center study, increasing age, comorbidity burden, ELN risk, low-intensity initial AML induction regimen, depression, and functional dependence increase risks of early mortality without HCT. In those who survived long enough to potentially receive HCT, age up to 69 years and/or multiple comorbidities were not found to be barriers to HCT, likely reflecting the widespread use of reduced-intensity conditioning regimens. However, the independent sharp decline in receipt of HCT in pts aged 70-80 years suggests continued bias, although pts in this age group have been shown to derive similar benefit from HCT as younger pts. Use of objective comorbidity and GA tools rather than age per se to decide on HCT is encouraged. The adverse impact of impairments in psychological health and function on survival and of impairments of cognition, geriatric health, and performance status on receipt of HCT emphasize the need for interventions that target these health limitations in conjunction with AML treatment to improve outcomes. Finally, the benefit of intensive vs. less-intensive induction therapies should be addressed with a randomized trial. Disclosures Gerds: Celgene: Consultancy; Apexx Oncology: Consultancy; Incyte: Consultancy; CTI Biopharma: Consultancy. Shami:Lone Star Biotherapies: Equity Ownership; Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees; JSK Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy. Rizzieri:Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wang:Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy; Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Faderl:Jazz Pharmaceuticals: Employment, Equity Ownership. Koprivnikar:Amgen: Speakers Bureau; Otsuka: Consultancy; Alexion: Consultancy, Speakers Bureau. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding

Survival Differences Among Patients (pts) with Acute Myeloid Leukemia (AML) Treated with Allogeneic Hematopoietic Cell Transplantation (HCT) Versus Non-HCT Therapies: A Large Real-Time Multi-Center Prospective Longitudinal Observational Study

Abstract Introduction: Survival rates continue to improve after allogeneic HCT (Gooley et al, NEJM, 2013). Population-based studies also indicate overall improvement in survival of older (60-80 years old) AML patients (pts) (Bower, Blood Cancer Journal, 2016). Yet, only a small minority (6%-8%) of them receive HCT (Medeiros, Ann Hematol. 2015). Given these potentially incongruent findings and the changing face of survival in AML, we designed the first prospective multi-center longitudinal study dating from first presentation of adults with AML to be treated at one of 13 different referral centers that provide both AML treatment and HCT. We compared survival according to whether or not pts received HCT at later time points. Methods: We enrolled 695 pts (Table 1). Data on demographics, AML status, cytogenetic risks per European Leukemia Network (ELN), and response; age; comorbidities per the HCT-comorbidity index (CI); function including activities of daily living (ADL); frailty; geriatric assessment including cognition; QOL including the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT), Euro-QOL 5-Dimension scale, ENRICHD Social Support Instrument, Social Activity Log, and Patient Health Questionnaire 9-item Depression Scale (PHQ-9) were collected at enrollment and at 1, 3, 6, 9, 12, 18, and 24 months thereafter. We used time-dependent Cox regression analyses to identify baseline and time-dependent risk factors associated with mortality in the overall population. The factors identified as significantly associated with mortality (p<0.05) were used to develop multivariate models examining the association between HCT and mortality within 1) the general population as well as those with 2) intermediate vs 3) unfavorable ELN risk, and 4) vulnerable pts (age ≥60 years or HCT-CI scores ≥4). The latter group constituted the majority (76%). In these analyses, all pts were considered to be in the non-HCT group until receipt of HCT at which time they enter the HCT group. The contribution of deaths to the hazard ratio (HR) for HCT reflects the relative number and characteristics of pts remaining at risk in the two groups at the time a death occurs. Results: Median follow-up was 16.8 months (range 0.1-52.4). In the initial multivariate analyses, the following were identified as significantly associated with an increased risk of mortality (Table 2): HCT-CI scores ≥5 (p<0.0001), age ≥70 years (p<0.0001), intermediate (p=0.03) and high ELN risk (p<0.0001), relapsed/refractory AML at enrollment (p=0.0005), relapse or refractory response to initial treatment after enrollment (p<0.0001), frailty per walk test (p=0.004), impaired QOL per FACT-G scores (p=0.02), increased depression per PHQ-9 (p=0.03), and dependent status per ADL scores <14 (p=0.05). Survival after HCT was 58% at 2-years. Initial unadjusted analyses showed significantly lower risks of mortality in association with receiving allogeneic HCT (p=0.0003). These findings were similar in pts with intermediate (p=0.0005) or unfavorable (p<0.0001) ELN risk and in vulnerable pts (p<0.0001) (Table 3). However, in the adjusted models, the advantage of HCT in reducing mortality rates was lost both in the overall population (p=0.21, see figure) as well as in the other groups (p>0.54, 0.40, and 0.51, respectively, Table 3). Formal tests of interactions (Table 3) showed no statistically compelling evidence that the association of HCT and mortality varies with respect to the timing of mortality or to the underlying ELN risk. Conclusions: In a prospective observational study, adjusting for key AML-specific and pt-specific variables negated the observed benefit of HCT over non-HCT therapies in reducing mortality rates among AML pts. Our results might reflect 1) improvement in supportive care and non-HCT therapies, 2) a relatively high non-relapse mortality early after HCT and the need for longer follow-up to demonstrate an adjusted benefit of HCT, and 3) the high selectivity of the transplant eligibility process, as we accounted here for variables that are often ignored in "genetic assignment" randomized studies (i.e. comorbidities and function). New randomized trials are needed; however, these trials have to be more inclusive of vulnerable pts and measure pt-specific variables. Trials focusing on reducing burden of comorbidities, frailty and poor function are needed alongside trials to treat AML with or without HCT. Disclosures Gerds: Celgene: Consultancy; Apexx Oncology: Consultancy; CTI Biopharma: Consultancy; Incyte: Consultancy. Shami:JSK Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees; Lone Star Biotherapies: Equity Ownership; Pfizer: Consultancy. Rizzieri:Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wang:Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Faderl:Jazz Pharmaceuticals: Employment, Equity Ownership. Koprivnikar:Alexion: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Otsuka: Consultancy. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding