Leukemia In Older Adults Research Articles

A precision medicine approach to management of acute myeloid leukemia in older adults.

Therapy selection in older adults with acute myeloid leukemia (AML) can be challenging because of a higher incidence of high-risk cytogenetic and molecular features conferring chemoresistance and poor functional status leading to increased treatment-related toxicities. The purpose of this review is to highlight the recent advances in precision medicine in AML that have shown promise to improve outcomes of older adults. The utilization of next generation sequencing to identify and target actionable mutations can influence therapy selection in one-third of patients and can result in higher response rates as well as survival compared with those who do not receive targeted therapy. Oral targeted agents are available for AML with IDH 1, IDH2, or FLT3 mutations. Low-intensity venetoclax-based regimens have shown high rates of responses in AML, particularly among those with NPM1 and IDH2 mutations; responses are often durable and associated with minimal residual disease (MRD) negativity. Multiple studies have demonstrated the prognostic significance of flow cytometric MRD, with potential implications for subsequent therapy. Novel approaches for AML risk-stratification, MRD assessment, and a precision medicine approach offer significant promise to improve survival and quality of life of older adults.

Outcomes of decitabine treatment for newly diagnosed acute myeloid leukemia in older adults​.

We evaluated the outcomes of decitabine as first-line treatment in older patients with acute myeloid leukemia (AML) and investigated the predictors, including a baseline mini nutritional assessment short form (MNA-SF) score, of response and survival. Between 2010 and 2018, 96 AML patients aged 65 and above who received decitabine treatment at 6 centers in Korea were retrospectively evaluated. Response rates, hematologic improvements (HI), progression-free survival (PFS), and overall survival (OS) were analyzed. The median age at diagnosis was 73.9 years, and the median number of decitabine treatments administered to the patients was 4 (range, 1-29). Of 85 patients, 15 patients (17.6%) achieved complete remission (CR) or CR with incomplete blood count recovery. Twelve patients (14.1%) showed partial remission (PR), and 18 (21.2%) demonstrated HI without an objective response. The median PFS and OS were 7.0 (95% confidence interval [CI], 4.9-9.0) and 10.6 (95% CI, 7.7-13.5%) months, respectively. In multivariate analyses, MNA-SF score ≥ 8 and the absence of peripheral blood (PB) blasts were significant predictors for improved PFS and OS. For older patients with newly diagnosed AML, a high MNA-SF score and the absence of PB blasts were independently associated with improved survival.

Physical Fitness As A Determinant Of Leukemia Cell Biology In Treatment-Naive Chronic Lymphocytic Leukemia (CLL)

PURPOSE: Chronic lymphocytic leukemia (CLL) is the most common leukemia in older adults. CLL patients are at an increased risk of frailty, secondary malignancies, and infectious diseases. The aim of this study was to determine the role of physical fitness and function on biological mediators of tumor control and progression. METHODS: We collected blood from sixty two (68 ± 11 yrs.) men and women with treatment naïve CLL [CLL-IPI: median 1.5 (range: 0-7] and were asked to complete a comprehensive battery of physical fitness and functional tests. The 10 most fit (FIT: estimated VO2peak 34±3 mL/kg/min) and 10 least fit (UNFIT: 25±3 mL/kg/min) adults were matched on age and gender. We completed immunophenotyping of blood leukocytes, NMR-spectroscopy of lipoprotein particles, and sequencing of exosomal micro-RNA (miRNA). The human CLL-like OSU-CLL cell line was co-cultured with autologous plasma and assessed for cell growth and death. RESULTS: The FIT group had 6% fewer CD4+ (p=0.019) and 4% fewer CD8+ (p=0.015) T-cells than the UNFIT group. The FIT group had 15% fewer NKG2A+ NK-cells (p=0.032), and 10% more cytotoxic NKG2A-/KIR+ NK-cells capable of recognizing HLA+ tumor cells. The FIT group had 63% lower concentrations of triglycerides (p=0.025), and 250% fewer large triglyceride rich lipoproteins (p=0.011), and 20% more HDL cholesterol (p=0.04), with no differences for LDL cholesterol. Greater concentrations of triglycerides and large lipoproteins were associated with increased OSU-CLL cell counts (r=0.497, p=0.03) and less OSU-CLL cell death (r=-0.632, p=0.003). A total of 32 miRNA signatures were significantly different between FIT and UNFIT groups (all p<0.05). Of these, 7 distinct miRNAs were positively correlated with OSU-CLL tumor cell growth (e.g. miR-451a: r=0.606, p<0.001), and 6 miRNAs negatively correlated with OSU-CLL tumor cell growth (e.g. miR-24: r=-0.669, p=0.002). CONCLUSIONS: Physical fitness in CLL patients appears to beneficially modify T-cells and NK-cells, plasma lipoproteins and exosomal miRNAs. Certain lipoproteins and miRNAs are associated with tumor cell growth and death. Further studies will hope to define the possible beneficial effects of exercise training for CLL patients. Supported by Internal Duke Funds

The Roles of Nurses in Hematopoietic Cell Transplantation for the Treatment of Leukemia in Older Adults.

To review and summarize nurses' roles in the care of the older adult undergoing an allogeneic hematopoietic cell transplant (HCT) for the treatment of leukemia. Published literature indexed in PubMed, CINAHL, textbooks, and clinical expertise. Nurses are a vital component of the highly specialized care delivered before, during, and after an allogeneic HCT. Nurses who are prepared for the complex HCT care trajectory will be able to optimally meet the complex needs of the older adult patient and their caregiver(s).

Acute Lymphoblastic Leukemia in the Older Adult.

Acute lymphoblastic leukemia (ALL) in older adults presents a real challenge as a result of adverse disease biology and comorbidities that preclude delivering curative regimens. Conventional chemotherapy approaches have generally yielded unsatisfactory results in older patients with ALL as a result of excessive induction mortality, chemotherapy resistance of the leukemia, and the need to omit or dose reduce key drugs during the course of therapy because of adverse effects. Philadelphia chromosome-positive ALL represents about a quarter of newly diagnosed older adults, and the striking single-agent activity and excellent safety profile of tyrosine kinase inhibitors has allowed incorporation of these agents into therapy, significantly improving the outcome of older adults with Philadelphia chromosome-positive ALL. Allogeneic hematopoietic cell transplantation using reduced-intensity conditioning is a potentially curative approach in the older adult with ALL, and ironically, it may be better tolerated than intensive combination chemotherapy in a subset of older patients with ALL. Immunotherapies such as chimeric antigen receptor-modified T-cells, the bispecific T-cell-engaging antibody targeting CD19 (blinatumomab), and the antibody-drug conjugate targeting CD22 (inotuzumab) have shown safety and exceptional activity even in advanced ALL, and the efficacy of these agents has been observed irrespective of patient age. Several promising studies tailored specifically toward older adults with ALL are ongoing, with the majority of them incorporating novel immunotherapies, targeted therapies, or third-generation tyrosine kinase inhibitors into the front-line treatment regimen.

Phase I Study of Ixazomib in Addition to Chemotherapy for the Treatment of Acute Lymphoblastic Leukemia in Older Adults

Introduction: While progress has been made in the treatment of childhood leukemia, the outlook for patients >60 years of age with acute lymphoblastic leukemia (ALL) is poor with complete remission rates of approximately 60% and 3-year survivals of less than 15% (Larson R., Hematology 2005). Ixazomib is an oral proteasome inhibitor, which has shown single agent activity and promising combination activity in pediatric ALL patients (Messinger, Blood 2012). We sought to assess the safety and tolerability, as well as an early appreciation of the therapeutic promise, of adding ixazomib to standard multi-agent standard treatment for older adults with ALL.Methods: Patients aged 51 to 75 years of age with newly diagnosed B-ALL and T-ALL were screened for eligibility. Excluded were patients with mature ALL (including Burkitt's). Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible and tyrosine kinase inhibitor therapy was added to the chemotherapy on Day 10 for these patients. The induction treatment consisted of the following:Prednisone 40 mg/m2/day, Days 2-22 for patients <60 years of age;Prednisone 40mg/m2/day Days 2-8 for patients ≥ 60 years of age;Vincristine (V) 2 mg IV on Days 2, 9, 16, 23;Doxorubicin (D) 30mg/m2/day on Days 2 and 3; intrathecal cytarabine 50 mg on Day 2;Intrathecal methotrexate 12 mg Day 29;G-CSF 300 mcg/kg sc or IV was started on Day 5 and continued until ANC was >2000 for 2 consecutive days. On Days 1, 8, 15, ixazomib was given orally at the dose prescribed according to 3 dose-escalation cohorts: 2.3 mg/day, 3.0mg/day, or 4.0 mg/day.A standard 3 +3 patient cohort dose escalation design was used to determine the dose of ixazomib for each patient. The primary objective of the study was to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients.After induction patients received consolidation I consisting of the following: cyclophosphamide 750 mg/m2/day, Days 2-3; prednisone 40 mg/m2/day, Days 2-6; PEG-asparaginase 500 units/m2 IV on Day 2 (for Ph- patients only); intrathecal methotrexate 12 mg on Days 2 and 15.On Days 1, 8, 15 of consolidation I, ixazomib was given orally at the dose previously prescribed for them during induction. After consolidation I, patients in complete remission (CR) with a suitable donor were offered stem cell transplantation as per institutional guidelines. Those not going to transplantation proceeded to continuation therapy as follows:CNS Phase: Intrathecal methotrexate 12 mg, cytarabine 40 mg, hydrocortisone 50 mg on days 1, 8, 15, vincristine Day 1, doxorubicin on Day 1, 6-MP Days 1-14, dexamethasone (DEX) Days 1-5, PEG-ASP Day 1+15Consolidation II: 8 cycles of V + D + 6-MP + DEX + PEG-ASP;Maintenance Phase: V + DEX + 6+MP + oral methotrexate (ends after 18 months of remission).Results: The dose escalation phase completed with 9 patients. Among these patients, 4 harbored BCR-ABL1 rearrangements, all had B-ALL, the median age was 65 years, 78% were male, and 78% were performance status 1. The MTD was 2.3 mg of ixazomib, as 2 patients at 3.0 mg developed DLT's, a grade 3 peripheral neuropathy and a grade 5 acute kidney injury. Grade 3 and 4 toxicities included grade 4 neutropenia in 8 patients and grade 4 thrombocytopenia in 7 patients. Two patients experienced grade 3 thrombocytopenia. There was 1 patient with a grade 2 neuropathy that did not meet the definition of DLT. Among the 9 patients, 7 (78%) achieved CR, and 2 patients went on to stem cell transplantation.Conclusions: A dose of 2.3 mg of ixazomib was well-tolerated in combination with induction chemotherapy among older patients with ALL, and is being tested in the expansion phase of this trial. The remission rate in this older adult population appears favorable in both Ph-negative and Ph-positive patients. [Display omitted] DisclosuresAmrein:Takeda: Research Funding. Fathi:Agios: Honoraria, Research Funding; Astellas: Honoraria; Boston Biomedical: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

Phase I Study of Ixazomib in Addition to Chemotherapy for the Treatment of Acute Myeloid Leukemia in Older Adults

Introduction: Treatment of acute myeloid leukemia (AML) has remained largely unchanged for several decades despite the emergence of new agents. Long-term survival for patients aged >60 years is less than 10% (median survival 10.5 months). Targeting the proteasome in treating AML is attractive, since leukemia stem cells have demonstrated sensitivity to proteasome inhibition, perhaps through down regulation of nuclear NF-KB (Guzman, Blood 2001). Preclinical studies in leukemia cell lines revealed synergistic cytotoxicity when bortezomib, a proteasome inhibitor, was combined with the standard agents daunorubicin and cytarabine. We have shown that adding bortezomib to standard treatment in AML results in a high remission rate, although neurotoxicity was noted among treated patients, 12% grade 3 sensory (Attar, …, Amrein, et al. Clin Cancer Res 2008, Attar, … Amrein, J Clin Oncol 2012). The next generation proteasome inhibitor, ixazomib, which is less frequently associated with neurotoxicity, was therefore selected for combination with conventional chemotherapy in this phase I trial. The primary objective was to determine the maximum tolerated dose (MTD) in the combination, initially in induction, and then in combination with consolidation in a subsequent portion of the overall study. We report here the results of the induction portion of the study, which has been completed.Methods: Adults >60 years of age with newly diagnosed AML were screened for eligibility. Patients with secondary AML were eligible, including those with prior hypomethylating agent therapy for myelodysplastic syndromes (MDS). We excluded those with promyelocytic leukemia. The induction treatment consisted of the following: cytarabine 100 mg/m2/day by continuous IV infusion, Days 1-7; daunorubicin 60 mg/m2/day IV, Days 1, 2, 3; ixazomib orally at the cohort dose, Days 2, 5, 9, and 12A standard 3 + 3 patient cohort dose escalation design was used to determine whether the dose of ixazomib could be safely escalated in 3 cohorts (1.5 mg/day, 2.3 mg/day, 3.0 mg/day), initially in induction and subsequently in consolidation. The dose of 3.0 mg/day was the maximum planned for this study. The determined MTD of ixazomib in the first portion of the trial would be used during induction in the second portion, which seeks to test dose escalation of ixazomib during consolidation. Secondary objectives included rate of complete remission and disease-free survival.Results: Fourteen patients have been analyzed for toxicity and activity during the induction portion of the study. There were 4 (28%) patients with either secondary AML or treatment related AML, 9 (64%) were male, and the median age was 67 years (range 62-80 years). There have been no grade 5 toxicities due to study drug. Three patients died early due to leukemia, 2 of which were replaced for assessment of the MTD. Nearly all the grade 3 and 4 toxicities were hematologic (Table). There was 1 DLT (grade 3 thrombocytopenia) indicated at the highest dose level. There has been no neurotoxicity with ixazomib to date. Among the 14 patients, there have been 10 complete remissions (CR's) and 1 CRi for a remission rate of 79%.Conclusions: The highest dose level planned for this portion of the trial, 3.0 mg of ixazomib, was reached with 1 DLT and is the recommended dose for induction in the next portion of this study, which will seek to determine a safe ixazomib dose in combination with conventional consolidation therapy. That no neurotoxicity was encountered was reassuring, and the remission rate in this older adult population is favorable. [Display omitted] DisclosuresAmrein:Takeda: Research Funding. Attar:Agios: Employment, Equity Ownership. Brunner:Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. Fathi:Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria; Agios: Honoraria, Research Funding; Jazz: Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

Cost-effectiveness of ibrutinib as first-line therapy for chronic lymphocytic leukemia in older adults without deletion 17p

AbstractIbrutinib is a novel oral therapy that has shown significant efficacy as initial treatment of chronic lymphocytic leukemia (CLL). It is a high-cost continuous therapy differing from other regimens that are given for much shorter courses. Our objective was to evaluate the cost-effectiveness of ibrutinib for first-line treatment of CLL in patients older than age 65 years without a 17p deletion. We developed a semi-Markov model to analyze the cost-effectiveness of ibrutinib vs a comparator therapy from a US Medicare perspective. No direct comparison between ibrutinib and the best available treatment alternative, obinutuzumab plus chlorambucil (chemoimmunotherapy), exists. Therefore, we compared ibrutinib to a theoretical treatment alternative, which was modeled to confer the effectiveness of an inferior treatment (chlorambucil alone) and the costs and adverse events of chemoimmunotherapy, which would provide ibrutinib with the best chance of being cost-effective. Even so, the incremental cost-effectiveness ratio of ibrutinib vs the modeled comparator was $189 000 per quality-adjusted life-year (QALY) gained. To reach a willingness-to-pay threshold (WTP) of $150 000 per QALY, the monthly cost of ibrutinib would have to be at most $6800, $1700 less than the modeled cost of $8500 per month (a reduction of $20 400 per year). When the comparator efficacy is increased to more closely match that seen in trials evaluating chemoimmunotherapy, ibrutinib costs more than $262 000 per QALY gained, and the monthly cost of ibrutinib would need to be lowered to less than $5000 per month to be cost-effective. Ibrutinib is not cost-effective as initial therapy at a WTP threshold of $150 000 per QALY gained.

Abstract 3976: Antihistamines as synergists with targeted therapies in chronic lymphocytic leukemia

Abstract Chronic Lymphocytic Leukemia (CLL) is a B-cell derived cancer and is the most commonly diagnosed leukemia in older adults. Several survival signals contribute to the accumulation of CLL cells including constitutive activation the B-cell receptor (BCR) signaling pathway. Approved treatments for CLL are nucleoside analogs such as Fludarabine, alkylating agents including Chlorambucil and Bendamustine, and targeted therapies inhibiting BCR-associated kinases such as Ibrutinib and Idelalisib. Unfortunately, CLL remains incurable, but other weaknesses of the disease have been identified. Recent studies have shown CLL cells to be sensitive to lysosomal membrane permeabilization (LMP) and release of lysosomal contents due to altered sphingosine metabolism. Drugs that induce LMP are referred to as lysosomotropic agents and include antidepressants and antimalarials. These drugs accumulate in lysosomes and inhibit enzymes in the sphingolipid metabolic pathway, causing lysosomal membrane damage. Effectors are released from lysosomes including cathepsin proteases and reactive oxygen species (ROS), which cause dysfunction in cellular machinery and cell death via apoptosis. Our data indicates that kinase inhibitors induce synergic death when combined with lysosomotropic agents in vitro in many cancer models. A non-small cell lung cancer study showed that antihistamines acted as lysosomotropic agents, and were correlated with better patient outcomes when combined with chemotherapy. Therefore, the objective of this study is to characterize the cytotoxicity of antihistamines in B-cell cancer models and identify synergistic interactions with clinically relevant drugs used in CLL. We have shown that three commonly prescribed over-the-counter antihistamines, Desloratadine, Loratadine and Clemastine, induce cell death at concentrations that are clinically achievable in the B-cell lines BJAB and I83, as well as CLL patient derived primary lymphocytes. Each antihistamine caused synergic cell death in combination treatments with Ibrutinib and Idelalisib, but not Fludarabine, Chlorambucil or Bendamustine, which may indicate that the synergy is specific to kinase inhibitors. In addition, the treatment with antihistamines was shown to induce cell death at significantly lower concentrations in primary CLL cells compared to normal lymphocytes from age-matched donors. Both the antihistamine-induced cell death and combination treatments depend on intracellular soluble ROS, but the main effectors of the apoptotic pathways remain to be determined. Taken together, this study intends to exploit the vulnerabilities of CLL by repurposing allergy drugs in combination with kinase inhibitors already available for treating CLL patients. Citation Format: Aaron P. Chanas-LaRue, James B. Johnston, Spencer B. Gibson. Antihistamines as synergists with targeted therapies in chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3976.

Treatment of chronic lymphocytic leukemia in older adults.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and it typically afflicts older adults, with a median age at diagnosis of 71. Traditional treatments for CLL have included chemotherapy, which can often be difficult for older patients to tolerate. Given the variability in fitness, cognition and comorbidities amongst older patients, a geriatric evaluation should be considered prior to commencement of cytotoxic therapy. More recently, novel oral agents are proving to be both safe and effective in this population, redefining the field of CLL therapy. In this article we describe high and low-risk disease and discuss contemporary treatment paradigms. We will discuss how the inclusion of targeted therapies may improve outcomes in older patients with CLL being treated in the frontline and relapsed settings. Finally, we will touch on new treatments and combination therapies that are undergoing further study and discuss their potential utility in the older patient with CLL.

High incidence of Philadelphia chromosome-like acute lymphoblastic leukemia in older adults with B-ALL.

High incidence of Philadelphia chromosome-like acute lymphoblastic leukemia in older adults with B-ALL

A New Peptide Vaccine Ocv-501, Phase 1 Study in Patients with Acute Myeloid Leukemia and In Vitro Pharmacology

Acute myeloid leukemia (AML) is the most common leukemia in older adults. Chemotherapy is the standard treatment, however, treatment efficacy and tolerability deteriorates with age, and patients are susceptible to relapse after complete remission (CR). Therefore, new therapeutic strategies for preventing relapse after consolidation therapy are urgently needed. Wilms' tumor 1 (WT1) is a promising target of new immunotherapies for acute myeloid leukemia (AML) as well as other cancers. OCV-501 is a helper peptide derived from the WT1 protein. Preclinical studies have shown that it induced OCV-501-specific Th1 responses dose-dependently and stimulated helper activity of the specific Th1 cells in peripheral blood mononuclear cells from healthy donors. OCV-501 also enhanced the increase in WT1-killer peptide-specific cytotoxic T lymphocytes (CTLs). The stimulated OCV-501-specific Th1 clones in an HLA class-II restricted manner formed a complex with HLA class-II protein and showed significant OCV-501-specific cytolytic activity against B-lymphoblastoid cell lines (B-LCL). These results suggested that OCV-501 activates both direct and indirect antitumor (anti-leukemic) cellular immunity, including specific cytotoxic Th1 cells and WT1-peptide-specific CTLs. Based on this, a phase 1 trial was carried out to assess the safety and tolerability as well as efficacy of OCV-501 in elderly AML patients in CR.This was an open label, multi-center trial conducted in Japan. The study involved AML patients who have achieved their first CR with an induction regimen and completed standard consolidation therapy, and have been identified as WT1 mRNA positive, with one of the following HLA class II types: HLA-DRB1*01:01, *04:05, *15:01, *15:02, *08:03, or *09:01. The trial consisted of 3 cohorts at a dose of 0.3 mg in cohort 1, 1 mg in cohort 2, and 3 mg in cohort 3, whereby administration commenced with cohort 1 and progressed to subsequent cohorts, depending on the assessment for dose limiting toxicity (DLT) in the preceding cohort. OCV-501 was administered subcutaneously weekly for 4 weeks, followed by end of treatment and post-treatment examinations after 1 and 4 weeks from the last administration, respectively. Safety and tolerability which included any occurrence of treatment-emergent adverse events (TEAEs) and DLT were assessed, and the maximum tolerated dose (MTD) was determined. Efficacy was evaluated by relapse of AML, WT1 mRNA level and immune response to OCV-501 using delayed-type hypersensitivity (DTH) test.Nine patients were enrolled and all completed the study. No DLT was observed in any of the 3 cohorts. Injection site reactions, including erythema, induration, mass, pain, and pruritus were observed in all patients. However, these drug-related TEAEs were Grade 1 or 2 in severity. There were neither deaths nor serious TEAEs during the treatment period and none of the patients discontinued OCV-501 administration due to TEAE. The result of this trial suggested that OCV-501 once a week for 4 weeks at doses of 0.3, 1, and 3 mg was safe and well-tolerated in AML patients in CR and the MTD was considered to be ≥ 3 mg. In the efficacy analysis, neither relapse nor blast cells were observed in any patients and a reduction in WT1 mRNA level was found in 5 patients. Immunological response was observed in all patients in the OCV-501-specific DTH test.In conclusion, OCV-501, which was suggested to activate both direct and indirect anti-leukemic cellular immunity, showed a favorable safety and tolerability profile in elderly patients who have AML in CR, and the MTD was shown to be ≥ 3 mg. The results suggested the clinical beneficial of this vaccine and further clinical studies are highly warranted. This trial was registered at www.clinicaltrials.gov as NCT 01440920. DisclosuresSakura:Otsuka Pharmaceutical: Research Funding. Kobayashi:Celgene: Research Funding; Pfizer: Research Funding; Ohtsuka Pharmaceutical: Research Funding; Ariad: Research Funding; SymBio Pharmaceuticals: Research Funding. Toga:Otsuka Pharmaceutical: Employment. Sogo:Otsuka Pharmaceutical: Employment. Heike:Sumitomo Dainippon Pharma: Consultancy; Chugai Pharma: Consultancy; Otsuka Pharma: Consultancy.

North American Leukemia, Intergroup Phase III Randomized Trial of Single Agent Clofarabine As Induction and Post-Remission Therapy, and Decitabine As Maintenance Therapy in Newly-Diagnosed Acute Myeloid Leukemia in Older Adults (Age ≥60 Years): A Trial of the ECOG-ACRIN Cancer Research Group (E2906)

▪Background: Induction therapy with daunorubicin (Dauno) & cytarabine (Ara-C) [DA] has been the standard of care for eligible older adults (age ≥ 60 years) with newly diagnosed acute myeloid leukemia (AML) for over 2 decades. Single agent Clofarabine (CLO) induction & consolidation (Consol.) therapy has demonstrated important clinical activity in this age group in large phase II studies. Lower induction mortality (IM) & similar reported complete remission rate (CR) & overall survival (OS), as well as notable activity in those with higher risk disease features [including unfavorable cytogenetics, therapy-related AML (t-AML) & prior antecedent hematologic disorder (AHD)] raises the possibility that a non-Ara-C-based regimen could achieve similar or superior OS with lower toxicity.Methods: We performed a randomized United States Intergroup Phase III trial of single agent CLO [30mg/m2 x 5 days induction; 20 mg/m2 re-induction (if indicated) & 2 cycles Consol.] vs. standard DA therapy [Dauno 60mg/m2 D1-3 & Ara-C 100mg/m2 D1-7 induction x 1-2 cycles; 2 cycles Consol. with Ara-C (1.5g/m2 Q12hrs D1-6 age 60-69; once daily if age 70+)] in patients (pts) age ≥ 60 yrs with newly diagnosed AML. Patients with serum creatinine >1.0 (or GFR <60 mL/min) and those with AML-M3 and ECOG performance status >3 (PS>2 if age 70+ yrs) were excluded. Randomization was stratified by age (60-69 vs. 70+), t-AML, & AHD. Pts with HLA-matched donor were eligible for allogeneic transplantation (AlloHCT) after induction, and those completing Consol. were eligible for randomization #2 (R#2) to maintenance decitabine [20mg/m2 x 3D, monthly x 1 year] versus observation. With a target accrual of 747, E2906 was powered to determine non-inferiority [and possible superiority] of CLO vs. standard DA, and primary endpoint was OS. A weighted statistical analysis was performed to account for confounding impact of R#2. AlloHCT patients were censored at transplant in this analysis. Responses & cytogenetics were confirmed centrally and OS & CR rates were monitored by an independent Data Safety Monitoring Committee (DSMC) at pre-specified time points.Results: As of Feb 23, 2015, 727 pts were randomized. Median age was 68 years (range 60-86); 57% were male, and 38% were age ≥70 yrs. Treatment arms are well balanced for all baselineclinical & AML characteristics, & 30% had unfavorable cytogenetics. Of 659 with complete treatment information reported, 30.4% on DA vs. 40.1% on CLO received 2 cycles of induction (p=0.006).Median follow-up of surviving patients is 7.6 months.Table 1shows early treatment results (CR, toxicity) for the 686 pts randomized as of Dec 23, 2014 (2 months prior to study end, & excluding 90 with ongoing response evaluation).DACLOp-valueCR/CRi43.8%42.8%p=0.8730-day mortality8.5%7.9%p=0.8960-day mortality14.9%13.1%p=0.58Gr 4-5 Non-Heme Tox.Induction27%19%p=0.02Gr 4-5 Non-Heme Tox.Consol.20%7%p=0.001374 pts have died (174, DA; 200, CLO) & significantly inferior OS was observed for CLO vs. DA [Hazard Ratio (HR) 1.41 (95% CI 1.12-1.78)] (Fig. 1). Planned subgroup analyses were performed (Table 2) demonstrating significant differences in OS after CLO for patients age 60-69 yrs, without AHD, & with intermediate risk cytogenetics; but not for those with Unfav. Cytogen. (Fig. 2) or t-AML. Based on the primary weighted analysis, DSMC recommended suspension of new accrual to E2906 on Feb 23, 2015 & all active patients on CLO were transitioned to DA Arm. Table 2NHR CLO/Standard (95% CI)*Weighted OS7271.41 (1.12-1.78)Unweighted OS7271.23 (1.00-1.50)Age 60-694491.48 (1.10-1.99)Age 70+2781.34 (0.93-1.93)Intermed. Risk Cytogen.3781.77 (1.27-2.47)Unfav. Risk Cytogen.2160.96 (0.65-1.43)No AHD6041.46 (1.13-1.89)AHD1231.22 (0.74-2.00)De novo AML6271.52 (1.18-1.96)Therapy-related AML1000.94 (0.54-1.61)Conclusions: Despite similar CR & IM, OS after single agent CLO is inferior to standard DA therapy for pts age ≥60 years with newly diagnosed AML who are fit for intensive therapy, and DA remains the standard of care. However no difference in OS was observed after CLO in some pre-specified high risk AML subgroups. R#2 & AlloHCT arms continue in E2906 for pts already enrolled. Embedded prospective minimal residual disease study at CR is being performed to identify pts at higher risk after CLO & DA. [Display omitted] [Display omitted] DisclosuresOff Label Use: Use of clofarabine in AML, and maintenance therapy with decitabine in AML. Claxton:Medimmune: Research Funding; BMS: Consultancy; Astellas: Research Funding; Cyclacel: Research Funding; Merck: Research Funding; Ambit: Research Funding. Levine:Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Foundation Medicine: Consultancy. Altman:Seattle Genetics: Consultancy; BMS: Consultancy; Spectrum: Consultancy; Astellas: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Al-Kali:Novartis: Research Funding.

Treating acute myeloid leukemia in older adults.

Acute myeloid leukemia (AML) is a disease of older adults, with a median age of 67 years at presentation. In the past, only a third of older patients (defined as individuals older than 60-65 years of age) with AML received definitive therapy for their disease due to concerns about their overall fitness and potential treatment-related mortality. However, compelling epidemiological data have shown unequivocally that older AML patients up to 80 years old both tolerate and survive longer after therapy than their untreated counterparts. Current therapeutic options for elderly individuals with AML include intensive chemotherapy with a cytarabine and anthracycline backbone, hypomethylating agents (decitabine and azacitidine), low-dose cytarabine, investigational agents, and supportive care with hydroxyurea and transfusions. Over the last few years, there has been increasing debate regarding the appropriate therapeutic approach to take in older adults given the diversity of the geriatric patient population and heterogeneous AML disease biology. This article discusses how performance status, comorbidities, disease characteristics, quality of life concerns, and long-term treatment goals affect the selection of appropriate therapy for older adults with AML. Risks and benefits of each treatment approach based on the most recent medical literature are discussed. Finally, a treatment algorithm summarizing these data and incorporating geriatric assessment and molecular and cytogenetic markers predictive of therapeutic response is proposed to aid in the clinical decision-making process.

Allogeneic hematopoietic cell transplantation for acute myeloid leukemia in older adults.

Acute myeloid leukemia (AML) is primarily a disease of the elderly and the numbers of these patients are increasing. Patients ≥60 years of age continue to have poor prognosis. Preliminary results suggest benefit from reduced-intensity allogeneic hematopoietic cell transplantation (HCT) in selected patients 60-80 years of age. However, although patients in this age range comprise >50% of those with AML, they currently constitute only 17% of those offered HCT. In the absence of prospective randomized studies comparing HCT and chemotherapy, the decision to recommend HCT rests on retrospective analyses of the risks of relapse and nonrelapse mortality after each approach. There is strong evidence that pre-HCT comorbidities can predict HCT-related morbidity and mortality. Age alone does not appear predictive and, particularly if the risk of relapse with chemotherapy is high, should not be the sole basis for deciding against HCT. Use of geriatric assessment tools, inflammatory biomarkers, and genetic polymorphism data may further aid in predicting nonrelapse mortality after HCT. Disease status and pretreatment cytogenetics with FLT3-TID, NPM-1, and CEBP-α status are the main factors predicting relapse and these are likely to be supplemented by incorporation of other molecular markers and the level of minimal residual disease after chemotherapy. HLA-matched related and unrelated donor grafts seem preferable to those from other donor sources. Donor age is of no clear significance. Models combining comorbidities with AML risk factors are useful in risk assessment before HCT. In this chapter, we integrated information on AML-specific, HCT-specific, and patient-specific risk factors into a risk-adapted approach to guide decisions about HCT versus no HCT.

Clofarabine in the treatment of acute myeloid leukemia in older adults

To review the literature evaluating the efficacy and tolerability of clofarabine as a single agent and in combination therapy for older patients with acute myeloid leukemia (AML). A literature search of the PubMed database (1996-April 2012) using the search terms clofarabine and acute myeloid leukemia was performed. All relevant English language articles were reviewed. Clinical trials with patients aged 50 years or older diagnosed with AML were included. Two studies evaluating clofarabine as monotherapy and five studies evaluating clofarabine in combination with cytarabine were reviewed. Clofarabine demonstrated activity in older adults with AML. Response rates and median overall survival (OS) for patients receiving clofarabine were similar to those for patients receiving conventional induction chemotherapy. The induction mortality rate with clofarabine was lower than that seen with intensive chemotherapy. However, clofarabine was associated with a significant risk of severe complications including myelosuppression and sepsis. Clofarabine is an active agent for the treatment of older patients with AML as a single agent or in combination therapy. Based on published data and side-effect profiles, clofarabine may be an appropriate alternative to intensive chemotherapy for older patients with AML, offering similar response rates to traditional 7+3 chemotherapy with potentially decreased induction mortality. The use of clofarabine in combination with newer agents including DNA methyltransferase inhibitors like decitabine is a promising approach for older patients who are not eligible for intensive chemotherapy. Additional randomized controlled trials are needed to directly compare the efficacy of clofarabine as a single agent and in combination therapy compared with intensive chemotherapy regimens.

Acute myeloid leukemia in older adults

Acute myeloid leukemia (AML) is predominantly a disease of older adults, with a median age at diagnosis of over 65 years. AML in older adults differs biologically and clinically from that in younger ones, and is characterized by stronger intrinsic resistance and lower tolerance to chemotherapy. The effects of age on both patient- and disease-related factors result in a higher incidence of early death during chemotherapy, a lower rate of complete remission, and a reduced chance of long-term survival. Treatment options for older adults with AML include intensive chemotherapy, less-intensive chemotherapy, best supportive care, or enrolment in clinical trials. Given the heterogeneous nature of AML in older adults, therapeutic decisions need to be individualized after systematic assessment of disease biology and patient characteristics. Regardless of treatment, however, outcomes for older AML patients remain in general unsatisfactory. In contrast with the progress made for younger adults, the treatment of AML in older adults has not improved significantly in recent decades. Development of less toxic and more targeted agents may well provide treatment alternatives for a majority of these patients. The overall dismal outcome with currently available treatment approaches has encouraged older AML patients to participate in prospective clinical trials.

Clofarabine in the Treatment of Newly Diagnosed Acute Myeloid Leukemia in Older Adults

To review the literature evaluating the efficacy and tolerability of clofarabine, a second-generation purine nucleoside analogue, for the treatment of previously untreated acute myeloid leukemia (AML) in older adults. A literature search of the PubMed database (1972-October 2011) using the search terms clofarabine and acute myeloid leukemia was performed. All relevant English-language articles were reviewed, and clinical trials with patients aged 50 years or older who were newly diagnosed with AML were included. Two studies evaluating clofarabine as monotherapy and 2 studies evaluating clofarabine in combination with cytarabine were reviewed. Clofarabine demonstrated activity in older adults with previously untreated AML. Response rates and median overall survival (OS) for patients receiving clofarabine were similar to those reported for conventional intensive chemotherapy regimens. Responses to the 2 types of treatment remained similar in the presence of unfavorable prognostic factors, such as secondary AML or adverse cytogenetics. Although clofarabine was associated with a lower induction mortality rate versus intensive chemotherapy regimens, a significant percentage of patients experienced severe complications, including sepsis. Compared to single-agent clofarabine, response rates and median OS were higher for clofarabine combined with cytarabine. Based on published data, adverse effect profiles, and cost, clofarabine may be an appropriate alternative to intensive chemotherapy regimens in certain subsets of older patients with newly diagnosed AML. These include patients with a baseline decreased performance status or history of cardiovascular disease who may not tolerate anthracyclines, which are typically a component of most intensive chemotherapy regimens. Additional randomized controlled trials are needed to directly compare the efficacy of clofarabine with that of intensive chemotherapy regimens and to evaluate the potential benefit of combining clofarabine with cytarabine.

The mystery of leukemia in older adults

According to the American Cancer Society, about 43,000 new cases of leukemia occur annually, most often in adults over age 60. There's no accepted treatment regime and treatment outcomes are poor. Nurses can be invaluable in educating patients and their families about this devastating disease.

The mystery of leukemia in older adults

The mystery of leukemia in older adults