ALBERT

Description: This phase 3 prospective randomized trial evaluated the efficacy and long-term safety of erythropoietin (EPO) with or without granulocyte colony-stimulating factor plus supportive care (SC; n = 53) versus SC alone (n = 57) for the treatment of anemic patients with lower-risk myelodysplastic syndromes. The response rates in the EPO versus SC alone arms were 36% versus 9.6%, respectively, at the initial treatment step, 47% in the EPO arm, including subsequent steps. Responding patients had significantly lower serum EPO levels (45% vs 5% responses for levels 〈 200 mU/mL vs ≥ 200 mU/mL) and improvement in multiple quality-of-life domains. With prolonged follow-up (median, 5.8 years), no differences were found in overall survival of patients in the EPO versus SC arms (median, 3.1 vs 2.6 years) or in the incidence of transformation to acute myeloid leukemia (7.5% and 10.5% patients, respectively). Increased survival was demonstrated for erythroid responders versus nonresponders (median, 5.5 vs 2.3 years). Flow cytometric analysis showed that the percentage of P-glycoprotein+ CD34+ marrow blasts was positively correlated with longer overall survival. In comparison with SC alone, patients receiving EPO with or without granulocyte colony-stimulating factor plus SC had improved erythroid responses, similar survival, and incidence of acute myeloid leukemia transformation.

Description: MDS are a heterogeneous group of clonal disorders characterized by the development of one or more symptomatic cytopenias. We evaluated the role of erythropoietin (EPO) with or without granulocyte colony stimulating factor (G-CSF) for the treatment of anemic patients with MDS. Patients with refractory anemia (RA n=40), RA with ringed sideroblasts( RARS n=36), and RA with excess blasts (RAEB n= 29) were initially randomized to either supportive therapy (ST) or EPO, 150 u/kg/d. Patients on the ST arm could cross over to the EPO arm if after at least a 4 month period of observation they had a ≥ 50% increase in their transfusion requirement. In patients who did not respond to or did not maintain their response to EPO( 150 u/kg) , G-CSF, 1mcg/kg/d was administered in addition to the EPO. Patients who did not respond after 4 months received an increased dose of EPO at 300u/kg/d + G-CSF. Bone marrow studies and iron stores were evaluated before each change in treatment. Response criteria were CR (complete response), GR (good erythroid response), which required a sustained increase of the pre-transfused Hgb value of 〉 2 g/dl or loss of the transfusion requirement or PR (partial response), defined as a decrease in the transfusion requirement by ≥ 50% or an increase in the Hgb by 〉 1 g/dl above the pretreatment level. A GR or PR must be sustained for at least 4 months. Transformation to acute leukemia was defined as ≥ 30% blasts in the bone marrow. 118 patients were enrolled , 109( 53 EPO, 56 ST) were eligible and 105 were evaluable for response. The median age was 73 (range 37–88 years). The response rate (CR+GR+PR) in the EPO arm was 35% vs. 9% in the ST arm (p=. 002). Of the 23 patients who crossed over from the ST arm, 30% responded to EPO (GR+PR). Six of 27 patients (22%) who received EPO 150u/kg + G-CSF responded (CR+GR+PR). Ten patients received EPO 300 u/kg + G-CSF and 6(60%) responded (CR+GR+PR). Transformation to acute leukemia occurred in 3.6% and 0% in the supportive therapy and EPO arm respectively( P=.50). A complete response (CR) was documented in 2 patients, 1 each on EPO and EPO+G-CSF. There was a survival difference for patients who had an erythroid response: median survival 53 months for responders vs 26 months for non-responders (p=.009). Neither EPO nor the addition of G-CSF was associated with an increase rate of transformation to acute leukemia. Toxicities were comparable in all the treatment arms. The pretreatment serum EPO level correlated with the response to treatment (P=.004): median EPO of 48 vs. 140 mu/ml for responders versus non-responders. Responses were observed in all subtypes. Responses were greater in RA〉RARS〉RAEB. In conclusion, EPO administration was associated with a significant increase in Hgb and a decrease in the transfusion requirement in anemic patients with MDS. Low doses of G-CSF + EPO were effective in EPO nonresponsive or refractory patients. In MDS patients EPO + low dose G-CSF was not associated with progression or transformation to acute leukemia.

Description: 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 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 1. shows 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). DA CLO p-value CR/CRi 43.8% 42.8% p=0.87 30-day mortality 8.5% 7.9% p=0.89 60-day mortality 14.9% 13.1% p=0.58 Gr 4-5 Non-Heme Tox.Induction 27% 19% p=0.02 Gr 4-5 Non-Heme Tox.Consol. 20% 7% p=0.001 374 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 2.NHR 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. Figure 1. Weighted Kaplan-Meier Curves for OS Figure 1. Weighted Kaplan-Meier Curves for OS Figure 2. Unfavorable Cytogenetics OS by Therapy Figure 2. Unfavorable Cytogenetics OS by Therapy Disclosures Off 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.

Description: While recent research has greatly enhanced understanding of the pathology of the disease, and new treatment modalities have been developed, little is known about myelodysplastic syndromes (MDS) from the patient’s perspective. The purpose of this qualitative study was to explore the impact of MDS on patients’ quality of life (QOL). Five focus groups were convened at different geographic locations throughout the United States; 70 MDS patients attended and 62 actively participated in the discussions (89%). The framework for the study was based on Ferrell’s work exploring the impact of cancer on QOL (Oncology Nursing Forum, 1996). Exploratory in nature, the discussions often proceeded in differing directions, but the core open-ended questions were asked at each session. Sessions were tape recorded and professionally transcribed. Transcripts were coded and emerging themes identified using thematic analysis methods aided by the qualitative analysis program N5 (QSR International). The patient sample was 93% Caucasian, 51% male, with a mean age of 69 ± 9 years; 26% lived alone. Known MDS subtype was: 19 RA, 19 RARS, 11 RAEB, 3 5q-, 2 other (16 unknown); median time since diagnosis was 26 months (3 – 276 months). MDS treatment varied considerably: 73% of patients received growth factors, 61% transfusions, 19% azacitidine, 16% thalidomide, 14% iron chelation; 29% all other; many patients received multiple (often concurrent) therapies. Findings from the focus groups revealed a multifaceted description of how MDS can affect one’s QOL. QOL was typically defined by these patients as maintaining functional ability and independence, sustaining positive relationships, and maintaining control over one’s life. In contrast, MDS was found to cause a substantial and sustained decrease in one’s ability to function in a variety of areas, in part due to fatigue (reported by 81% of the patients). QOL was adversely affected by the work expended on managing the disease: frequent office visits, monitoring symptoms, administering therapy, and managing side effects. Family functioning was also disrupted, with family members resuming patients’ roles, limiting activities, and providing direct care. Interestingly, the emotional impact from MDS was often viewed as more problematic than the physical impact; emotional reactions included shock, anger, depression, and anxiety. In contrast, spiritual well-being was often enhanced, with a renewed appreciation for life, relationships, and faith (29% of patients). Many patients (50%) voiced concern about their future and the inability to plan for it effectively. Frustration with their current status caused the majority of patients to continue to seek out additional information about MDS and potential treatment options, as well as to make attempts to take some control over a seemingly uncontrolled situation. Data from this study suggest that MDS has a substantial, often negative impact on patients’ lives, and clinicians should be cognizant of this impact. Moreover, attention must be directed at providing more comprehensive support for the patient, including utilizing ancillary support services, throughout the illness trajectory. In so doing, the adverse impact of MDS on patients’ QOL may be diminished.

Description: Background: The results of the primary endpoint of the E2906 North American Intergroup phase 3 trial - demonstrating significantly inferior OS after single agent clofarabine versus standard intensive daunorubicin & cytarabine induction and consolidation - strongly support the use of intensive therapy for patients age ≥60 years with newly-diagnosed AML who are fit for treatment. This result was achieved despite similar CR rates (including CRi - CR with incomplete blood count recovery) and similar early (30- & 60-day) induction mortality between study arms, raising the question as to the importance of achieving CR as an endpoint. Therefore, we performed a follow-up analysis to address the factors that contribute to early mortality, the necessity for 2nd induction cycle to achieve CR, and to assess the survival impact of the quality of remission. Methods: E2906 design, study population and results for the primary objective were reported previously (ASH 2015, abstr. #217a). We performed this updated analysis to evaluate clinical risk factors for early mortality and re-induction, and to assess the impact of response quality on OS. Univariate comparisons were made with Fisher's exact test (category) and t-test (continuous variable), and logistic regression models were used to examine risk factors associated with early mortality, and with requiring a 2nd cycle of induction therapy. We performed a landmark analysis (beginning Day 60 after initiation of therapy) to determine the impact of response quality (CR/CRi, morphologic leukemia-free-state (MLFS), and treatment failure - i.e. residual/refractory AML) on OS. Survival comparisons were performed with log-rank test. Results: A total of n=727 patients were registered to E2906, the median age is 68 years (range 60-86) and the median follow-up of surviving patients is now 18.3 months. Adjusting for treatment, cytogenetic risk group, FAB subtype, WBC count, and secondary AML, increasing age (p=0.06) and performance status (PS) 〉1 (p=0.05) were associated with 30-day mortality and only PS 〉1 (p=0.06) with 60-day mortality. Treatment arm (p=0.003), adverse cytogenetic risk group (p=0.02), increasing age (p=0.03) and baseline WBC

Description: Most physicians presume their relationship with the patient is a crucial component when managing chronic illness, such as myelodysplastic syndromes (MDS). This assumption was validated in a convenience sample of 70 adults with MDS who participated in five focus groups throughout the United States. The primary purpose of this qualitative study was to explore the impact of MDS on patients’ quality of life (QOL). The groups were facilitated by an advanced practice nurse with clinical expertise in MDS and qualitative research experience. Given the exploratory nature of the study design, discussions proceeded in differing directions; however, core questions were asked at each session (based on Ferrell’s work exploring QOL in patients with cancer (Oncology Nursing Forum, 1996). Sessions were audio-taped and professionally transcribed. Transcripts were coded and emerging themes identified using thematic analysis methods aided by the qualitative analysis program N5 (QSR International). The sample was 93% Caucasian, 51% male, with a mean age of 69 ± 9 years; 26% lived alone. Known MDS subtype was: 19 RA, 19 RARS, 11 RAEB, 3 5q-, 2 other (16 unknown); median time since diagnosis was 26 months (3 - 276). 73% received growth factors, 61% transfusions, 19% azacitidine, 16% thalidomide, 14% iron chelation; 29% all other; many patients received multiple (often concurrent) therapies. A significant finding from the focus groups revealed a detailed depiction of the patient-physician relationship from the patient’s perspective (discussed by 46 of the 62 patients who actively participated). Patients acknowledged many barriers that interfered with the relationship. These barriers were system related (e.g., extreme time constraints for physicians, priority to others who were more ill) or treatment related (e.g., lack of cure, limited treatment options). In addition, patients identified physician attributes that adversely impacted the relationship, including seeming indifference to the patient’s concerns, displays of arrogance, limited knowledge about MDS and its treatment, and especially, lack of confidence in managing the illness. In contrast, positive physician attributes that enhanced the relationship included: providing comprehensible explanations, willingness to seek assistance or opinions from MDS experts when the physician was unsure of the best treatment approach, and displays of compassion and concern. Patients identified displaying respect and interest in them as individuals as essential elements in establishing and maintaining a therapeutic relationship. Patients reacted to a difficult patient-physician relationship in various ways. Those patients who ascribed to the view that a physician had a revered position and was not to be challenged tended to suffer in silence, and remained anxious or depressed. Other patients described a more proactive position, where they continually sought new information about the disease and managing side effects and even felt responsible to explore other treatment options. However, this approach required much work and energy, and did not consistently alleviate the patient’s anxiety. MDS is a complex disease, where advances in understanding its pathology and identifying new treatments are beginning to have an impact in routine clinical practice. Data from this study suggest that physicians need to be aware of the barriers present in the patient-physician relationship and strive to ameliorate them. In so doing, patient’s anxiety, depression, and hyper-vigilance may be diminished, and quality of life enhanced.