CALGB Trial Research Articles

Progress in radiotherapy for small‐cell lung cancer

AbstractSmall‐cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor that is prone to spread extensively. Compared to non‐small‐cell lung cancer (NSCLC), SCLC treatment progresses slowly. Although SCLC is highly sensitive to chemotherapy during the initial treatment, most patients still experience resistance and recurrence after receiving chemotherapy. A meta‐analysis demonstrated that thoracic radiotherapy (TRT) improves overall survival in SCLC. The results of the CALGB and CONVERT trials provide evidence for the efficacy of once‐daily high‐dose TRT. TRT at 60 Gy administered twice daily significantly improved survival without increasing toxicity. The long‐standing debate over the optimal timing of radiotherapy has not been fully resolved. SBRT has excellent local control rates and is a safe and effective treatment option for patients with stage I or II SCLC. Prophylactic cranial irradiation (PCI) is used to reduce treatment‐related neurotoxicity to the extent that there has been a recent discussion on whether magnetic resonance imaging (MRI) monitoring can replace PCI. Radiotherapy combined with immunotherapy significantly improves the survival rate of patients with NSCLC; however, its clinical effectiveness has not been systematically explored in patients with SCLC. Therefore, we summarize the evolving therapeutic strategies, (TRT for limited stage‐SCLC and consolidative TRT for extensive stage‐SCLC) and improved radiotherapy techniques (role of SBRT in stage I or II node‐negative SCLC, progress of PCI, and stereotactic radiosurgery), and discuss the possibilities and prospects of radiotherapy combined with immunotherapy for SCLC.

Phase I Study of Ixazomib Added to Chemotherapy in 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 (CR) of approximately 60% and 3-year survivals (OS) of less than 15%. Intensified treatment in a later CALGB trial showed little improvement with a CR=61% and 5-year OS=6% (Stock, Cancer 2013). 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 early efficacy of adding ixazomib to a current MGH-DFCI/HCC multi-agent regimen 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. Patients with mature ALL (including Burkitt's) were excluded. Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible, and dasatinib was added to the chemotherapy on Day 10 for these patients. The chemotherapy treatment schedule from induction through maintenance is outlined in Table 1. A standard 3 + 3 patient cohort dose escalation design was used to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients, the primary objective of the trial. After consolidation I, patients in complete remission (CR) with a suitable donor were offered a hematopoietic stem cell transplantation (HSCT) as per institutional guidelines. Those not going to HSCT continued therapy as noted in the table. Results: There were 19 patients with B-ALL enrolled, none with T-ALL. Among these patients, 7 harbored BCR-ABL1 rearrangements. The median age was 65 years, 74% were male, and 90% had a performance status 0 or 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 (Table 2). Grade 3 and 4 toxicities encountered at any time consisted mainly of grade 4 neutropenia in 13 patients and grade 4 thrombocytopenia in 12 patients. One patient experienced grade 3 neutropenia and 5 patients experienced grade 3 thrombocytopenia. Two patients with grade 2 neuropathy did not meet the definition of DLT. Among the 19 patients, 15 (79%, [95% confidence interval (CI), 54-94%]) achieved CR (14) or CRi (1), and 5 patients went on to HSCT. The median follow-up time was 2 years (range, 1-5) for 8 patients remaining alive. The 1-year overall survival estimate was 53% [95% CI, 29-72%], while the 2-year overall survival estimate was 47% [95% CI, 24-67%]. Conclusions: A dose of 2.3 mg of ixazomib in combination with induction chemotherapy among older patients with ALL was well-tolerated and associated with a promising rate of complete remission. Disclosures Amrein: Takeda: Research Funding; AstraZeneca: Consultancy, Research Funding; Amgen: Research Funding. Brunner:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Hobbs:Novartis: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding. Neuberg:Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company. Fathi:Takeda: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Blueprint: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy. OffLabel Disclosure: MLN 9708, ixazomib is FDA approved for multiple myeloma. In this trial it is used to treat acute lymphoblastic leukemia.

The Influence of Histologic Grade on Outcomes of Elderly Women With Early Stage Breast Cancer Treated With Breast Conserving Surgery With or Without Radiotherapy

BackgroundTwo large randomized trials, CALGB 9343 and PRIME II, support omission of radiotherapy after breast conserving surgery (BCS) in elderly women with favorable-risk early stage breast cancer intending to take endocrine therapy. However, patients with grade 3 histology were underrepresented on these trials. We hypothesized that high-grade disease may be unsuitable for treatment de-escalation and report the oncologic outcomes for elderly women with favorable early stage breast cancer treated with BCS with or without radiotherapy. Materials and MethodsThe Surveillance, Epidemiology, and End Results database was queried for women between 70 and 79 years of age with invasive ductal carcinoma diagnosed between 1998 and 2007. This cohort was narrowed to women with T1mic-T1c, N0, estrogen receptor-positive, invasive ductal carcinoma treated with BCS with or without external beam radiation (EBRT). The primary endpoints were 5- and 10-year cause-specific survival (CSS). Univariate and multivariate analyses were performed. Propensity-score matching of T-stage, year of diagnosis, and age was utilized to reduce selection bias while comparing treatment arms within the grade 3 subgroup. ResultsA total of 12,036 women met inclusion criteria, and the median follow-up was 9.4 years. EBRT was omitted in 22% of patients, including 21% with grade 3 disease. Patients in the EBRT cohort were slightly younger (median, 74 vs. 75 years; P < .01) and had fewer T1a tumors (11% vs. 13%; P = .02). Histologic grades 1, 2, and 3 comprised 36%, 50%, and 14% of the cohort, respectively, and there were no differences in EBRT utilization by grade. Utilization of EBRT decreased following the publication of the CALGB trial in 2004 decreasing from 82% to 85% in 1998 to 2000 to 73% to 75% in 2005 to 2007 (P < .01). Unadjusted outcomes showed that in grade 1 disease, there were no differences in CSS with or without EBRT at 5 (99%) and 10 years (95%-96%). EBRT was associated with an improvement in CSS in grade 2 histology at 5 years (97% vs. 98%) and 10 years (92% vs. 95%) (P = .004). The benefit was more pronounced in grade 3 disease with CSS increasing from 93% to 96% at 5 years and from 87% to 92% at 10 years (P = .02) with EBRT. In the grade 3 subgroup, propensity-score matching confirmed EBRT was associated with superior CSS compared with surgery alone (hazard ratio, 0.58; 95% confidence interval, 0.34-0.98; P = .043). ConclusionIn this database analysis, omission of radiotherapy after BCS in elderly women with favorable-risk, early stage, grade 3 breast cancer was associated with inferior CSS. Further prospective data in this patient population are needed to confirm our findings and conclusions.

Individualized, Low Dose, Fixed Duration Lenalidomide Maintenance Is an Effective Strategy in High MRD Disease Post Chemo-Immunotherapy in CLL: Outcomes of a Randomized Controlled Trial

Introduction Chemo-immunotherapy (CIT) continues to be an acceptable treatment option in CLL without deletion 17. Patients with early progression (&lt;2 years) have poor response to second line chemoimmunotherapy and a reduced PFS with every subsequent relapse. In developed countries, novel agents like ibrutinib and venetoclax are the standard of care for relapsed CLL and are finding approval as part of frontline therapy as well. In middle to low socio demographic index (SDI) countries, these drugs cost 4 to 40 times the per capita GDP and are unlikely to be affordable to a majority in near future. Therefore, strategies to prolong PFS and the time to next treatment are still relevant in these settings. Lenalidomide has shown promise as maintenance treatment in CLL in two large randomized trials (CLLM1 and CALGB). In this randomized trial, we evaluated the efficacy and safety of individualized, low dose, fixed duration, lenalidomide maintenance versus observation in non-deletion 17p CLL. Methods The study period was from January 2018 to June 2019. CLL patients who had achieved at least partial remission (iwCLL response criteria) after frontline CIT were included in the study. Patients with deletion 17p or mutated TP53 were excluded. Baseline and follow-up bone marrow MRD assessment was done using 8-color flow cytometry with a detection threshold of 10-4. MRD was classified into three groups; nil: &lt; 10-4, intermediate: 10-4 to 10-2 and high: &gt;10-2. Patients were randomly assigned to lenalidomide maintenance or observation. Lenalidomide was started at 5 mg every alternate day and escalated to a maximum dose of 10 mg daily in a 20/28 day schedule as per patient tolerance. Maintenance therapy was given for a fixed duration of 6 cycles. PFS was defined as the time from study recruitment to progression or death due to any cause. Haematological toxicity was graded using the iwCLL guidelines for grading of toxicity and other adverse events were graded according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE). Results A total of 32 patients were included in the study and randomized to lenalidomide maintenance (n=19) or observation (n=13). The two arms were matched for cytogenetics, comorbidity burden, disease status and MRD at recruitment. At a median follow up of 10.5 months, median PFS was not reached for either arm with no significant difference between the two arms (p=0.338). High MRD at the end of treatment was associated with an increased risk of early progression (p=0.165). Lenalidomide showed PFS benefit in the high MRD subgroup (median PFS 7 months vs. not reached), with a trend towards statistical significance (p=0.067) (see figure). Skin toxicity was the most common adverse event and was more common in the lenalidomide arm (63.2%). Grade 3 neutropenia was reported in only 5.3% patients in the lenalidomide arm. Incidence of grade 3 or more severe infections was not different between the two arms. Conclusions Maintenance therapy with 6 cycles of dose-escalated lenalidomide is safe and may afford PFS benefit in patients with non-deletion 17p CLL and high MRD at the end of frontline chemo-immunotherapy. The CLLM1 and the CALGB trials had a fixed ramp up dosing schedule of lenalidomide and reported more adverse events (38% and 71% grade 3/4 neutropenia) compared to our individualized, low dose lenalidomide protocol. The encouraging results of this study warrant further investigation into the role of lenalidomide maintenance in CLL in larger trials, especially in low and middle SDI setting where access to novel agents is limited and is going to remain so in the foreseeable future. Figure Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Lenalidomide maintenance in CLL

Cost-Effectiveness Analysis of Lenalidomide for Maintenance Therapy after Autologous Stem Cell Transplant (ASCT) in Newly Diagnosed Multiple Myeloma (NDMM) Patients: A United States Payer Perspective

Introduction: ASCT in multiple myeloma (MM) is associated with prolonged progression-free survival (PFS) compared with chemotherapy alone. Studies have shown that lenalidomide maintenance therapy after ASCT significantly improves PFS and overall survival (OS) in patients (pts) with NDMM. Although post-ASCT lenalidomide maintenance therapy is approved by the US FDA and the EMA for pts with MM, a small percentage of pts either use bortezomib or no maintenance in this setting. The current study aimed to assess the cost-effectiveness of lenalidomide maintenance versus no treatment or bortezomib maintenance after ASCT in pts with NDMM from a US third-party payer perspective.Methods: A partitioned survival model with a 28-day cycle was developed to estimate costs and outcomes of lenalidomide maintenance versus either no treatment or bortezomib maintenance therapy after ASCT among pts with NDMM over a lifetime time horizon. The model included four health states: PFS on treatment, PFS off treatment, progressed disease, and death. The OS and PFS for lenalidomide and no treatment arms were estimated using observed data from the phase 3 CALGB trial. Crossover adjustment was implemented to adjust for the potential diluting effects introduced by pts crossing over to lenalidomide from the no treatment arm before progression in the CALGB trial. Time on treatment for lenalidomide was estimated using the observed data in the pooled phase 3 trials (CALGB, IFM, GIMEMA). Efficacy inputs for bortezomib maintenance were estimated based on published literature. Standard parametric models were fitted to extrapolate OS and PFS for each treatment, and best fit was determined based on Akaike or Bayesian information criterion and clinical judgement. OS was adjusted using natural mortality rates in the USA. Treatment costs (including drug and drug administration costs), post-progression treatment costs, adverse event (AE) costs, and medical costs associated with health states were obtained from publicly available databases, literature, and real-world data. All costs were inflated to 2018 US dollars. Utilities for each health state and disutilities associated with AEs were obtained from the literature. Incremental costs per quality-adjusted life year (QALY) and life year (LY) gained were estimated comparing lenalidomide maintenance therapy with each comparator. Deterministic sensitivity analyses (DSAs) were performed to test the robustness of the results.Results: Over a lifetime time horizon, lenalidomide maintenance was associated with an increase of 3.64 and 2.76 in LYs compared with no treatment and bortezomib maintenance, respectively; and an increase of 2.99 and 2.42 in QALYs, respectively. Pts in the lenalidomide maintenance arm incurred higher total direct costs with an incremental cost of $476,690 and $412,872 versus no treatment and bortezomib maintenance, respectively. Initial and post-progression treatment costs comprised the majority of direct costs. The annual treatment costs for lenalidomide maintenance decreased by 49% and 86%, 3 years and 5 years after treatment initiation, respectively.Incremental cost per LY gained for lenalidomide maintenance versus no treatment and bortezomib maintenance was $130,817 and $149,411, respectively, and incremental cost per QALY gained was $159,240 and $170,408, respectively. The base-case results suggest that lenalidomide is cost-effective at a willingness-to-pay threshold of $200,000.Results from the DSA generally supported the base-case findings, with the largest variation observed when time horizon and treatment costs for lenalidomide were varied. Longer time horizons yielded greater cost-effectiveness for lenalidomide because of the reduction in treatment costs and increased effectiveness benefits. Lower initial treatment costs also yielded greater cost-effectiveness for lenalidomide.Conclusions: Over a lifetime time horizon, compared to no treatment and treatment with bortezomib, lenalidomide maintenance resulted in better effectiveness with incremental QALYs of 2.99 and 2.42, respectively, favorable incremental cost-effectiveness ratios, and an OS advantage. Annual treatment costs for lenalidomide decrease with incremental effectiveness increasing over time. Lenalidomide maintenance after ASCT offers a cost-effective strategy in the treatment of pts with NDMM from a US third-party payer perspective. DisclosuresZhou:Celgene Corporation: Research Funding; Analysis Group, Inc.: Employment. Parikh:Celgene Corporation: Employment, Equity Ownership. Chai:Celgene Corporation: Research Funding; Analysis Group, Inc.: Employment. Rokito:Analysis Group, Inc.: Employment; Celgene Corporation: Research Funding. Udeze:Celgene Corporation: Employment. Xie:Celgene Corporation: Research Funding; Analysis Group, Inc.: Employment. Agarwal:Celgene Corporation: Employment.

Genomic Characterization and Experimental Modeling Of BCR-ABL1-Like Acute Lymphoblastic Leukemia

BCR-ABL1-like B-progenitor acute lymphoblastic leukemia (B-ALL) accounts for 10-15% of childhood B-ALL and is characterized by alteration of IKZFI, a gene expression profile similar to BCR-ABL1 ALL and poor outcome. Using next-generation sequencing, we have shown that BCR-ABL1-like ALL patients harbor genetic alterations activating kinase pathways that are sensitive to tyrosine kinase inhibitors (TKIs), and have shown that refractory BCR-ABL1-like ALL is responsive to TKIs in vivo (Weston et al., J. Clin. Oncol 2013). Furthermore, the outcome of ALL in adolescent and young adult (AYA) patients is inferior to children, yet the genetic basis underlying treatment failure is poorly understood.To define the frequency and genomic landscape of BCR-ABL1-like ALL in children, adolescents, and young adults we have extended our studies to include 665 high-risk childhood (<16 years, 14% BCR-ABL1-like), 370 adolescent (16-21 years, 21% BCR-ABL1-like) and 161 young adult (21-39 years; 26% BCR-ABL1-like) B-ALL cases from the Children's Oncology Group, St Jude Children's Research Hospital, Eastern Cooperative Oncology Group, MD Anderson Cancer Center and the Alliance - CALGB trials. Event-free survival (EFS) for BCR-ABL1-like cases was inferior to non BCR-ABL1-like cases with 5-year EFS rates of 40.0±7.1 vs 85.0±3.3 (p<0.0001) for adolescent cases and 16.1±8.5 vs 57.9±8.0 (p=0.006) for young adult cases. In each age group, 50-60% of BCR-ABL1-like cases harbored rearrangements of CRLF2 (IGH@-CRLF2 or P2RY8-CRLF2) (Fig. 1).To characterize the full spectrum of kinase lesions in the remaining BCR-ABL1-like ALL cases we performed mRNA-seq on pediatric (n=39), adolescent (n=21) and young adult (n=22) cases, and whole genome (WGS; n=18) or exome sequencing (n=10) on cases with matched tumor and normal material. Fusion transcripts were identified using deFuse and CICERO, a novel assembly-based structural variation detection method specifically designed for mRNA-seq analysis. We identified 23 different kinase rearrangements involving 7 tyrosine kinase or cytokine receptor genes. These consist of 5 ABL1, 2 PDGFRB, 8 JAK2 fusions and 2 EPOR translocations to IGH@ and IGK@ loci, along with new fusions involving the tyrosine kinases ABL2 (n=3), CSF1R (n=1), AKT2 (n=1) and STAT5B (n=1). We performed frequency testing for 15 of these fusions on 555 cases from the COG AALL0232 trial of high-risk B-ALL. Several alterations were recurrent in BCR-ABL1-like ALL, including NUP214-ABL1, RCSD1-ABL2, SSBP2-CSF1R, PAX5-JAK2 and EPOR translocations. Notably, we did not identify any of these fusions in non BCR-ABL1-like cases. The frequency of ABL1/ABL2 and EPOR translocations was consistent across all age groups (∼16% and 7% of BCR-ABL1-like cases, respectively), while JAK2 rearrangements were more common in young adult than in pediatric and adolescent ALL (12%). Importantly, ∼10% of BCR-ABL1-like ALL cases lacked a kinase-activating alteration on analysis of mRNA-seq data. Notably, we identified two additional cases with IL7R or SH2B3 sequence mutations, indicating the requirement for complementary approaches such as WGS to fully define the genomic landscape of BCR-ABL1-like ALL.Current functional studies include the development of experimental models using the Ba/F3 hematopoietic progenitor cell line, primary mouse pre-B cultures and the generation of xenografts to determine the role of these alterations in leukemogenesis, and to enable testing of targeted therapies. For example, we show that RCSD1-ABL1 and SSBP2-CSF1R confer factor-independent growth and constitutive activation of JAK/STAT pathways in Ba/F3 cells. Furthermore, RCSD1-ABL1 and SSBP2-CSF1R are both sensitive to the TKIs, imatinib (IC50 378nM and 327nM, respectively) and dasatinib (IC50 2.1nM and 2.5nM, respectively). Together, these complementary approaches will further define the genetic landscape of both pediatric and AYA ALL, and facilitate the development of diagnostic and therapeutic strategies to improve the treatment outcome for high-risk BCR-ABL1-like ALL patients. [Display omitted] Disclosures:Hunger:Bristol Myers Squibb: Consultancy.

Integrated Genomic and Mutational Profiling Of Adolescent and Young Adult ALL Identifies a High Frequency Of BCR-ABL1-Like ALL with Very Poor Outcome

The genetic basis underlying inferior outcome of adolescent and young adult acute lymphoblastic leukemia (AYA ALL) as compared to childhood cases is largely unknown. To comprehensively characterize the genetic landscape of AYA ALL we studied 423 adolescent (16-21 yrs; median 17.7±1.3 yrs) and 250 young adult (21-39 yrs; median 28.3±7.0 yrs) samples from the Children's Oncology Group high-risk trial AALL0232, St Jude Children's Research Hospital Total XV and XVI, Eastern Cooperative Oncology Group E2993, MD Anderson Cancer Center and the Alliance - CALGB trials. Single nucleotide polymorphism (SNP) microarray analysis and gene expression profiling were performed to identify copy number alterations and distinct genetic subgroups. Samples were also sub classified using hierarchical clustering, ROSE outlier and PAM analysis of gene expression profiling data. Sequence mutation analysis was performed on candidate genes known to be mutated in pediatric ALL (including IKZF1, PAX5, JAK1/2, NRAS, KRAS, FLT3, IL7R, SH2B3, TP53 and CREBBP), and mRNA-seq was performed on selected BCR-ABL1-like cases (n=41).The genetic subgroups were divided into ETV6-RUNX1, TCF3-PBX1, hyperdiploid (>50 chromosomes), MLL rearrangements, BCR-ABL1, BCR-ABL1-like, ERG and other (cases with no known lesions). As expected, ETV6-RUNX1 and hyperdiploid ALL were less frequent in adolescents (4% and 11%, respectively) and adults (2% for both) than in childhood ALL (<16 years; 25% for both). In contrast, the frequency of BCR-ABL1-like ALL, a recently described subgroup in 10-15% of pediatric ALL associated with kinase-activating lesions and a poor outcome, was very frequent and increased with age (21% in adolescent, 25% in young adults), similar to cases with the classic BCR-ABL1 translocation (6% in adolescent, 22% in young adults).Notably, BCR-ABL1 and BCR-ABL1-like ALL patients presented with higher white blood counts at diagnosis compared to non BCR-ABL1-like ALL patients in both adolescents (117.6 and 76.8 vs 21.9 x109/L, p<0001), and young adults (72.6 and 94.1 vs 17.6 x109/L, p<0001). BCR-ABL1-like ALL patients were also more likely to be male compared to non BCR-ABL1-like ALL patients, with 74% vs 62% in adolescents (p<0.05; Fisher's exact test), and 81% vs 63% in young adults (p=0.07; Fisher's exact test). The outcome of BCR-ABL1 and BCR-ABL1-like ALL was markedly inferior to other ALL subtypes, with 5-year event free survival (EFS) rates of 53.7+18.3 and 40.0+7.1 vs 85.0±3.3 (p<0.0001) in adolescent cases, and 23.2±9.1 and 16.1±8.5 vs 57.9±8.0 (p=0.006) for young adults (Figure 1). IKZF1 alterations, a marker of poor outcome in pediatric ALL, were enriched in BCR-ABL1 and BCR-ABL1-like ALL cases (70% and 77%, respectively) compared to non BCR-ABL1-like patients (26%). Regardless of genetic subtype, the presence of an IKZF1 alteration correlated with inferior 5 year EFS in adolescent (60.3±6.0 vs 77.4±4.1; p=0.0015) and young adults (25.7±7.0 vs 52.7±6.4; p=0.0011). [Display omitted] We then sought to characterize the alterations activating kinase signaling in AYA BCR-ABL1-like ALL cases. As observed in pediatric ALL, approximately 55% of these cases harbored CRLF2 rearrangements. Using mRNA-seq we identified a variety of additional rearrangements involving the tyrosine kinase or cytokine receptor genes ABL1, ABL2, CSF1R, JAK2, EPOR or PDGFRB, with a marked enrichment of fusions involving JAK2 (6 different fusions in 9/20 cases sequenced), thus providing a rationale for the investigation of targeted therapies directed against these alterations. Collectively, the kinase-activating BCR-ABL1 and BCR-ABL1-like subtypes are associated with poor outcome and make up ∼25% of adolescent and ∼50% of young adult ALL patients. The identification of these patients at diagnosis will provide an opportunity to incorporate tyrosine kinase inhibitor treatment to current chemotherapeutic regimens, and significantly improve the treatment outcome for AYA ALL. Disclosures:Hunger:Bristol Myers Squibb: Consultancy.

High-Dose Cytarabine Consolidation (≥1.5 g/m2) Might Have Shown a Better Outcomes Than Intermediate-Dose Cytarabine (1.0 g/m2) Combined With Anthracyclines In AML Patients Who Had Achieved Complete Remissions In The First Induction by Standard 3+7 Regimen

▪ PurposeBased on CALGB trial in 1994, 3-4 cycles of high-dose cytarabine have been one of the standard consolidation therapies. Despite the confirmed efficacy of anthracyclines for remission induction, the role of anthracyclines for postremission consolidation is a subject still under debate. In this retrospective analysis, we compared the efficacy of high-dose cytarabine (>=1.5 g/m2) and intermediate-dose cytarabine (1 g/m2) combined with anthracyclines as postremission therapy. MethodsThe patients enrolled in the Korea University AML registry from September 2002 to August 2011 were analyzed. Inclusion criteria were as follows; 1) Complete remission was achieved in first induction by standard 3+7 regimen (idarubicin 12 mg/m2 or daunorubicin 45 or 60 or 90 mg/m2 on D1-3 + cytarabine 100 mg/m2 on D1-7) 2) Postremission therapy was performed for 3-4 cycles by one of the following regimen; Arm A (high-dose cytarabine): cytarabine 3 g/m2 for patients =< 60 years old or 1.5 g/m2 for patients > 60 years old, q 12 hours on D1, 3, 5. Arm B (intermediate-dose cytarabine combined with anthracyclines): cytarabine 1.0 g/m2 q 12 hours on D1-3 combined with mitoxantrone or idarubicin 12 mg/m2 on D1,2. Univariate and multivariate analysis for survival were performed by Kaplan-Meier and Cox-regression analysis, respectively. ResultsAmong 172 AML patients enrolled in the registry, 95 patients (55%) were satisfactory for inclusion criteria. The number of arm A and B was 51 and 44, respectively. Some patients (N=47) with intermediate or high-risk cytogenetics have undergone autologous or allogeneic stem cell transplantation. Univariate analysis for relapse-free survival (RFS) demonstrated that age (=< 60 vs. >60, p=0.007), stem cell transplantation (p=0.001), and consolidation regimen (Arm A vs. Arm B, p=0.007) were statistically significant. The median RFS of arm A was not reached and significantly superior to that of arm B (14.0 months, 95% CI 8.5 months to 19.5 months) (Figure 1). Multivariate analysis showed that stem cell transplantation (HR 0.384, 95% CI 0.195 to 0.758, p=0.06) and consolidation regimen (HR 0.454, 95% CI 0.237 to 0.872, p=0.018) were independently significant factors for RFS. With regard to overall survival (OS), age (p<0.001), performance status (ECOG 0,1 vs. 2,3, p<0.001), WBC count at diagnosis (<20000/μL vs. >=20000/μL, p=0.033), WHO classification (de novo vs. secondary, p=0.05), stem cell transplantation (p=0.001), and consolidation regimen (p=0.007) were statistically significant by univariate analysis. The median OS of arm A was also not reached and significantly superior to that of arm B (18.1 months, 95% CI 7.7 months to 28.5j months) (Figure 2). Multivariate analysis for OS showed that age (HR 0.482, 95% CI 0.248 to 0.939, p=0.032), stem cell transplantation (HR 0.469, 95% CI 0.244 to 0.899, p=0.023), and consolidation regimen (HR 0.474, 95% CI 0.252 to 0.894, p=0.021) were independently significant factors. There was no statistical significance in treatment-related mortality between arm A and arm B (7% and 4%, respectively, p=0.541). [Display omitted] [Display omitted] ConclusionsThis analysis showed that as compared with intermediate-dose cytarabine (1.0 g/m2) combined with anthracyclines, high-dose cytarabine consolidation (>=1.5 g/m2) was independently favorable factor for both RFS and OS in AML patients who had achieved complete remissions in first induction by standard 3+7 regimen. Based on this study, we hypothesize that the addition of anthracycline during consolidation might have a limited value as compared with cytarabine intensification. The confirmatory prospective trial should be required. Disclosures:No relevant conflicts of interest to declare.

Survival analysis of induction cisplatin (CDDP)-docetaxel (DOC)-bevacizumab (BEV) chemotherapy followed by maintenance BEV-pemetrexed (PEM) therapy in advanced nonsquamous non-small cell lung cancer (NonSq NSCLC): A phase II trial from Okayama Lung Cancer Study Group 0903.

e19040 Background: BEV maintenance therapy and PEM maintenance therapy in platinum-based chemotherapy yield a significant survival advantage in CALGB and PARAMUNT trials, respectively, but each agent gave only modest impact on survival. We conducted a phase II trial of CDDP-DOC-BEV therapy followed by maintenance BEV-PEM therapy inchemo-naïve advanced NonSq NSCLC. Methods: Forty-one patients (pts) participated in the induction phase, specified as four cycles of induction CDDP (80 mg/m2), DOC (60 mg/m2) and BEV (15 mg/kg) on day 1 of a 21-day cycle. Pts who had not progressed during CDDP-DOC-BEV received maintenance BEV (15 mg/kg) and PEM (500 mg/m2) on day 1 of a 21-day cycle until disease progression. The primary endpoint was PFS, and the secondary endpoints included OS, toxicity, and response. Survival time was calculated from the date of registration. Results: Pt characteristics were as follows: median age: 62 yrs; 76% male; 32% PS 0; 73% stage IV; 93% Ad; 5% EGFR-mutant and 2% ALK-mutant. At the time of this analysis, 34 pts (83%) discontinued the treatment, mainly due to progressive disease (53%). The principal toxicity was myelosuppression (gr. 4 hematological: 21 pts [51%]), and grs. 3/4 febrile neutropenia was observed in 10 (24%) despite no treatment-related deaths. The objective response rate and disease control rate (DCR, % pts with CR/PR/SD) was 82.9% and 97.6%, respectively. Median follow-up time was 15.6 months, and 1-yr PFS rate was 34.2% with 95% confidence interval (CI) of 20.3-48.5%, which met the primary endpoint. Also, 1-yr OS rate was 75.6% (95%CI: 59.4-86.1%). Exploratory analysis for pts with both EGFR- and ALK-wild-typed NonSq NSCLC (n = 16) demonstrated 1-yr PFS and OS rates of 50.0% (24.5-71.1%) and 87.5% (58.6-96.7%), respectively. Also, pts with maintenance therapy (n = 34) had 1-yr PFS and OS rates of 41.2% (24.8-56.9%) and 82.4% (64.9-91.7%), respectively. Conclusions: CDDP-DOC-BEV followed by BEV-PEM maintenance seems highly effective despite moderately toxic profiles in chemo-naïve pts with advanced NonSq NSCLC. Clinical trial information: UMIN000004127.

MicroRNA Dysregulation in Acute Myeloid Leukemia

In the article that accompanies this editorial, Marcucci et al present data on the clinical significance of the overexpression of miR-155 in patients with cytogenetically normal acute myeloid leukemia (CN-AML). miR-155 is a microRNA that is dysregulated in aggressive lymphomas, in the aggressive form of CLL, and in some solid malignancies such as lung, breast, and colorectal cancer. miR-155 has been shown to inhibit expression of tumor suppressors and genes involved in DNA repair. Interestingly, dysregulation of miR-155 in B cells of mice causes acute lymphoblastic leukemia and high-grade lymphomas. The authors carried out mRNA and microRNA profiling by using microarrays and measured the expression of the transcripts of the miR-155 gene by nCounter technology (NanoString, Seattle, WA), a sensitive amplification independent method. They investigated CN-AML patients, including 153 younger ( 60 years) and 210 older ( 60 years) patients, with untreated primary CN-AML who received intensive first-line therapy on CALGB trials and had diagnostic bone marrow or blood specimens available for molecular analyses. The results of their careful analysis show that miR-155 expression levels constitute an independent prognostic factor in patients with CN-AML. While higher miR-155 expression levels had a negative impact on the outcome of younger and older patients, higher miR-155 expression was associated with lower complete response (CR) rate, and shorter disease-free survival (DFS) and overall survival (OS) in younger patients. Higher miR-155 expression level was associated only with lower CR and shorter OS in older patients. Such findings could be related to biologic differences and differences in the intensity of consolidation therapy. At diagnosis, high miR-155 levels occurred more frequently in patients with AML who were FLT3-ITD positive, RUNX1-mutated, WT1 mutated, and had high ERG and BAALC expressors, and less frequently in CEBPA-mutated, IDH2-mutated and FLT3-tyrosine kinase–positive patients with AML. Thus, higher miR-155 levels associate with unfavorable prognosticators and predict worse CR and survival in both young and old patients. In multivariable analysis, patients with CN-AML with higher levels of miR-155 were approximately 50% less likely to achieve CR. Higher miR-155 expressors had also a 60% increased risk of death and were independent of FLT3-ITD. An international panel of experts on CN-AML on behalf of the European LeukemiaNet recommended a modified classification of patients with CN-AML. When the authors analyzed the prognostic significance of miR-155 in patients classified in the ENL favorable genetic group, younger patients with high miR-155 expression had significantly lower CR rates and shorter event-free survival and OS than patients with low expression, respectively. These correlations were not found with any other microRNA. This is the first clinical study, to our knowledge, where expression of miR-155 was evaluated by using the nCounter technology to understand how different expression levels of miR-155 may affect the aggressiveness of the disease, outcome, and response to treatment of patients with CN-AML. The results indicate that high levels of expression of miR-155 positively correlate with antiapoptotic activity and NF B activation. Although dysregulation of miR-155 in B cells and myeloid cells has been shown to be associated to aggressive malignancy and myeloproliferative disorders respectively in mouse models, the present study tries to assess the role of the dysregulation of this microRNA in patients with CN-AML. Their results support the hypothesis that miR-155 expression contributes to different degrees of aggressiveness in leukemia by affecting proliferation and survival of the leukemia cells. A conclusion of this study, as clearly indicated by the authors, is that if we want to have an effect in the treatment of this group of AML patients, we should try to revert miR-155 overexpression, for example, by using anti-miR-155 oligonucleotides or by inhibiting the pathways that regulate the levels of miR-155 expression. In addition, given that miR-155 is relatively easy to measure at diagnosis, we should consider the levels of miR-155 as a biomarker for risk stratification and guidance for treatment.

The Effects of Azacitidine On Quality of Life: A Prospective Longitudinal Assessment

Abstract 4938The effect of azacitidine (AZA) on health related quality of life (QOL) compared with best supportive care in MDS patients has been evaluated by Kornblith A. et al (JCO 2002) in a prospective randomized CALGB trial. The study demonstrated improved fatigue, dyspnea, physical functioning and psychological state in patients receiving AZA. One limitation is the relatively short follow up (last QOL measured at 8. 6 months) and the lack of validation in a non-trial setting. We have been conducting prospective assessments of QOL in all patients registered at our MDS clinic using the instruments EORTC QLQ-C30, FACT-Fatigue, EQ-5D and a global fatigue scale. We present longitudinal data on 56 registered patients registered in our program who were treated with AZA, 50 with serial QOLs. Methods:We examined and compared QOL scores at AZA start (baseline) and over time in all patients. We considered the following co-variates’ potential impact on QOL scores: age, sex, IPSS, time from diagnosis, being a responder, # cycles and transfusion dependence. We used univariate linear regression analysis for continuous variables and analysis of variance (ANOVA) for categorical variables to determine their relationship with QOL scores at baseline and over time. For time-dependent covariates, linear mixed model was performed with random intercept and unstructured covariance matrix. Clinically significant (CS) score differences were considered 10 points for the QLQ-C30, 4 for the FACT-Fatigue and 0. 08 for the EQ-5D (7 for the visual analog score). The impact of baseline covariates on the QOL scores for global health, fatigue and dyspnea were determined by backward selection procedure of regression analysis using the Bonferroni adjusted P value of <0. 01 for multiple comparisons. Patients provided informed consent for this REB approved study. Results:56 MDS patients consented to our registry have been treated with AZA between Oct 2008 and July 2012. The median age was 72, 60% were male and 77% had int-2/high risk IPSS MDS. 64 % were transfusion dependent (TD) at baseline. With a median time to death or last follow up of 16 months (range 1. 5–45) a median of 11 cycles of AZA were administered with 34% remaining on drug for a median of 25 cycles (IQR 8–32). The overall response rate (ORR) was 62%: 25% CR; 5% MCR; 4% PR; 28% HI. Stable disease (SD) was seen in 26% and not considered a response. 53% became transfusion independent (TI). 59% have died and 61% developed leukemia or progressed to > 30% blasts at a median time of 13 months. Overall survival was 18 months (95% CI 14. 5–26). 50 were evaluable for HrQOL with a median time between each serial QOL of 13 weeks (IQR 10–18). QOL was assessed at baseline (within 12 weeks pre-AZA start) in 50 patients, 2x in 44, 3x in 32, 4x in 22 and 5x in 14 patients (exceeding 52 weeks follow up). Looking at all 50 patients, overall, function and symptom domains remained stable over time in all instruments. At baseline, there were no statistically significant differences in QOL scores between responders and non responders. Nevertheless, clinically important differences were seen in physical, role, cognitive and social functioning, global health status (all higher in responders). Assessing QOL changes over time and considering baseline and time-dependent predictive factors in multivariate analysis, responders had significantly superior global health status (p=. 001) and EQ-5D scores (p=. 0002) and lower levels of fatigue (p<. 0001). If transfusion dependence status at time of QOL was included in the model, this often supplanted response as predictive of higher scores over time, likely representing the strong relationship between response and transfusion dependence. Conclusions:In addition to validating the clinical outcomes of AZA-001 study, we validate the importance of clinical response on QOL in MDS patients treated with AZA. Unlike the CALGB study, we observed relative stability in global health status and fatigue scores in responding patients and overall declines in non-responding patients. The higher scores at baseline in the patients destined for response raises the intriguing possibility that QOL at AZA start may be independently predictive of response perhaps because of improved tolerability and ability to remain on drug for the requisite number of cycles to achieve response. [Display omitted] Disclosures:Wells:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Buckstein:Celgene: Honoraria, Research Funding.

Phase II trial of galiximab (anti-CD80 monoclonal antibody) plus rituximab (CALGB 50402): Follicular Lymphoma International Prognostic Index (FLIPI) score is predictive of upfront immunotherapy responsiveness

This phase II CALGB trial evaluated the activity and safety of an extended induction schedule of galiximab (G) plus rituximab (R) in untreated follicular lymphoma (FL). Patients with previously untreated FL (grades 1, 2, 3a) received 4 weekly infusions of G + R, followed by an additional dose every 2 months four times. International Workshop Response Criteria were used to evaluate response. Sixty-one patients were treated and antibody infusions were well tolerated. The overall response rate (ORR) is 72.1% (95% confidence interval 59.2% to 82.9%): 47.6% complete response (CR)/unconfirmed complete response (CRu) and 24.6% partial response. At a median follow-up time of 4.3 years (range, 0.3-5.3 years) median progression-free survival (PFS) is 2.9 years. Notably, Follicular Lymphoma International Prognostic Index (FLIPI) correlated with ORR, CR rate, and PFS, and the low-risk FLIPI group (n = 12) achieved a 92% ORR, 75% CR/CRu rate, and 75% 3-year PFS. An extended induction schedule of G + R in previously untreated FL is well tolerated and appears particularly efficacious in those patients with low-risk FLIPI scores. In addition, this trial served as the initial platform for additional CALGB 'doublet' combination regimes of rituximab plus other novel targeted agents.

A randomized phase III trial of single-agent pemetrexed (P) versus carboplatin and pemetrexed (CP) in patients with advanced non-small cell lung cancer (NSCLC) and performance status (PS) of 2.

7506 Background: No standard of care exists for patients with advanced NSCLC and PS 2 and clinical practice ranges from supportive care to combination chemotherapy. Methods: In a Brazilian multicenter phase III randomized trial, advanced NSCLC patients, with any histology at first, amended to non-squamous only, PS 2, no prior chemotherapy, and adequate organ function, were randomized to P alone (500 mg/m2) or CP (AUC 5 + same P) administered every 3 weeks for 4 cycles. Stratification factors included stage (IIIB vs. IV); age (≥70 vs. &lt;70); and weight loss (≥5 kg vs. &lt;5kg). The primary endpoint was overall survival and the study was powered to demonstrate an improvement in median survival from 2.9 to 4.3 months based on a prior CALGB trial. Results: A total of 217 patients were enrolled from 8 centers in Brazil and 1 in the US from April 2008 to July 2011. Twelve patients were ineligible and excluded. The 2 arms (P=102; CP=103) were balanced for patient characteristics. 14 patients had squamous and another 12 had unknown histology. The response rates were P = 10% and CP = 24% (p=0.019). In the ITT population, the median PFS was P = 3.0 mo and CP = 5.9 mo (HR=0.46, 95% CI 0.34; 0.63, p&lt;0.001) and median OS was P = 5.6 mo vs. CP = 9.1 mo (HR=0.57, 95% CI 0.41; 0.79, p=0.001). 1-year survival rates were 22% and 39% respectively. Similar results were seen when squamous patients were excluded from the analysis. Grade ¾ anemia (5.5%; 12%) and neutropenia (2.8%; 5.6%) were more frequent in CP. There were 4 treatment-related deaths in the CP arm. 30% of patients in each arm received 2nd line therapy Conclusions: Combination chemotherapy with CP significantly improves survival, with acceptable safety, in eligible patients with advanced NSCLC and PS 2, and represents a new standard.

Second Malignancies in Total Therapy 3 Trials for Newly Diagnosed Multiple Myeloma: Influence of Lenalidomide Versus Thalidomide in Maintenance Phases

Abstract 823 Background:Recent data from IFM, CALGB and GEMIMA trials suggest that utilizing lenalidomide as maintenance therapy is associated with a higher incidence of second cancers, including both hematologic and solid malignancies. Two successive Total Therapy 3 (TT3) trials, one employing as maintenance thalidomide (TT3A, n=303) and the other lenalidomide (TT3B, n=177), after tandem transplants offered the opportunity of investigating whether lenalidomide therapy was associated with greater probability of inducing second malignancies. Patients & Methods: The details of TT3A and TT3B trials and patient outcomes have been reported previously. Briefly, both employed identical induction therapy with 2 cycles of VTD-PACE (bortezomib, thalidomide, dexamethasone plus 4-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide), followed by melphalan 200mg/m2-based tandem autologous transplantation and 2 cycles of dose-reduced VTD-PACE consolidation. Maintenance consisted of VTD in the first year and TD for years 2 and 3 in TT3A, while TT3B employed VRD for all 3 years. All patients had signed an informed consent in keeping with institutional and federal guidelines. For the purpose of this analysis, the MM data base was interrogated for the development of CA-2 arising after protocol initiation and after start of maintenance therapy in TT3 trials. This was based on frequently scheduled positron emission tomography (PET) scanning, performed at baseline and on average every 3 months in the first year and semi-annually thereafter. For the early detection of potential MDS or AML, all bone marrow examinations included metaphase karyotyping and, when indicated because of pathological or clinical suspicion, inter-phase fluorescence in situ hybridization (FISH) for the detection of MDS- and AML- associated abnormalities. Chi-square and Fisher’s exact tests were used to compare baseline characteristics between protocols. Univariate and multivariate Cox proportional hazard regression were used to model associations between baseline covariates and onset of second malignancy. Furthermore, the Kaplan and Meier method was used to model cumulative incidence of second malignancy from the initiation of maintenance therapy. Results: TT3B patients had notably higher proportions of patients with ISS III disease and GEP70-high risk as compared to TT3A patients. There was an incidence of 16 new second primary cancers on TT3A over the entire period of observation with 7 solid tumors and 9 hematologic malignancies. We only observed 2 new second primaries on protocol TT3B (1 solid, 1 hematologic malignancy). There were no differences in cumulative incidence of hematologic CA2 or solid CA2 between the protocols from the initiation of maintenance therapy on the two TT3 trials (Figure 1). Cox regression analysis identified old age (> 66yrs) and high Kappa FLC levels (>168 mg/dl) as the only factors negatively associated with timing of onset of a second malignancy, when modeled from initiation of maintenance therapy. MDS associated cytogenetic abnormalities (MDS-CA) can occur as either transient or persistent anomalies on serial bone marrow analyses in post-transplant MM patients in absence of cytopenias or morphologic evidence of MDS, as previously reported. The 4-year incidence of MDS-CA in TT3B was significantly higher than TT3A. It remains to be seen whether such MDS-CAs progress to overt clinical MDS and therefore need to be followed prospectively. Conclusion: Our study has the great advantage containing large cohorts of patients who underwent treatment that only differed in the maintenance regimen. Furthermore we did not have to rely on multiple different methods of detecting incidental CA2 but rather obtained PET scans in regular intervals thus avoiding underreporting of CA2s. In terms of treatment our aproach can be best compared to the IFM 2005-02 and CALGB 100104 who both included HDT and HSCT. Overall we had a significant lower incidence of CA2 in the treatment arms than these comparable trials. Taken together, the data suggest that there are no discernable differences in CA-2 when combining different IMiDs with BZ/D as maintenance strategy. There is, however, a higher incidence of MDS karyotypic abnormalities, both transient and persistent, in patients who remain on the Bz/D/Len maintenance after having undergone autologous stem cell transplantation on TT3B. Disclosures:Barlogie:Celgene, Genzyme, Novartis, Millennium: Consultancy, Honoraria, Patents & Royalties.

A Phase II Trial of Ofatumumab for Older Patients and Patients Who Refuse Fludarabine-Based Regimens with Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma,

Abstract 3912 Background:Fludarabine (FLU), cyclophosphamide and rituximab (FCR) or other FLU-based regimens have shown improvement in response rates, progression-free survival, and in some studies overall survival in patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). However, a randomized trial of older patients demonstrated no improvement in progression-free and overall survival with FLU-based therapy (Eichhorst BF, et al: Blood 114; 3382, 2009). A recent retrospective analysis of serial CALGB trials (Woyach J, et al: ASH 2011) confirmed the lack of PFS and OS advantage of fludarabine in elderly patients but did find benefit of the anti-CD20 antibody rituximab across all age groups. Ofatumumab (OFA) is a fully human immunoglobulin G1 kappa, monoclonal antibody that targets a unique epitope on the CD20 molecule. Pre-clinical data indicate that OFA has greater NK cell and monocyte-mediated killing, complement-dependent cytotoxicity and direct killing against CLL cells. Based on pre-clinical and clinical studies indicating possible increased efficacy of OFA in patients with CLL, our aim was to develop an antibody-only regimen for older patients and patients who refuse FLU-based regimens. Methods:Eligible patients had previously untreated, symptomatic CD20+ B-cell chronic lymphocytic leukemia (B-CLL) or small lymphocytic lymphoma (SLL), ECOG PS of ≤ 2, and were either ≥ 65 years of age, or patients 18–64 years of age who had declined FLU-based regimens. All patients in this study received OFA as an IV infusion once weekly for a total of 8 weeks. To reduce the possibility of infusion reactions, the first dose of OFA was administered at a dose of 300 mg. If the initial 300-mg dose of OFA was well tolerated, without occurrence of any infusion associated AEs of ≥ grade 3, subsequent doses of OFA (i.e., Week 2 through Week 8) were given at a dose of 2000 mg. Eight weeks after the 8-week study treatment period ended, patients were assessed for response to the treatment. Patients who progressed received no further treatment. Patients who responded to the treatment or who did not have disease progression received maintenance therapy consisting of OFA at a dose of 2000 mg IV every 2 months for 2 years (for a total of 12 doses, in the absence of PD or intolerable toxicity) beginning 3 months after the last dose of OFA. Results:Between 8/2010 and 4/2011, 42 patients were enrolled and are included in this analysis. Patients were 57% male with median age 69 yrs (range: 47–88 yrs). Fourteen patients (33%) were < age 65. All but 1 patient had CLL; 1 patient had SLL. The median WBC at study entry was 41.1 (range 1.7–236.5). Rai stage at entry to study was Stage 0 = 8, Stage I = 8, Stage II – 4, Stage III – 10, Stage IV – 11. Interphase cytogenetics demonstrated 2/42 (5%) 17p-, 4/42 (10%) 11q-, 11/42 (26%) trisomy 12, 9/42 (21%) normal, 14/42 (33%) 13q-, and 2 (5%) unknown. To-date, 41 (98%) patients remain on study and 35 have completed 8 weeks of initial therapy with 24 (57%) having already begun maintenance therapy. Lymphocyte count normalized in 85% of patients at the end of the initial 8 weeks of therapy. Thirty patients have been evaluated for response according to IWCLL criteria (Hallek 2008): 13 patients (44%) achieved an objective response (CR, 0; PR, 13); 16 (53%) patients had SD; 1 patient (3%) had PD. SAEs were infrequent with 2 patients hospitalized for unrelated events: g2 fracture, g3 chest pain, g3 hematoma and g4 pulmonary emboli; 2 patients hospitalized for events possibly OFA-related had g2 fever, g3 anemia and g3 pneumonia. Only 1 patient experienced significant infusion-related toxicity that required repeat administration of the initial 300-mg dose instead of dose escalation at dose 2. Baseline FcγR polymorphisms for patients enrolled are currently being analyzed and will be presented. Conclusion:Single-agent OFA is a highly active and well tolerated front-line therapy for older patients with CLL or patients refusing FLU as evidenced by both early response and also ability of virtually all patients to proceed to maintenance therapy. A low incidence of serious infusion toxicity, infectious morbidity and other heme / non-heme toxicities was observed. Continued long-term assessment will further characterize the toxicity and efficacy of this single-agent OFA regimen in patients with CLL, as well as overall and progression-free survival rates. Disclosures:Flinn:GSK: Research Funding. Off Label Use: Ofatumumab in front-line CLL. Jones:Abbott Labs: Research Funding; GSK: Consultancy.

Zoledronic acid preserves bone mineral density in premenopausal women who develop ovarian failure due to adjuvant chemotherapy: Final results from CALGB trial 79809

Background Chemotherapy-induced ovarian failure (CIOF) is a frequent side-effect of adjuvant chemotherapy that results in rapid bone loss. We hypothesised that zoledronic acid (ZA), a third-generation amino bisphosphonate, would prevent bone loss in premenopausal women who developed CIOF. Methods Women (439) were randomised to intravenous (i.v.) ZA 4 mg every 3 months for 2 years starting within 1–3 months after randomization (arm A) or 1 year after randomization (arm B, controls). CIOF was prospectively defined as ⩾3 months of amenorrhoea, follicle-stimulating hormone (FSH) ⩾30 MIU/ml and non-pregnant at 1 year. The primary end-point was the percentage change in bone mineral density (BMD) in the lumbar spine (LS) from baseline to 12 months in the ZA and in control groups in women who developed CIOF; the secondary end-point was BMD in LS at 3 years in all randomised women. Findings One hundred and fifty (56%) met the definition of CIOF at 1 year. Overall, grade 3 toxicities of ZA were fatigue (1%) arthralgias (21%) and pain (84%). The median percent change (interquartile range, IQR) at 1 year was +1.2% (−0.5% to +2.8%) and −6.7% (−9.7% to −2.9%) p < 0.001 and at 3 years was +1.0% (−1.6% to +5.2%) and −0.5% (−3.7% to +3.2%) p = 0.019 in arms A and B, respectively. Interpretation ZA every 3 months is well tolerated and prevents rapid bone loss in premenopausal women that develop CIOF. Giving ZA with rather than 1 year after the start of adjuvant chemotherapy is the preferred sequence to prevent bone loss.

Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Patients with Hematologic Malignancies Who Relapse following Autologous Transplantation: A Multi-institutional Prospective Study from the Cancer and Leukemia Group B (CALGB trial 100002)

Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Patients with Hematologic Malignancies Who Relapse following Autologous Transplantation: A Multi-institutional Prospective Study from the Cancer and Leukemia Group B (CALGB trial 100002)

The Effects of Azacitidine on Quality of Life Measured Longitudinally In MDS Patients Treated at a Tertiary Care Center

AbstractAbstract 2571 Background:Myelodysplastic syndromes (MDS) are clonal hematopoetic stem cell disorders characterized by ineffective hematopoiesis and a propensity to develop AML predicted by conventional scoring systems such as the International Prognostic Scoring System (IPSS). Azacitidine (AZA), a hypomethylating agent is indicated for high and high intermediate IPSS scores based on survival and leukemia-free survival benefits demonstrated in randomized trials (Silverman 2002, 2006, Fenaux 2009). Additionally, improvements in fatigue, dyspnea, physical functioning, affect and psychological distress were demonstrated in the CALGB study (Kornblith 2002).We previously showed that most symptom and functional domains of quality of life (QOL) are impaired in MDS patients measured by several instruments and are primarily determined by Hb and transfusion dependence (Buckstein 2009). With the exception of the CALGB paper, there is a paucity of data assessing the ‘real world’ QOL in MDS patients treated with AZA longitudinally. All consented patients with MDS followed at our center have QOL assessed every 3–4 months as part of routine care. We present the QOL scores of patients on AZA as assessed by the EORTC QLQ-C30, EQ-5D and a global fatigue scale. Methods:Clinically significant score differences were considered to be 10 points for the EORTC, and 0.05 for the EQ-5D. Linear regression analysis was used to detect each QOL change over time. Log-transformation was applied for all QOL scores to normalize the distribution. To search for significant predictive factors of each QOL, linear regression analysis (for continuous predictive factors) or Analysis of Variance (for binary predictive factors) was conducted at baseline. A two-sided p-value less than 0.05 was considered statistically significant. Results:30 patients in our database were/are currently treated with AZA. The median age was 73 years, with 63% being male. Of the 26 patients with measureable IPSS scores, 54% were high/high intermediate risk. Seventy percent had a Hb <100 at the time of baseline QOL prior to AZA, 50% had a ferritin ≥ 1000 ug/L, 65% were transfusion dependent (TD) as defined by the WPSS (Malcovati 2007). Sixty-seven percent of patients were on AZA for ≥ 4 cycles of treatment.Of the 19 TD patients only 3 became transfusion independent (TI) on AZA and 3 patients who were TI at baseline became TD.Of the 30 patients, 20 have QOL data available for analysis with a median follow up time of 10 weeks (range 0–80) and an interval duration between QOL assessments of 15.5 weeks. Fourteen out of twenty patients have serial QOL assessments, 5 with two, 9 with three or more. The only clinically significant improvements were observed with the EORTC physical functioning and fatigue subscales but constipation scores were higher and global health status/QOL deteriorated over time (Figure 1). At baseline assessment ferritin ≥ 1000 ug/L was negatively associated with physical functioning (p=.0007), cognitive functioning (p=.0012), global QOL (p=.0048) and global fatigue (p=.0003) while transfusion dependence was not predictive of QOL scores. No significant clinical improvements were detected by linear regression or ANOVA over time, but constipation worsened using both models. The health utilities (determined by the summary score of the EQ-5D) are seen in table 1.Table 1:Median EQ-5D summary scores measured over time.Follow up category (month)NMedianBaseline190.848Month 1–2150.812Month 3–4120.849Month 5–7100.866 [Display omitted] Conclusion:Many clinically important function and symptom domains of 3 different QOL instruments have not changed significantly over time in our patients receiving AZA. This is likely explainable by the limited sample size and serial number of assessments in our patients. Our present patient population is higher risk than that tested in the CALGB study and our previous report on the MDS patients in our database. Furthermore, we have yet to see the rates of transfusion independence that might be associated with improved QOL. The negative association of increased ferritin with numerous symptom and function scores may simply be a surrogate for the extent of transfusion dependence. We hope that with longer follow up and larger sample size, we will be able to reproduce the QOL benefits observed in the pivotal CALGB trial (Kornblith 2002). Disclosure:No relevant conflicts of interest to declare.

Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Patients with Hematologic Malignancies Who Relapse following Autologous Transplantation: A Multi-institutional Prospective Study from the Cancer and Leukemia Group B (CALGB trial 100002)

We prospectively treated 80 patients with relapse of malignancy or secondary myelodysplasia after autologous hematopoietic cell transplantation (AHCT) with allogeneic HCT (allo-HCT) using a reduced-intensity conditioning regimen of fludarabine 150 mg/m(2) plus intravenous busulfan 6.4 mg/kg. Both matched sibling (MSD) and unrelated donors (MUD) were allowed. Patients transplanted from MUD donors received more intensive graft-versus-host disease (GVHD) prophylaxis, including rabbit antithymocyte globulin (ATG) 10 mg/kg, mycophenolate mofetil, and an extended schedule of tacrolimus. With a median follow-up of 3.1 years (0.9-5.8), treatment-related mortality (TRM) at 6 months and 2 years was 8% and 23%, respectively. Neither TRM nor the rates of acute GVHD (aGVHD) were different in those with sibling or MUD donors. Donor CD3 cell chimerism >90% at day +30 was achieved more often in patients with MUD than with matched sibling donors, 70% versus 23% (P < .0001). Median event-free suvival was higher in patients who achieved early full donor chimerism (14.2 versus 8 months, P = .0395). Allo-HCT using this reduced-intensity conditioning regimen can be performed with low TRM in patients who have received a prior AHCT. Efforts to improve early donor CD3 chimerism may improve event-free survival.

Treatment of older patients with de novo acute myeloid leukemia (AML) with one or more postremission chemotherapy courses: Analysis of four CALGB studies.

6531 Background: AML in older patients is rarely cured by chemotherapy, but treatment is given to induce complete remission (CR) and prolong disease-free and overall survival (DFS, OS). Optimal post-CR chemotherapy has not been defined. We analyzed outcomes in previously untreated de novo AML patients ≥ 60 years (n = 1,525) among 4 consecutive CALGB trials using different consolidation regimens. A randomized trial (8923) produced similar results using 2 courses of cytarabine (AraC) 1 g/m2 x 5 days plus mitoxantrone 10 mg/m2 x 3 days compared to 4 courses of AraC at 100 mg/m2 x 5 days (Blood 2001;98:548). CALGB 9720 used ADE induction (AraC 100 mg/m2, daunorubicin 60 mg/m2 and etoposide 100 mg/m2 for 7, 3 and 3 days) with only a single post-remission course of the same drugs and doses for 5, 2 and 2 days. Methods: Results of 9720 were compared with results from similar patient populations treated on 3 other CALGB trials that used more than one post-CR course – either 4 courses (8525, 8923) or 2 intensified courses (8923, 10201). Results: The CR rate on 9720 did not differ compared to the other trials (52 vs. 53%), but DFS was significantly shorter (medians, 7.0 vs. 9.3 mos; p = 0.002), while OS did not differ (median, 8.4 mos), nor did survival following attainment of CR (13.9 vs. 14.5 mos; p = 0.13). DFS was shorter on 9720 for patients both 60-69 (n = 480; 6.9 vs. 9.3 mos; p = 0.02) and 70-79 (n = 294; 7.4 vs. 10.3 mos; p = 0.04) years; there were too few CR patients ≥ 80 years (n = 20) to allow a reliable conclusion. Conclusions: This historical comparison suggests that a single consolidation course results in significantly shorter DFS for de novo AML patients ≥ 60 years, but has no effect on OS nor survival following attainment of CR. The value of administering additional consolidation courses to prolong DFS without an effect on OS is debatable. Outcomes within cytogenetic and molecular subsets as well as quality of life measurements would be of interest. DFS and OS have remained short among older AML patients over the 25-year period covered by these studies; experimental approaches, including nonmyeloablative allogeneic hematopoietic cell transplantation in appropriate patients, are thus warranted. No significant financial relationships to disclose.