Favorable Risk Pts Research Articles

Treatment-free survival (TFS) outcomes from the phase II study of nivolumab and salvage nivolumab + ipilimumab in advanced clear cell renal cell carcinoma (aRCC) (HCRN GU16-260-Cohort A).

604 Background: Treatment with immunotherapy can be associated with prolonged disease control after discontinuation without the need for further anticancer therapy. Toxicity from therapy can also persist after cessation. TFS with and without toxicity can characterize survival time. Significant TFS was reported for CheckMate 067 trial in pts with metastatic melanoma (Regan et al JITC 2021) and CheckMate 214 trial for pts with aRCC (Regan et al CCR 2021), but treatment was often halted for toxicity rather than a pre-defined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16 260 trial, which was designed to reduce toxicity and to cap immunotherapy duration (Atkins et al JCO 2022). Methods: Data were analyzed from 128 patients (pts) with clear-cell aRCC treated with first-line nivolumab (NIVO) monotherapy for up to 2 years. As part of the protocol, salvage nivolumab/ipilimumab (NIVO/IPI) for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (28% of pts). TFS was defined as the area between Kaplan-Meier curves for time from registration to protocol therapy cessation and for time from registration to subsequent therapy initiation or death, estimated from 36-month (mo) mean times. The time on treatment or off treatment with grade 3+ treatment-related adverse events (TRAEs) was also captured. Results: At 36 mos from enrollment, 68.3% of pts were alive: 96.8% of IMDC favorable-risk (FAV) pts and 56.6% of those with intermediate/poor-risk (I/P), respectively. The 36-mo mean time on protocol therapy was 11.5 mos (16.0 mos for FAV pts and 9.6 mos for I/P pts). The 36-mo mean TFS for the whole population was 9.4 mos. For FAV pts the mean TFS was 12.9 mos, of which TFS with grade 3+ TRAEs was 1.5 mos. For I/P pts, the mean TFS was 8.0 mos, of which TFS with grade 3+ TRAEs was 1.0 mos. At 36 mos, 65.6% of FAV pts and 27.1% of I/P pts were alive and second-line treatment-free. Conclusions: NIVO monotherapy with salvage NIVO/IPI in non-responders is an active treatment approach in treatment-naïve pts with aRCC and results in substantial TFS and toxicity-free TFS. TFS was particularly noted in pts with FAV disease, further supporting the use of an immunotherapy-only regimen in this population. Clinical trial information: NCT03117309 . [Table: see text]

Regularized Mixture Cure Models Identify a Gene Signature That Improves Risk Stratification within the Favorable-Risk Group in 2017 European Leukemianet (ELN) Classification of Acute Myeloid Leukemia (Alliance 152010)

Introduction: The 2017 ELN Favorable-risk group comprises specific recurrent cytogenetic and molecular alterations. Assignment to this group has important clinical implications, as allogeneic stem cell transplantation in first complete remission (CR) is not advised due to a relatively good outcome of patients (pts) receiving chemotherapy and transplant-associated mortality. However, not all Favorable-risk pts experience long-term survival and their outcomes are affected by co-occurring genetic features making recognition of pts who would most likely be cured of high importance. Thus, we used our regularized mixture cure model (MCM) that embeds false discovery rate control to identify prognostically relevant transcripts that can distinguish pts cured from pts susceptible to lower- or higher-risk of relapse. Methods: We analyzed 312 pts <60 years with de novo AML classified in the 2017 ELN Favorable-risk group excluding APL who achieved a CR, had RNA-seq data available, and treated on one of 8 CALGB/Alliance frontline protocols with intensive 7+3-based induction chemotherapy. No pt received an allogeneic stem cell transplant in first CR. MCMs assume the population consists of 2 subgroups, cured and susceptible, thus there are 2 regression components, which permit identification of features associated with cure and/or latency of susceptible pts. 'Cured' is synonymous with attaining long-term relapse-free survival and thus pts have a survival probability of 1. We fit univariable MCMs to identify baseline demographic, clinical features, or selected gene mutations related to the probability of being cured and/or to the latency distribution (time to relapse). RNA-seq expression values were candidate covariates in a regularized MCM to identify a parsimonious list of transcripts associated with cure or latency. We then used 2017 ELN Favorable pts in an independent dataset (GSE37642) for validation. Results: The estimated proportion cured (39.5%) was significant (P < 0.001) indicating that a MCM should be fit. Other than % of bone marrow blasts (P = 0.009) and % of blood blasts (P = 0.048), no other pretreatment features were significant in univariable MCMs. CEBPAdouble and TET2 mutations were the only ones significantly associated with latency (P = 0.008 and P = 0.013, respectively), but neither was associated with cure (P = 0.881 and P = 0.507, respectively). Our regularized MCM identified 101 transcripts associated with cure and 71 transcripts associated with latency. Kaplan-Meier curves of cured vs susceptible pts as well as of those susceptible with lower vs higher risk of relapse or death were well separated. We mapped the 168 unique transcripts to GSE37642 Affymetrix HG-U133Plus2 GeneChip for validation and found that 65 cure-related probe sets and 57 latency probe sets mapped to 34 and 32 unique genes, respectively. The validation data yielded AUC=0.788 and C-statistic=0.887, indicating good predictive ability of the selected genes. As desired, the predicted cured group had a survival probability of 1 throughout the observation period (Fig 1), with good separation between predicted susceptibles in the lower- versus higher-risk groups (Fig 2). Cell death and survival was the top molecular/cellular function for both the cure and latency portions of the model with 22 and 20 transcripts involved, respectively, with only BRD2, HLA-A, HLA-B, NAIP, and TXNIP in common. Cell death and survival molecules unique to the latency portion of the model included CD300A, CRNDE, DDX39B, FAS, GPI, HLA-DRA, KLF13, LAT, let-7, LMO2, LSP1, NOTCH1, PLCG2, PSMB8, and U2AF1; those unique to the cure portion included ARID5B, BAG6, BMI1, CCL5, CDK7, DPPA4, ELOVL5, HLA-DRB1, IL18, INTS6, MAP4K4, mir-25, mir-491, NOMO1, NR1H3, RPS16, and TUBB. Conclusion: Our regularized MCM identified important subsets of genes associated with cure and latency in the 2017 ELN Favorable-risk pts. Our results suggest that the Favorable-risk group includes distinct transcriptionally defined subgroups with different biological properties, which may be useful for refining this risk category by identification of pts who might be cured with chemotherapy alone. Given similar treatment with 7+3-based cytotoxic chemotherapy, the identified subgroups (cured, susceptible lower risk, susceptible higher risk) seem to have different sensitivities to 7+3-based therapy. Support: R01LM013879, U10CA180821, U10CA180882, U24CA196171 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Fludarabine, Cyclophosphamide and Rituximab (FCR) As First Line Treatment in Patients with Chronic Lymphocytic Leukemia (CLL): A Long-Term Analysis of the German CLL Study Group (GCLLSG) Registry

Introduction: Large randomized trials investigating targeted agents have resulted in a markedly improved progression-free survival (PFS) when compared to standard chemoimmunotherapy. However, for small subgroups with a favorable risk profile, overall survival was not consistently superior for targeted agents. Long-term follow up on FCR suggested that favorable risk patients (pts) benefit significantly from this therapy and can expect an exceptionally long PFS. In addition, targeted first line (1L) therapies for favorable risk pts are reimbursed only in a minority of countries. Here, we report long-term efficacy data of FCR treatment obtained from pts documented within the GCLLSG registry. Methods: Documentation within the GCLLSG registry started in 2013 and included both pts from prospective trials (29.7%), most importantly of the CLL8 trial (22.6%) and CLL10 trial (62.1%) as well as retrospective data. Pts with confirmed diagnosis of CLL who received FCR as 1L treatment were included. Patient characteristics were reported in median, interquartile ranges or frequencies and percentages. Response was reported as response or non-response. Event-free survival (EFS), which was defined as the time from start of (first) FCR treatment to disease progression, initiation of subsequent treatment for CLL or death. EFS was chosen as an endpoint for this report due to concerns that PFS might give unrealistically good results due to lack of documentation. However, PFS and TTNT data will be presented at the meeting. Overall survival was calculated from initiation of 1L treatment for all pts who received 1L treatment after 2013. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated by Cox proportional hazards regression. Variables that were significantly associated with EFS in univariate analyses (significance level was set at 5%) were considered as candidates for the multivariate modelling to identify independent prognostic risk factors. Results: As of September 2021, a total of 5922 pts were enrolled in the registry of which 417 received FCR as 1L treatment between 2003 and 2021. 223 pts (53.5%) received treatment before 2013 and 194 (46.5%) after 2013. Median observation time from 1L treatment was 95.8 (interquartile range 58.7-126.8) months. Patient characteristics showed a median age of 58 (range 24-83) years. Unmutated IGHV (U-CLL) was present in 61.4% of the pts. Regarding genomic aberrations based on the hierarchical model, del(17p) was found in 1.9%, del(11q) in 15.2%, trisomy12 in 15.5%, mono-allelic del(13q) in 34.3% and none of these changes in 33.0% of the pts. 88.8% of the pts responded to first line therapy, 11.2% were documented as non-responder. Median EFS was 71.1 month, for 188 pts no event was documented at the time point of data cut-off. Age group (≤ 65 years, >65 years), del(11q), IGHV mutational status, TP53 status, and serum thymidine kinase (TK) were associated with EFS in univariate analyses. Overall, 116 pts with 67 events were included in the final multivariable model for EFS. U-CLL (HR 1.949 (95%CI: 1.170-3.247; p=0.010) and TK >10 U/l (HR 2.107 (95%CI: 1.153-3.849; p=0.015) were independent adverse prognostic risk factors for EFS. When low TK and M-CLL were combined, the median EFS was not reached, with a 5-year survival rate of 95.8%. In contrast, median EFS was 84.1 months for pts with U-CLL and high TK. In U-CLL pts, median EFS was 87.0 months for pts with TK ≤ 10 U/l, and 58.9 months for pts with TK > 10 U/l. Median overall survival was not reached with a 5-year survival rate of 92.7%. Conclusion: Within this cohort of pts with a long follow up in the GCLLSG registry, FCR treatment was associated with a long EFS especially in pts with a low risk profile exhibiting a mutated IGHV status und low TK. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Multi-Dimensional Analysis of Adult Acute Myeloid Leukemia (AML) Landscape Cross-Continents Reveals Age Associated Trends in Mutations and Outcomes

Multi-Dimensional Analysis of Adult Acute Myeloid Leukemia (AML) Landscape Cross-Continents Reveals Age Associated Trends in Mutations and Outcomes

Structural and Social Barriers to Survival in Adolescent and Young Adult (AYA) Patients with Acute Myeloid Leukemia (AML)

IntroductionAYA cancer patients (pts) face unique healthcare disparities due to their social development stage. AYA with AML and minorities continue to suffer reduced survival (Kahn, Cancer, 2016). Our group demonstrated that structural violence, specifically neighborhood socioeconomic status (SES), significantly impacts adult AML survival (Abraham, Blood, 2020). This real-world study, in a segregated metropolitan area, confirms inferior survival in the non-white (NW) AYA AML population and explores social barriers that contribute to disparities.MethodsAYA AML (non-APL) pts, age 18 to 39, diagnosed and treated between 2012- 2018 at 6 cancer centers across the Chicago area were included. Race/ethnicity was categorized as Non-Hispanic White (NHW), Hispanic, non-Hispanic Black (NHB), and Other. Census tract data was collected using the FFIEC Geocoding/Mapping System and computed tract disadvantage and affluence scores, divided into high, moderate, and low tertiles. A survival analysis was performed to generate hazard ratios (HR) for all-cause mortality between NHW and NW pts. Social determinants of health explored for AYA outcomes included caregiver responsibilities, employment, time off work, mental health, Charlson Comorbidity Index (CCI) and obesity.ResultsTable 1 shows demographic data (n=101); 46% were NHW, 17% were NHB, 30% were Hispanic, and 8% were other. Median age was 31 years. The number of pts with children was similar across all groups, while more NHW (29%) and Hispanic (21%) pts reported being caregivers to other household members compared to NHB pts (0%), despite their young age (p=0.09). Overall, 68% of pts never met with a fertility specialist, more frequently due to no counseling (77%) than patient preference (23%). Most pts were not in school during treatment. NHW pts took time off work and filed for disability more commonly than NHB and Hispanic pts. NHW (65%) and Hispanic (71%) pts both reported anxiety and/or depression during treatment more than NHB pts (33%). Yet, NHW pts (68%) were referred to psychiatry more often than Hispanic pts (54%).Payer source differed significantly. Most NHW pts had private insurance, unlike NHB and Hispanic pts (74% vs. 41% vs. 43% respectively). The largest uninsured population was Hispanic (33%) compared to NHW (4%) and NHB (6%) pts. NHB pts (76%) tended to reside in more disadvantaged areas, while Hispanics (60%) tended to live in less affluent areas.ELN classification was comparable amongst NHW and NHB pts, while the largest group of favorable risk pts were Hispanic (37%). Extramedullary disease was more frequent in NHB (25%) and Hispanic (14%) compared to NHW (7%) pts. FLT3-ITD mutations and NPM1 mutations were more prevalent in NHW pts. Molecular testing was not done on most pts.Overall, 87% achieved CR/CRi. Notably, ICU stays during or post induction were higher in NHB (41%) and Hispanic (57%) compared to in NHW (33%) pts. Transplant status differed significantly with 87% of NHW pts receiving a transplant compared to NHB (41%) and Hispanic (57%) pts. Relapse rates were similar between all groups. However, the incidence of death within 2 years of diagnosis was highest in NHB (24%) and Hispanic (30%) pts, and nearly half that in the NHW pts (17%). (Table 2)32 pts died, 22 due to leukemia. Hazard of all-cause mortality was over twice as great for NW than for NHW pts HR=2.22 (95% CI:1.06, 4.65). Statistical adjustment for tract SES accounted for 57% of the survival disparity, reducing the HR to 1.53 (95% CI:0.59, 3.87). Further adjustment for treatment center reduced the HR to 1.25 (95% CI: 0.48, 3.28); together, treatment center and tract SES accounted for 80% of the survival disparity. Adjustment for private insurance, transplant status, clinical trial enrollment, prognosis (based on ELN classification and secondary AML) and BMI/CCI did not appear to account for any of the survival disparity. (Table 3)ConclusionOur study shows that Hispanic and NHB AYA AML pts have inferior survival compared to NHW pts despite similar ELN risk groups, treatment, response and relapse rates. Census tract-level SES related to differential resources in neighborhoods explained a significant proportion of the disparity in hazard of all-cause mortality. Our work highlights social determinants of health in AYA leukemia pts must be elucidated to determine mechanisms underlying structural barriers and inform future interventions to mitigate survival disparities. [Display omitted] DisclosuresPatel: Pfizer: Research Funding; Celgene/BMS: Research Funding. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Altman: Theradex: Consultancy; Syros: Consultancy; Kuro Oncology: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; AbbVie: Consultancy; Glycomimetics: Membership on an entity's Board of Directors or advisory committees; BioSight: Consultancy, Other: Travel fees to attend an advisory meeting (I did not accept payment for the advisory board). Dinner: Kite/Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Venetoclax and Azacitidine for Newly Diagnosed Non-Elderly Adult Patients with Acute Myeloid Leukemia and Adverse Risk Features

Background: Venetoclax (ven)+azacitidine (aza) is the standard of care for untreated acute myeloid leukemia (AML) patients (pts) ≥75 years or unfit for intensive induction chemotherapy (IC) due to comorbidities. While the standard of care for younger newly diagnosed pts is IC, long term outcomes for all but favorable risk pts are suboptimal. Specifically, pts with adverse risk disease, per the European Leukemia Network (ELN), are more likely to be refractory to IC and have low rates of long term survival. Ven based regimens have a ~70% response rate in the upfront setting; in contrast to IC, those with adverse risk do not have lower response rates. This study explores the feasibility and outcomes of ven+aza for newly diagnosed younger AML pts who are not necessarily unfit for IC, but carry adverse risk features that make them less likely to respond to this therapy. Methods: This is an interim analysis of an ongoing phase 2 study (NCT03573024) of a planned 36 untreated adverse risk AML pts 18-59. Pts have adequate organ function and white blood cell counts &amp;lt;25x109/L (hydrea permitted); "fitness" for IC is not a consideration. In cycle 1, pts receive aza 75mg/m2 on days (d)1-7 and ven, escalated from 100 to 200 to 400 to 600mg on d1-4. Ven continues at 600mg d5-28 and bone marrow biopsies (BMBX) occur on d14 and 28. Pts who achieve morphologic remission without count recovery have up to 14 days off therapy before subsequent cycles. Non responders discontinue or receive up to 1 additional cycle. Post response (defined as a morphologic leukemia free state [MLFS], complete remission [CR] with incomplete count recovery [CRi] or CR), pts who are measurable residual disease (MRD) negative by multiparameter flow cytometry (MFC) and/or droplet digital PCR (ddPCR) may proceed to MRD negative maintenance: ven 400mg d1-28 with aza 75mg/m2 d1-5 of sequential 28-day cycles. Pts who are MRD-positive may receive up to 3 additional cycles of consolidation: ven 600mg/day d1-28 and aza 75mg/m2 d1-7 of a 28-day cycle. Pts who become MRD negative may proceed to MRD negative maintenance. Pts who are MRD positive after induction and consolidation may proceed to MRD positive maintenance: ven 600mg daily d1-28 with aza 75mg/m2 d1-7 of a 28-day cycle. Conversion to MRD negativity results in a transition to MRD-negative maintenance (Fig 1). While these post-remission options are available, pts are encouraged to discontinue the study and proceed to transplant after achieving a morphologic remission. The primary objective is to determine the overall response rate (CR+CRi+MLFS). The endpoint is to show ven+aza is noninferior to historical controls: younger newly diagnosed adverse risk AML pts who receive IC. Frequent analysis of outcomes, using 6 stages, was adopted to ensure the CR rate remains ≥60%. Results: 8 have enrolled between November 2018 and July 2020; median age is 33 (22-52). All have adverse risk disease (Table 1). There were 179 adverse events (AEs); 35 related. The ≥grade 3 events were: fatigue (N=1), leukopenia (N=2), neutropenia (N=2), anemia (N=2), thrombocytopenia (N=1). There were no deaths in the first 60 days. In cycle 1 pts spent a median 10 days (4-19) inpatient and required a median of 2 (0-10) red blood cell transfusions and 3 (0-15) platelet transfusions. Six of 8 (75%) pts responded; all 6 were CRs. 4/6 responses were cytogenetic remissions, 5/6 were MRD negative by MFC and 1/6 was MRD negative by ddPCR. Two pts relapsed, 35 and 84 days after remission; one was successfully salvaged with IC and proceeded to transplant while the other was refractory to IC and died from AML. Two pts were refractory to ven+aza; both were successfully salvaged with IC and have proceeded to transplant. 7/8 proceeded to transplant; 4 required only ven+aza for this outcome and proceeded to transplant a median of 89 days (56-93) after diagnosis. No pts who have proceeded to transplant have relapsed, a median of 340 days (136-444) after transplant. 7/8 remain alive, 345 days (91-586) after enrolling. Conclusions: At the stage 1 interim analysis, the CR rate for ven+aza remains &amp;gt;60% in adverse risk younger patients. With small numbers, up-front treatment with ven+aza allows some younger pts with adverse risk disease a non IC opportunity to achieve a response and proceed to transplant; most of those who relapsed or were refractory were salvaged with IC. Disclosures Pollyea: Syndax: Consultancy; Syros: Consultancy; Abbvie: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Genentech: Consultancy; Amgen: Consultancy; 47: Consultancy, Research Funding; Janssen: Consultancy; Agios: Consultancy; Glycomimetics: Other; Celgene/BMS: Consultancy; Pfizer: Consultancy; Takeda: Consultancy. OffLabel Disclosure: Venetoclax for younger patients fit for induction chemotherapy

Routine Use of Gemtuzumab Ozogamicin in 7+3-Based Inductions for All “Non-Adverse” Risk AML

Introduction: The addition of gemtuzumab ozogamicin (GO) to 7+3 chemotherapy for newly diagnosed acute myeloid leukemia (AML) has been shown to significantly improve event-free survival (EFS) for cytogenetically favorable-risk AML, with marginal benefit for intermediate-risk AML, and no benefit for cytogenetically adverse-risk AML. Of note, with the exception of mutated FLT3-ITD, little is known about the impact of GO in ELN 2017-defined genotypically adverse-risk AML, and a recent randomized trial found no EFS benefit for 7+3+GO in patients (pts) with genotypically favorable-risk, NPM1-mutated AML. Since 2017, our institution incorporated GO into 7+3-based inductions for all "non-adverse" risk AML pts, as defined by wild-type FLT3 and no abnormalities on rapid FISH analysis for del(5q)/monosomy 5, del(7q)/monosomy 7, and del(20q). We report our experience treating all pts with "non-adverse" risk AML-as defined by this algorithm-with 7+3+GO. Methods: An institutional database was queried in order to identify all pts ≥18 years old who received 7+3-based chemotherapy for newly diagnosed AML between 2017 and 2020; pts who received the FDA-approved fractionated dose of GO were included in the analysis. Data collection included demographic variables, karyotype/FISH, targeted PCR analyses, and multigene NGS panels for AML-related mutations including, but not limited to, mutations in FLT3, NPM1, CEBPA, TP53, RUNX1, and ASXL1. Outcome data included response to induction, relapse, and death, as well as hematopoietic cell transplant (HCT) rates, conditioning regimens, and post-transplant complications. Results: Between January 2017 and July 2020, 96 pts received 7+3-based induction at our institution. Of these, 29 (30%) received 7+3 in combination with GO. Median age at diagnosis was 46 years (range 23-66), with 17 (59%) males. Sixteen (55%) pts had ELN favorable-risk AML (5 [31%] by cytogenetics and 11 [69%] by genotype), 6 (21%) pts had ELN intermediate-risk AML, and 7 (24%) pts had ELN adverse-risk AML (4 [57%] by cytogenetics and 3 [43%] by genotype). Median time from diagnosis to start of induction was 4 days (range 0-43). For cytogenetically adverse-risk pts, median time from diagnostic bone marrow biopsy to receipt of adverse karyotype results was 8 days (7-14). Median time from start of induction to receipt of multigene NGS results for all pts was 15 days (3-32). Overall, 22 (76%) pts achieved remission. All genotypically adverse-risk pts (1 with mutated TP53 and 2 with mutated RUNX1) were refractory to induction, while 3 of 4 (75%) cytogenetically adverse-risk pts (1 with t(6;9), 1 with monosomy 7, and 2 with 11q23 abnormalities) achieved remission. Eight of the 29 (28%) pts proceeded to HCT, including 4 adverse-risk pts. Of the adverse-risk pts, all received myeloablative conditioning prior to HCT and 3 (75%) developed veno-occlusive disease (VOD), with 2 (50%) requiring defibrotide therapy. In favorable/intermediate-risk pts, 4 (18%) proceeded to HCT (2 intermediate-risk pts in first remission and 2 favorable-risk pts in second remission). Of these, 2 (50%) received myeloablative conditioning and 1 (25%) developed VOD. At last follow-up, 23 of 29 pts (79%) remained alive, with a median overall survival not reached (range 1-29 months) and a median EFS of 20 months (9-31). The percentage of ELN favorable-, intermediate-, and adverse-risk pts who remained event-free at last follow-up was 75%, 33%, and 43%, respectively. Discussion: This single-center, retrospective cohort describes the outcomes of pts with "non-adverse" risk AML who received induction chemotherapy with 7+3+GO according to a pre-defined algorithm. Using this algorithm, 30% of all pts receiving 7+3-based inductions received GO. Of these, nearly 25% were ultimately found to have adverse-risk AML as defined by ELN 2017 criteria, largely driven by long turn-around times for karyotyping and NGS multigene panel results. No patient with genotypically adverse-risk AML by ELN criteria responded to induction chemotherapy, and 75% of cytogenetically adverse-risk pts who proceeded to HCT developed VOD. Routine use of 7+3+GO induction outside of the context of cytogenetically favorable-risk AML remains controversial, and further study is needed to define the role of GO, particularly for pts with ELN genotypically adverse-risk AML. Table Disclosures Gotlib: Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding. Liedtke:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Muffly:Adaptive: Research Funding; Amgen: Consultancy; Servier: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding.

Validation of ELN2017 Risk Stratification in a Post-Hoc Analysis of the Prospective Biomarker-Based Gimema AML1310 Protocol

Background: In the 2017 version of the ELN recommendations (ELN2017), a comprehensive evaluation of karyotype and mutational status of specific genes (e.g. FLT3 and NPM1) allows to classify patients (pts) with Acute Myeloid Leukemia (AML) into 3 prognostically distinct risk groups (favorable, intermediate and adverse-risk). Before the publication of the ELN2017 guidelines, the Gruppo Italiano Malattie Ematologiche MAligne (GIMEMA) conducted a prospective trial (AML1310) in which prognostic classification relied on the risk assessment criteria (NCCN2009) at that time available. In this post-hoc analysis, we investigated the applicability of the ELN2017 risk stratification to the AML1310 study population. Methods: After induction and consolidation, pts in complete remission (CR) were to receive autologous stem cell transplant (AuSCT) if categorized as favorable-risk (FR) (CBF-AML, NPM1-mutated) or allogeneic stem cell transplant (ASCT) if adverse-risk (AR) (FLT3-ITD, complex karyotype). Intermediate-risk pts (IR) were to receive AuSCT or ASCT based on the post-consolidation levels of MRD as measured by flow-cytometry. Baseline genetic/cytogenetic, together with RUNX1/RUNX1T1, CBFb/MYH11, NPM1, FLT3 mutational status (including the FLT3 allelic ratio for those positive) were used to retrospectively classify pts according to the ELN2017. Results: All 500 pts, enrolled in the AML1310 trial, were included in the present analysis. Retrospective allocation was feasible in 445/500 (89%) cases and pts lacking crucial information for a proper ELN2017 assignment, defined a control group (ELN2017-NC). Median age was 49 (range 18-61). The re-assignmentaccording to the ELN2017, resulted in 186 pts (41.8%) belonging to the FR category (ELN2017-FR), 179 (40.2%) to the IR (ELN2017-IR) and 80 (18%) to the AR (ELN2017-AR) ones. Moreover, 55 (11%) pts were considered ELN2017-NC. Based on this process of re-assignment, 173 pts were reclassified according to ELN2017: 6 from NCCN FR (1 ELN2017-NC, 4 ELN2017-IR, 1 ELN2017-AR), 54 from NCCN IR (34 ELN2017-NC, 4 ELN2017-IR, 1 ELN2017-AR), and 113 from NCCN AR (20 ELN2017-NC, 38 ELN2017-FR, 55 ELN2017-AR) groups. After 1-2 cycles of induction, 361 (72%) pts obtained CR or CR incomplete (CRi): 163 (88.1%), 114 (65%), 45 (56.2%) and 39 (70%) in the ELN2017-FR, ELN2017-IR, ELN2017-AR and ELN2017-NC groups, respectively (p&amp;lt;0.001). Among 342 transplant candidates, 111/177 (82 [73.9%] ELN2017-FR, 19 [17.1%] ELN2017-IR, 2 [1.8%] ELN2017-AR, 8 [7.2%] ELN2017-NC) and 132/165 (25 [18.9%] ELN2017-FR, 61 [46.2%] ELN2017-IR, 25 [18.9%] ELN2017-AR, 21 [15.9%] ELN2017-NC) received AuSCT and ASCT, respectively (p&amp;lt;0.001). According to ELN2017 risk classification, the four groups significantly differed (p &amp;lt; 0.001) in terms of 2-years overall survival (OS) (68.8% vs. 51.3% vs. 45.8% vs. 42.8% for the ELN2017-FR, ELN2017-IR, ELN2017-NC, and ELN2017-AR groups, respectively). [Figure 1] Then, we investigated the impact of AuSCT and ASCT on each ELN2017 category; this evaluation was not possible for ELN2017-AR pts since only 2 of them received AuSCT. Among ELN2017-FR pts, a significant benefit of AuSCT over ASCT was observed (2-years OS of 83.3% vs. 66.7%, respectively; p=0.0421). In the ELN2017-IR group, AuSCT and ASCT performed equivalently (2-years OS of 73.9% vs. 70.8%, respectively). In univariate analyses, OS duration was shorter for pts from the ELN2017-AR (HR=2.203, CI 1.496-3.246; p&amp;lt;0.0001), ELN2017-IR (HR=1.796, CI 1.293-2-494; p=0.0005), and ELN2017-NC (HR=2.267, CI 1.488-3.228; p=0.0001). Multivariate model for OS prediction highlighted the role of age (HR=1.033, p&amp;lt;.0001), ELN2017 assignment and transplant (analyzed as a time-dependent covariate) (HR=0.674, p=0.0185), as the most significant prognostic variables. Summary/Conclusion: In this GIMEMA AML1310 post-hoc analysis, we confirmed that the ELN2017 classification is able to accurately define pts that can benefit from different post-remission strategies. Specifically, AuSCT granted longer survival in FR pts, while for IR pts AuSCT and ASCT performed equally when minimal residual disease was used as a driver for opting between one of the two. In conclusion, ELN classification is a reliable grouping system that, combined with MRD assessment, helps addressing pts to the most appropriate treatment. Such an hypothesis will be prospectively challenged in the next GIMEMA trial AML1819. Disclosures Luppi: Abbvie: Consultancy; Novartis: Consultancy, Speakers Bureau; Gilead Sci: Consultancy, Speakers Bureau; Sanofi: Consultancy; Daiichi-Sankyo: Consultancy; MSD: Consultancy. Voso:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Venditti:Pfizer: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Amgen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Jazz: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company).

Treatment-free survival (TFS) after discontinuation of first-line nivolumab (NIVO) plus ipilimumab (IPI) or sunitinib (SUN) in intention-to-treat (ITT) and IMDC favorable-risk patients (pts) with advanced renal cell carcinoma (aRCC) from CheckMate 214.

564 Background: TFS characterizes the antitumor activity of immuno-oncology agents after treatment discontinuation. In CheckMate 214, pts with IMDC intermediate/poor-risk aRCC who discontinued first-line NIVO+IPI experienced significantly longer TFS than those who discontinued SUN (McDermott et al, ESMO 2018). Here, we continue the analysis of TFS from CheckMate 214 in ITT and IMDC favorable-risk pts. Methods: Pts with previously untreated, predominantly clear cell aRCC were randomized 1:1 to intravenous NIVO 3 mg/kg + IPI 1 mg/kg every 3 weeks for 4 doses followed by NIVO 3 mg/kg every 2 weeks, or oral SUN 50 mg daily for 4 weeks on, 2 weeks off (6-week cycles). TFS was defined as the time from protocol therapy cessation to the start of subsequent systemic anticancer therapy or death, whichever occurred first. TFS in pts who discontinued NIVO+IPI or SUN was compared using Kaplan–Meier methods and log-rank tests. This analysis was conducted for all ITT (NIVO+IPI, 550; SUN, 546) and IMDC favorable-risk (NIVO+IPI, 125; SUN, 124) pts in CheckMate 214. Results: Among 463 NIVO+IPI and 477 SUN ITT pts who discontinued protocol therapy, the median TFS was 3.0 months with NIVO+IPI vs 1.3 months with SUN (HR [95% CI]; 0.54 [0.46–0.62]; P&lt;0.0001); the TFS rates 2 years post-discontinuation were 21% vs 7%, respectively. In IMDC favorable-risk pts, 111 and 94 pts discontinued from NIVO+IPI and SUN, respectively. TFS in IMDC favorable-risk pts was also significantly longer with NIVO+IPI vs SUN (median, 6.3 vs 1.1 months; HR [95% CI]; 0.47 [0.34–0.65]; P&lt;0.0001). The TFS rates 2 years post-discontinuation in favorable-risk pts were 29% for NIVO+IPI vs 13% for SUN. Conclusions: Similar to the TFS benefit seen in intermediate/poor-risk pts with aRCC, first-line therapy with NIVO+IPI resulted in reduced need for second-line therapy in ITT and IMDC favorable-risk pts compared with SUN. The durable TFS benefit across risk groups despite discontinuation of therapy provides further evidence of the encouraging benefit-risk profile of NIVO+IPI over SUN in pts with previously untreated aRCC. Clinical trial information: NCT02231749.

Additional Gene Mutations Refine the 2017 European Leukemianet (ELN) Classification of Adult Patients (Pts) with De Novo Acute Myeloid Leukemia (AML) Aged

The ELN recommendations for diagnosis and management of AML in adults, authored by a panel of international experts, have become an important tool to assess pts' prognosis and guide treatment decisions. Following advances in our understanding of the molecular landscape of AML, several gene mutations were added as criteria for assigning pts to genetic risk categories in the 2017 ELN classification.The aim of our study was to apply the 2017 ELN risk groups to a large cohort of 864 AML pts aged <60 years who were similarly treated with intensive cytarabine/daunorubicin based chemotherapy on Cancer and Leukemia Group B/Alliance protocols. In addition, we sought to identify novel gene markers that could refine the ELN classification.Using the 2017 ELN genetic risk-stratification criteria, we assigned 49% of pts to the Favorable-risk group, whereas 22% and 29% of pts belonged to the Intermediate- and Adverse-risk groups, respectively. The complete remission (CR) rate of Favorable-risk pts was 92%, compared with 77% and 48% CR rates of Intermediate-risk and Adverse-risk pts. Fifty-two percent of Favorable-risk pts were disease-free and 63% were alive 3 years after diagnosis, compared with the respective 3-year rates of 22% and 32% for pts belonging to the Intermediate-risk group, and only 10% and 19%, respectively, for pts classified in the Adverse-risk group. Using a targeted 80-gene sequencing panel, we detected 2,354 mutations, with a median of 3 per pt. The frequencies of specific mutations differed between the ELN risk groups. We performed multivariable outcome analyses for the achievement of CR, disease-free (DFS) and overall (OS) survival within each of the ELN groups. Within the Favorable-risk group MVA analyses, the presence of WT1 mutations associated with lower CR rates (P=0.02). Mutations in BCOR (P=0.02), IDH1 (P=0.04), KIT (P<0.001), PTPN11 (P=0.01) and SETBP1 (P=0.02) associated with a shorter DFS; mutated BCOR (P=0.02), IDH1 (P=0.006), SETBP1 (P=0.004), WT1 (P<0.001) and ZRSR2 (P=0.002) associated with a shorter OS. In the Intermediate-risk group MVA analyses, mutations in WT1 associated with lower CR rates (P=0.02). Mutations in DNMT3A and WT1 associated with shorter DFS (DNMT3A, P<0.001; WT1, P=0.01) and OS (DNMT3A, P<0.001; WT1, P=0.005). In the Adverse-risk group MVA analyses, IDH2 mutations associated with lower CR rates (P=0.05). NRAS mutations associated with shorter DFS (P<0.001) and OS (P=0.008). In addition, IDH2- (P=0.03) and TET2-mutated pts (P=0.009) had shorter OS than pts without these mutations. Among FLT3-ITDlow pts, those harboring NPM1 mutation had higher CR rates (P<0.001) and longer OS (P=0.001), but not DFS (P=0.16), than pts with wild-type (wt) NPM1. Within the FLT3-ITDhigh cohort, pts with an NPM1 mutation had higher CR rates than those without (P<0.001). However, there was no difference in either DFS or OS between NPM1 mutated and NPM1 wt pts, indicating that the negative prognostic impact of FLT3-ITDhigh may outweigh the positive prognostic impact of NPM1 mutations with respect to those survival endpoints. We also noted that the negative prognostic impact of WT1 mutations was worsened by co-occurring NPM1 mutations. Similarly, the impact of IDH1 mutations within the Favorable group was influenced by NPM1 mutations, with IDH1/NPM1 co-mutated patients having inferior survival. Based on the results of our multivariable analyses, as well as co-occurring mutations, we provide a possible refinement of the ELN genetic risk stratification in Table 1. DFS and OS of the re-classified pts were comparable to DFS and OS of the original ELN groups (Figure 1). Importantly, the re-classification also changed the percentages of AML patients assigned to specific risk groups, reducing the Favorable-risk group from 49% to 39% and increasing the Adverse-risk group from 29% to 38%, with the Intermediate-risk group remaining almost the same (23% vs 22%). In summary, our study provides a comprehensive analysis of genetic prognostic markers in younger AML pts treated with standard chemotherapy within the framework of the ELN risk classification. Furthermore, we identified several combinations of co-occurring mutations with prognostic significance. Our results provide a refinement of the 2017 ELN risk classification, and identify additional pts that may need more intensive treatment early on.Support: U10CA180821, U10CA180882, U10CA180861, U24CA196171; ClinicalTrials.gov [Display omitted] DisclosuresMims:Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Kolitz:Magellan Health: Consultancy, Honoraria. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Unsuccessful Cytogenetics and Outcomes in Acute Leukemia

Introduction:Cytogenetic features at diagnosis have significant independent prognostic impact in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Failed or unsuccessful cytogenetics (UC) is estimated to occur in 10% of AML cases and 25-30% of ALL cases (Grimwade, 2010; Pullarkat, 2008). Previous studies suggest worse outcomes in AML patients (pts) with UC, similar to pts with unfavorable karyotype with lower response rates to induction chemotherapy and poor 5-year (yr) survival rates (Medeiros, 2014; Lazarevic, 2015). Hydroxyurea (HU) and steroids are often given urgently for cytoreduction prior to obtaining cytogenetics. The effects of such pretreatment on rates of UC have not been studied previously. In this study, we compared clinical outcomes of acute leukemia pts with UC versus successful cytogenetics (SC) and determined whether the use of HU or steroids affects cytogenetics success rates.Methods:All pts <70 yrs with de novo acute leukemia (AML or ALL) with available diagnostic bone marrow and cytogenetics testing seen at the Leukemia/Bone Marrow Transplant (BMT) Program of British Columbia between January 2010 and December 2016 were included. Pertinent information was reviewed from the program database. Cytogenetic failure was defined by the presence of <10 metaphases with a normal karyotype in the absence of a clinically actionable FISH abnormality. Pts with SC were risk stratified based on NCCN guideline criteria (NCCN, 2018). Baseline features of pts with SC and UC were compared using Chi-squared and two-tailed t-testing. Overall survival (OS) was calculated from the date of initial diagnosis to the date of death from any cause. Disease free survival (DFS) was calculated from the date of attaining first complete remission (CR1) to the date of relapse or death from any cause. Survival outcomes were estimated using the Kaplan-Meier method, with p values determined using the log rank test. A p < 0.05 was considered significant.Results:We identified 654 cases of acute leukemia (AML N=515; ALL N=139). Of these, 39 (6%) had UC (AML N=16, 3%; ALL N=23, 17%). There was no difference in age at diagnosis between groups (UC vs SC, 46 vs 51 yrs, p=0.08). AML pts with UC had higher initial white blood count (WBC) at diagnosis (71 vs 34, p<0.001). No effect of WBC was seen in ALL pts with UC versus SC. HU and/or steroid use prior to cytogenetics was similar between UC and SC groups in both AML and ALL pts (UC vs SC, HU: 8% vs 12%, p=0.61; steroids: 5% vs 1%, p=0.07. Therapy with intensive induction was also similar between groups (UC vs SC, 92% vs 90%; p=1.00). 137 (27%) of AML pts with SC had favorable risk disease, 182 (37%) intermediate, and 180 (36%) high risk. In ALL pts with SC, 32 (28%) had standard risk, and 84 (72%) had high risk disease. Follow up time in UC and SC groups was similar (32 vs 27m, p=0.18).CR rates in AML pts with UC was 81%, which was similar to pts with intermediate risk disease (84%, p=0.72) and better than CR rates of 39% observed in high risk pts (p=0.03). Compared to pts with SC, AML pts with UC had similar 5-yr OS and DFS as pts with intermediate risk disease (5-yr OS 25% vs 37%, p=0.45; 5-yr DFS 28% vs 28%, p=0.84), superior survival to high risk pts (5-yr OS 25% vs 17%, p=0.01; 5-yr DFS 28% vs 13%, p=0.036), and inferior survival to favorable risk pts (5-yr OS 25% vs 68%, p=0.07, 5-yr DFS 28% vs 52%, p=0.008), Figure 1.CR rates in ALL pts with UC was 83% and not significantly different than standard (94%, p=0.22) or high risk pts (86%, p=0.74). Compared to pts with SC, ALL pts with UC had similar 5-yr OS and DFS to pts with standard and high risk disease (UC vs standard vs high; 5-yr OS 58% vs 51% (p=0.93) vs 55% (p=0.85); 5-yr DFS 50% vs 37% (p=0.86) vs 36% (p=0.27)). Subgroup analysis of UC pts demonstrated no difference in survival in UC pts receiving BMT (N=12) vs no BMT (N=27). UC pts with high WBC >20 (N=14) had inferior survival compared to those with WBC ≤ 20 (N=25) (5-yr OS 60% vs 29%, p=0.025; 5-yr DFS 52% vs 12%, p=0.013).Conclusions:Unsuccessful cytogenetics was more frequently observed in ALL as compared to AML pts, though at lower rates than reported in previous studies. HU and steroid use had no effect on the rates of cytogenetic success. In comparison to previous reports, UC in AML was not associated with inferior outcomes, and survival was similar to intermediate risk pts. High initial WBC count was prognostic in pts with UC, and further studies are warranted to evaluate factors that affect outcomes in pts with UC. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Response and survival rates with frontline hypomethylating agent (HMAs) in favorable risk AML.

7039 Background: HMAs are an accepted frontline therapy for AML patients (pts) who are unfit for intensive induction therapy (IIT), particularly pts with unfavorable cytogenetics and/or p53 mutations. However, little is known about the response of favorable risk AML to HMAs. We previously reported that NPM1 mutated and/or CD34- AML status were predictors of response to HMAs. Here, we evaluated responses to frontline HMAs in AML. Methods: A total of 117 patients with de novo AML diagnosed between 7/2013 and 9/2016 were evaluated based on pt and disease related variables, overall response rate (ORR = CR + CR with incomplete count recovery + hematologic remission (ANC &gt; 1000/µL, Hgb &gt; 10g/dL, Plts &gt; 100,000/µL, &amp; no circulating blasts)), and overall survival (OS). Categorical variables were compared using Fisher’s exact test. Kaplan Meier methods estimated survival outcomes, and log rank tests compared survival between groups. Multivariable analyses were performed using Cox proportional hazards models. Results: 51 pts, considered unfit for IIT, received frontline HMAs. ORR and OS were highest in the ELN favorable risk AML pts (n = 13; ORR = 92%, p = .009; median OS = 17.5 months, p = .022). Among 41 NPM1 mutated pts, 15 received HMAs; and 26 received intensive induction. ORRs were 73% and 84%, respectively (p = .434). No difference was found in OS distributions between the HMA and IIT groups in univariate and multivariate (adjusted for age and FLT3 status) models (p = .329 and .241, respectively). Interestingly, ORR was 100% among 9 HMA-treated pts with NPM1 mutated, CD34-, FLT3/ITD-, cytogenetically normal AML. Conclusions: HMA therapy is highly effective frontline treatment in favorable risk AML pts considered unfit for IIT. Survival results with HMAs in NPM1 mutated AML are comparable to those of fitter pts treated with IIT. In selected favorable risk pts considered unfit for standard induction, HMAs can be a successful bridge to potentially curative therapy, including more intensive therapy or transplant. Cytogenetically normal AML with an isolated NPM1 mutation and CD34- status appears to be exceptionally responsive to frontline treatment with HMAs. Prospective validation of these findings is necessary.

A Series of 116 Therapy-Related Myeloid Neoplasms (t-MN) Patients from 2 French Comprehensive Cancer Centers

Background: Cancer patients (pts) who receive chemotherapy and/or radiation therapy for their primary tumor are at risk for developing therapy-related myeloid neoplasms (t-MN). Estimates of t-MN prevalence are mainly derived from retrospective series from hematology departments: they account for 10 to 20% of all AML cases. However this condition is frequently diagnosed in daily practice in comprehensive cancer centers (CCC). This suspected higher frequency might be due to optimized follow-up protocols and improved survival outcomes after tumor remission. The aim of this study was to assess clinical factors associated with t-MN in 2 French CCC focusing on delay of onset, survival, cytogenetically defined prognosis, treatment received for primary tumor and myeloid disease presentation.Methods: We conducted a retrospective study of cancer pts who developed t-MN seen at Institut Gustave Roussy, Villejuif, France and Institut Curie, Saint-Cloud, France between 2004 and November 2014. As defined in the current 2008 WHO classification, t-MN includes therapy-related acute myeloid leukemia (t-AML), myelodysplastic syndrome (t-MDS) and myelodysplastic/myeloproliferative neoplasms (t-MDS/MPN). The study inclusion criteria were development of t-MN after chemotherapy and/or radiation therapy for any primary tumor.Results: 116 patients were retrieved from our records. 86 patients were women (74%) and the median age at t-MN diagnosis was 65 years (range, 25-91 years). The distribution of primary malignancies by site was as follows: breast cancer 46 pts, hematologic malignancy (lymphoma and myeloma) 24 pts, gynecologic cancer 14 pts, head and neck cancer 8 pts, urologic cancer 6 pts, gastrointestinal cancer 4 pts, miscellaneous (sarcoma, neurooncology, neuroendocrinology cancer) 14 pts. The median interval between primary cancer and t-MN was 60 months (range, 12-324). At the time of t-MN diagnosis, 69 (59%) had t-AML, 46 (40%) had t-MDS and 1 (1%) had t-MDS/MPN. Of note, among t-AML pts 15 (13%) had AML with recurrent genetic abnormalities and 14 had AML (12%) with MDS-related changes. Median survival from the diagnosis of t-MN was 6.5 months (5y OS was below 20%). Adverse risk karyotypes were prominent (63 pts, 59%) followed by intermediate risk (32 pts, 30%). Of note 12 pts (10%) had favorable risk karyotype. The impact of karyotype on survival was crucial: median survival was 60 months for favorable risk pts, 14 months for intermediate risk pts and only 6 months for adverse risk karyotypes. 26 pts (22%) were treated by radiation therapy alone. Treatment modality (radiation therapy alone, chemotherapy alone or combined treatment) did not affect survival or delay of onset. Of note, when we isolated pts treated by alkylating agents without topoisomerase inhibitors from those treated by topoisomerase inhibitors without alkylating agents we found that the disease presentation did not differ (same proportion of t-AML vs. t-MDS in each group), an observation in contrast with the classical description of post-alkylating agent t-MDS vs. post- topoisomerase inhibitor t-AML.Conclusion: We report a heterogeneous cohort of 116 pts with numerous primary tumors and treatment protocols. Prominent adverse risk karyotypes are in line with a dismal survival yet favorable risk karyotypes are not uncommon and remain associated with a relatively good prognosis. DisclosuresNo relevant conflicts of interest to declare.

Maintenance Therapy with Decitabine in Younger Adults with Acute Myeloid Leukemia (AML) in First Remission: A Phase II Cancer and Leukemia Group B Study (CALGB 10503, Alliance)

AbstractAbstract 44CALGB (now part of the Alliance for Clinical Trials in Oncology) performed a non-randomized phase II study testing one year (yr) of investigational maintenance therapy with decitabine for newly diagnosed adult AML patients (pts) <60 yrs of age (CALGB 10503, Alliance). The study included induction followed by molecular and cytogenetic risk-adapted consolidation identical to that given in the prior CALGB study for younger AML pts (19808). Induction used daunorubicin 90 mg/m2 for 3 days, etoposide 100 mg/m2 for 3 days, and cytarabine 100 mg/m2 for 7 days (3+3+7). Reinduction (2+2+5) was given for residual disease on day 14. Favorable risk pts [defined here as t(8;21), inv(16), or t(16;16)] in complete remission (CR) received 3 cycles of high dose cytarabine (HiDAC); all other pts received two-step consolidation with chemo-mobilization and autologous transplantation (autoHCT) if eligible, or HiDAC-based consolidation if not. However, removal from study for alloHCT in 1st CR, instead of the two-step autoHCT, was permitted for non-favorable risk pts. Maintenance decitabine began as soon as possible after recovery from consolidation; pts had to have CR with neutrophils >1 × 109/L, platelets >75 × 109/L, and be within 90 days after day 1 of the final consolidation. Decitabine 20mg/m2 was given IV over 1 hour for 4–5 days, every 6 weeks, for 8 cycles. 546 pts enrolled with a median age of 48 yrs (range, 17–60) and median presenting white blood count (WBC) of 12.6 × 109/L (range, 0.3–380 × 109/L). 75% achieved CR (412/546). Reasons for CR pts not receiving maintenance were mainly early relapse, alloHCT in 1st CR, inadequate count recovery, and patient refusal (Blum et al. ASH 2011). 33% of CR pts (134/412) received investigational maintenance. Of these, 46 (34%) were favorable risk; among the remaining 88 pts, 73 were consolidated with autoHCT, and 15 received HiDAC-based consolidation. The median time from initial study registration to initiation of maintenance therapy was 6.3 months. Pts receiving decitabine had a median age of 45 yrs (range, 18–60) and presenting WBC of 13.5 × 109/L (range, 0.4–221 × 109/L). Treatment with decitabine maintenance was feasible and reasonably well tolerated; the primary toxicity was myelosuppression. Preplanned dose reduction criteria for neutropenia were met after the first 20 pts had been treated. After this early timepoint, all subsequent pts who had been consolidated with autoHCT received only 4 days of decitabine per cycle (HiDAC consolidated pts continued to receive 5 days per cycle). The median number of cycles of decitabine received was 7 (range, 1–8); 46% of pts (62/134) received all 8 cycles, and 75% completed at least 4 cycles. Reasons for discontinuation of decitabine before completing 8 cycles included relapse (28%, 38/134), pt refusal (13%), adverse events (4%), and others. In this selected cohort of pts who received post-CR maintenance with decitabine, 1-yr and 3-yr overall survival (OS) were 96% and 66%; 1-yr and 3-yr disease-free survival (DFS) were 80% and 53%. 1-yr “failure-free survival” calculated from the time of registration to decitabine was 68% (70% for favorable risk, 68% for others). These results are similar to the outcomes for comparable pts enrolled on our prior CALGB study 19808 who received identical chemotherapy for induction and consolidation and then were randomized to observation or maintenance with interleukin-2 (3-yr OS 61% and 68%, 3-yr DFS 45% and 56%, for observation and IL-2 respectively). Post-consolidation maintenance with decitabine appears to provide only modest, if any, benefit overall. Correlative studies for CALGB 10503 are ongoing, including investigations into the impact of decitabine in unique molecular and cytogenetic subsets of disease, the prognostic/predictive value of aberrant methylation and other molecular markers, and assessment of minimal residual disease. Supported by CA33601 and CA128377. Disclosures:No relevant conflicts of interest to declare.