International Working Group Response Research Articles

Validation of the Composite Complete Response (cCR) Definitions in the International Working Group (IWG) 2023 Criteria in Patients (Pts) with Higher-Risk Myelodysplastic Syndromes/Neoplasms (HR-MDS) Treated with Hypomethylating Agents (HMA) - a Large, Multicenter, Retrospective Analysis from the Validate Database

JPB and TK are co-first authors; RK and AMZ are co-senior authors Introduction: Efficacy of therapies used in HR-MDS pts has long been assessed using IWG 2006 MDS criteria, but important limitations in clinical utility and practical application of these criteria have become apparent. The revised IWG response criteria for HR-MDS were proposed in 2023 (Zeidan et al., Blood 2023) were proposed to address these gaps. IWG 2023 re-defined CR by lowering hemoglobin (Hb) threshold from 11 to 10 g/dL and bone marrow [BM] blasts from ≤5% to <5%. Further, CR with partial hematologic recovery (CRh; <5% BM blasts, no Hb threshold, platelets ≥50 × 10 9/L; neutrophils ≥0.5 × 10 9/L; peripheral blood [PB] blasts 0%), CR with limited count recovery (CR-L; <5% BM and 0% PB blasts + PB parameters for CR met in 1 [CRuni] or 2 lineages [CRbi]), and CR equivalent (CRequ; defined for pts with baseline BM of <5%.) were all proposed as provisional endpoints. Per IWG 2023 hierarchical response assessment, if a pt met criteria for both CR-L and CRh, they would be recorded as CR-L. We sought to validate the IWG 2023 definitions of cCR (CR+CR-L+CRh+CRequ) in a large, multi-center dataset of HR-MDS pts who received HMAs. Methods: The VALIDATE database includes HR-MDS pts treated with HMA-based therapies in frontline setting from 14 specialized centers. HR-MDS was defined as IPSS ≥1.5 or IPSS-R >3.5 (n=213 pts excluded). Pts were excluded (N=90) if age at diagnosis was <18 years, BM blasts ≥20% or unknown at HMA initiation, or if survival status, follow-up time, HMA type or initiation date were unknown. To preserve validity of response assessments, pts also were excluded (N=290) if no BM evaluation was performed or if first BM assessment was >180 days after HMA initiation, except in cases of overt disease progression. Best responses were assessed based on IWG 2006 and 2023 criteria. Kaplan-Meier analysis estimated OS from HMA initiation, and the log-rank test was used to compare subgroups. Cox multivariable regression models identified predictors of OS. This study was supported by an independent research grant from AbbVie. Results: Of 1,223 pts in VALIDATE database, 629 were met eligibility. Median age was 68 years, 27.7% and 27.4% were red blood cell and platelet transfusion-dependent, respectively, 38.1% had TP53 mutations, and 45.3% underwent allogeneic transplantation (allo-HCT). Most pts (71.6%) received HMA monotherapy (51.7% azacitidine, 19.9% decitabine), while 28.4% received HMA-based combinations. Median duration of therapy was 4 cycles (Range: 1-94). Median OS of different subgroups pts are shown in Figure 1. Median OS for pts with IWG 2023-defined cCR (CR+CR-L+CRh+CRequ; N = 230) was 26.5 months (mo; 95% CI: 20.7 - 32.2 mo) vs 14.3 mo (95% CI: 12.5 - 16.9 mo) for pts who did not achieve cCR (p=0.002). Median OS for pts who achieved IWG 2023-defined CR (N = 90) was 29.8 (95% CI: 23.1 - 41.8) vs. 26.4 mo (95% CI: 22.0 - 41.3) for IWG 2006-defined CR (p=0.71). The 124 pts (19.7%) who achieved CR-L had a median OS of 26.4 mo (95% CI: 17.6 - 36.2 mo); of those 67 pts achieved CRbi and had a median OS of 29.1 mo (95% CI: 20.7 - not reached), while 57 pts achieved CRuni and had a median OS of 18.7 mo (95% CI: 15.5 - 54.4 mo), with no significant difference in OS between CRbi and CRuni (Hazard ratio: 1.24; 95% CI: 0.78-1.98, p=0.71). Given the hierarchical prioritization of CR-L designation over CRh in IWG 2023 if a pt meets both response definitions, only 6 pts achieved CRh which precluded a reliable estimate of their OS. Similarly, CRequ was achieved only in 10 pts limiting a reliable assessment of OS in these pts. In a multivariable Cox model that adjusted for sex, HMA type, age, allo-HCT, complex karyotype, TP53 mutation, and IPSS-M risk group, achieving a cCR per IWG 2023 criteria was statistically significantly associated with improved OS was associated with improved OS compared to those who did not achieve cCR (HR: 1.64; 95% CI: 1.30 - 2.08; p<0.001, Figure 2). Discussion: In this real-world analysis of HR-MDS pts treated with HMA-based therapy, cCR according to IWG 2023 were associated improved OS. In particular, CR and CRL (including CRbi and CR uni) were associated with improved OS, supporting their inclusion in the overall response rate in clinical trials. The number of pts who achieved CRh and CRequ was too small to reliably assess their specific association with OS. Additional pts are being added to the database and detailed analyses will be presented in the meeting.

Post Allogeneic Stem Cell Transplant Outcomes Following Response to Hypomethylating Agent Therapy in Myelodysplastic Syndromes Are Predicted By Persistent International Prognostic Scoring System-Molecular Risk

Introduction: The International Prognostic Scoring System-Molecular (IPSS-M) ( Bernard NEJM Evidence 2022) and the 2023 International Working Group (IWG) response criteria for myelodysplastic syndrome (MDS) ( Zeidan Blood 2023) are used to more accurately assess prognosis and therapeutic response in MDS. However, it is unknown if these tools can be used to predict outcomes post-allogeneic hematopoietic stem cell transplant (HCT). We sought to understand the impact of pre-HCT IPSS-M on post-HCT outcomes in patients (pts) with MDS who responded to hypomethylating agent (HMA) therapy. Methods: Pts with MDS treated with HMA (azacitidine or decitabine) who received an HCT post-HMA at Dana-Farber Cancer Institute from January 2014 to December 2020 were included. Response to HMA was assessed by 2023 IWG response criteria and was defined as complete remission (CR) + CR with bi-lineage blood count recovery (CRbi) + CR with uni-lineage blood count recovery (Cruni) + CR with partial hematological recovery (CRh). Combined clinical and molecular risk was assessed by IPSS-M at times of diagnosis and of HCT, the latter using the bone marrow biopsy and sequencing data collected closest to HCT. High risk was defined as IPSS-M moderately high, high, and very high, whereas low risk was defined as IPSS-M very low, low, and moderately low. Results: A total of 148 pts with MDS who received HMA and underwent subsequent HCT were included. Median age was 64 years (range 26-79) and 61.5% were men. Pts were diagnosed with MDS-EB1 (26.4%), MDS-EB2 (45.3%), and other MDS subtypes (28.3%). IPSS-M at time of diagnosis was very low (2%), low (10.1%), moderate low (6.1%), moderate high (8.8%), high (31.8%), and very high (22.3%). IPSS-M pre-HCT was very low (12.8%), low (8.8%), moderate low (10.8%), moderate high (12.8%), high (20.3%), and very high (10.8%). IPSS-M at diagnosis and pre-HCT could not be calculated because of missing molecular data in 18.9% and 23.6% of pts, respectively. Pts received a median of 4 HMA cycles (range 1-20) and were treated with azacitidine for 7 days (54.1%), decitabine for 5 days (39.2%), and other schedules (6.7%). Prior to HCT, IWG 2023 responses were: CR (15.5%), CRbi (14.9%), CRuni (19.6%), CRh (0.7%), partial remission (PR: 1.4%), hematological improvement (HI: 9.5%), and no response (38.5%). Most pts received HCT from either a matched unrelated (60.8%) or matched related donor (18.2%) with reduced intensity conditioning (74.3%). Pts received graft versus host disease prophylaxis with tacrolimus (tac)/methotrexate (MTX) (54.7%), tac/MTX/sirolimus (19.6%), post-transplant cyclophosphamide/mycophenolate mofetil/tac (15.5%), tac/sirolimus (8.1%), other (2%). Median HCT-comorbidity index (CI) was 2 (range 0-13) and 48.6% pts had HCT-CI ≥ 3. For the entire cohort, the median follow-up time among ongoing survivors was 48.3 months (range 5.5-101.3). Among pts who responded to HMA per IWG 2023 criteria (CR/CRbi/CRuni/CRh), those who had high risk by IPSS-M prior to HCT had significantly shorter median overall survival (OS) (27 months; 95% CI 7.5-51) compared to pts with a low risk by IPSS-M (not reached; p=0.016) ( Figure A). Cumulative incidence of relapse (CIR) at 4 years was 66% for pts with high risk and 31% for low risk (p=0.034) ( Figure B). Pts with response to HMA with high risk by IPSS-M had lower OS (4-year OS: 27% versus 53%; p=0.016) and progression-free survival (4-year PFS: 19% versus 50%; p=0.018) but similar non-relapse mortality (NRM) (4-year NRM: 16% vs. 19%; p=0.66) post-HCT compared to pts with low risk at time of HCT. Conclusion: For pts with MDS who achieve a response to HMA prior to HCT, combined clinical/molecular risk, as assessed by IPSS-M, has an important prognostic impact on post-HCT outcomes. Pre-HCT risk should be evaluated for prognostication and to guide patient care, including future prospective studies evaluating novel agents for post-HCT therapy.

Time to Achieve Platelet Count Response after Intravenous Efgartigimod in Adults with Primary Immune Thrombocytopenia: A Phase 3, Multicenter, Double-Blinded, Placebo-Controlled, Randomized Clinical Trial (ADVANCE IV)

Background In primary immune thrombocytopenia (ITP), immunoglobulin G (IgG) anti-platelet autoantibodies contribute to platelet clearance and impair platelet production. IgG homeostasis is regulated by the neonatal Fc receptor (FcRn), which binds to IgG in a pH-dependent manner and recycles bound IgG. Efgartigimod (EFG), a human IgG1 Fc fragment, is a natural ligand of FcRn engineered to bind competitively to FcRn with high affinity, preventing recycling of endogenous IgG, thereby reducing IgG levels, including pathogenic IgG autoantibody levels. Methods Intravenous (IV) EFG was evaluated in ADVANCE IV, a phase 3, multicenter, randomized, double-blinded, placebo (PBO)-controlled trial (NCT04188379) in adults with persistent or chronic ITP (Broome CM, et al. ASH 2022). Participants who received 2 prior or 1 prior and 1 concurrent ITP therapy with an average of 2 platelet (PLT) counts of <30×10 9/L during screening were randomized 2:1 to receive EFG IV 10 mg/kg or PBO IV for 24 weeks. Concurrent oral corticosteroids, immunosuppressants, dapsone, danazol, fostamatinib, and oral thrombopoietin receptor agonists were permitted but required to remain at the entry dosage and frequency. Participants received weekly dosing of either EFG or PBO (weeks 1-4) followed by response-dependent weekly or every-other-week dosing (weeks 5-16) and then maintained their dosing regimen from weeks 17-24. PLT counts were measured weekly starting at day 7 after treatment initiation. The extent of disease control, defined as cumulative weeks with PLT counts of ≥50×10 9/L in the chronic ITP population, was assessed as a key secondary endpoint. This analysis evaluates trends in time to response in ADVANCE IV. The time to achieve 2 consecutive PLT counts of ≥50×10 9/L was evaluated as a secondary endpoint. Time to 2 consecutive PLT counts of ≥100×10 9/L and time to single counts of ≥50×10 9/L and 100×10 9/L were analyzed as defined a priori. Post hoc Kaplan-Meier (KM) analyses, including time to a single PLT of ≥30×10 9/L and time to the International Working Group (IWG) response, were also performed. Change from baseline in mean PLT counts over time was evaluated based on a mixed model for repeated measurements. Results One hundred thirty-one participants (118 chronic ITP, 13 persistent ITP) were randomized (86 EFG, 45 PBO). Least-squares mean estimate changes from baseline in PLT counts were significantly different in EFG group compared with PBO group starting at day 7 (22×10 9/L vs -1×10 9/L; P=0.0293) and remained significant at most time points throughout the study. 38.4% of EFG-treated participants compared with 11.1% of PBO treated participants achieved a PLT count of ≥30×10 9/L in 7 days. The EFG group showed a higher proportion of PLT count responders ≥50×10 9/L on ≥4 occasions until week 12 compared with PBO (34.9% vs 4.4%, respectively). Based on KM analysis, 31.8% of participants receiving EFG and 2.2% of those receiving PBO achieved 2 consecutive PLT counts of ≥50×10 9/L by day 42 (Figure). 41.5% of participants receiving EFG vs 11.4% of those receiving PBO achieved the first PLT count ≥50×10 9/L by day 42. 22.5% of participants receiving EFG vs 2.2% of those receiving PBO achieved the first PLT count ≥100×10 9/L by day 42 (Table). The cumulative number of weeks in disease control was significantly higher in the EFG group compared with PBO (mean [SD]: 6.1 [7.66] vs. 1.5 [3.23]; P=0.0009) (Broome CM, et al. ASH 2022).KM estimates for IWG response by day 42 in the overall (chronic and persistent ITP) population were 29.7% in participants receiving EFG vs 4.6% in those receiving PBO. Overall, EFG was well tolerated; most adverse events were mild or moderate in severity. Conclusions In ADVANCE IV, EFG demonstrated a rapid PLT count increase, as early as the first time point measured (7 days after EFG treatment). Irrespective of the specific measure of response utilized, these data demonstrate that at all time points evaluated more participants in the EFG group achieved response compared with the PBO group. In addition to this early response, significantly more sustained responses were observed in the EFG group compared with the PBO group. The response rate, regardless of definition, in participants who received EFG continued to increase over time suggesting that some participants may have delayed responses to EFG. These data further demonstrate early and sustained responses with EFG in ITP.

Preliminary Results from a Phase 1b Dose De-Escalation Stage of Abnl-Marro 001: An International MDS/MPN Working Group Study

Background: Myelodysplastic/Myeloproliferative neoplasms (MDS/MPN) represent a group of rare hematologic malignancies, distinguished by their concurrent dysplastic and proliferative features. Patients with these neoplasms have an increased risk of acute leukemia transformation and often present with extramedullary and constitutional symptoms. The only approved therapies for MDS/MPNs are hydroxyurea, decitabine (oral decitabine/cedazuridine and parenteral decitabine) or azacitidine (parenteral) for pts with CMML. Given the rarity and the heterogeneity of MDS/MPNs, prospective studies focusing specifically on MDS/MPN have been uncommon, and refining treatment strategies has been difficult. ABNL-MARRO ( A Basket study of Nove l therapy for untreated MDS/MPN and Relapsed/ Refractory Overlap Syndromes) is an international cooperative effort that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides a framework for collaborative studies around the world to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response (Moyo TK et.al BMC Cancer. 2022). Methods: ABNL-MARRO 001 (AM-001) is an open-label, phase 1b/2 study testing the treatment combination of ASTX727 (days 1-5), a fixed dose oral combination pill containing 35 mg of the DNMTi decitabine (DEC) and 100 mg of the cytidine deaminase inhibitor cedazuridine (CED), together with a series of active agents in myeloid disease (see Figure 1a) for MDS/MPN. In arm A, ASTX727 is combined with itacitinib 300 mg (days 1-28), a selective JAK1 inhibitor in newly diagnosed and relapsed/refractory (R/R) pts. Here we report results from the 3+3 dose de-escalation phase 1b portion used to determine the recommended Phase 2 dose (RP2D) in arm A. Dose-limiting toxicities (DLTs) were assessed in cycle 1. Disease response was assessed by the MDS/MPN IWG response criteria (Savona et.al., Blood. 2015). Results: Seven patients were enrolled with a median age 75 (range 32-82) years with newly diagnosed (4 pts) or R/R (3 pts) MDS/MPN. Three patients had CMML, 2 had MDS/MPN-U, and 2 had refractory MDS/MPN RST. One patient was not DLT evaluable given severe disease-induced cytopenia, and was not included in the assessment (patient 4 in Figure 1b). The majority of pts experienced a treatment-emergent adverse event (TEAE) of any grade; the most common (≥30% of pts) were thrombocytopenia (50%), neutropenia (30%), and constipation (30%); 50% of pts experienced a Grade ≥3 TEAE; the most common was neutropenia (30%). No DLTs were reported, and these AEs were consistent with what has been reported in the use of ASTX727 (Savona et al. Blood. 2022). One patient achieved a CR, and two additional patients had the best overall response of optimal marrow response after receiving 6 cycles of treatment. All patients are alive with a median follow-up of 12 months (range 6-17 months). The clinical responses and time-on-treatment of all pts in phase 1b are summarized in Figure 1b. Summary/Conclusion: Based on the preliminary results of the phase 1b study, the dosing schedule of 35 mg DEC / 100 mg CED daily for 5 days in combination with itacitinib 300 mg daily for 28 days was selected as the RP2D as it balanced clinical efficacy with an acceptable and manageable safety profile. This regimen and dose are being utilized in a 28-day cycle in the ongoing global, multi-center phase 2 study (NCT04061421).

Postazacitidine clone size predicts long-term outcome of patients with myelodysplastic syndromes and related myeloid neoplasms.

Azacitidine is a mainstay of therapy for myelodysplastic syndrome (MDS)-related diseases. The purpose of our study is to elucidate the effect of gene mutations on hematological response and overall survival (OS), particularly focusing on their posttreatment clone size. We enrolled a total of 449 patients with MDS or related myeloid neoplasms. They were analyzed for gene mutations in pretreatment (n= 449) and posttreatment (n= 289) bone marrow samples using targeted-capture sequencing to assess the impact of gene mutations and their posttreatment clone size on treatment outcomes. In Cox proportional hazard modeling, multihit TP53 mutation (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.42-2.91; P< .001), EZH2 mutation (HR, 1.71; 95%CI, 1.14-2.54; P= .009), and DDX41 mutation (HR, 0.33; 95%CI, 0.17-0.62; P< .001), together with age, high-risk karyotypes, low platelets, and high blast counts, independently predicted OS. Posttreatment clone size accounting for all drivers significantly correlated with International Working Group (IWG) response (P< .001, using trend test), except for that of DDX41-mutated clones, which did not predict IWG response. Combined, IWG response and posttreatment clone size further improved the prediction of the original model and even that of a recently proposed molecular prediction model, the molecular International Prognostic Scoring System (IPSS-M; c-index, 0.653 vs 0.688; P< .001, using likelihood ratio test). In conclusion, evaluation of posttreatment clone size, together with the pretreatment mutational profile as well as the IWG response play a role in better prognostication of azacitidine-treated patients with myelodysplasia.

International Working Group (IWG) Response Criteria and Association with Overall Survival in Patients with Myelodysplastic Syndromes Treated with Hypomethylating Agents - a Systematic Review and Meta-Analysis

* A.M.Z. and M.S. contributed equally Introduction: Response assessments in clinical trials and routine practice for patients (pts) with myelodysplastic syndromes (MDS) treated with hypomethylating agents (HMA) are based on the International Working Group (IWG) criteria proposed in 2000 and revised in 2006. However, it is not clear whether response criteria correlate with overall survival (OS). Methods: We conducted a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines with a systematic search using controlled vocabulary and free text terms for MDS and survival of Cochrane Library, Google Scholar, Ovid Embase, Ovid Medline, Pubmed, Scopus, and Web of Science Core Collection databases to find relevant articles published from inception to January 2022. The search was peer-reviewed by a second medical librarian. A targeted search of recent conference proceedings was also performed. Titles, abstracts, and full texts were reviewed for inclusion in the meta-analysis by two reviewers independently and conflicts were resolved by consensus discussion. Clinical trials and cohort studies with >100 pts reporting on the association of IWG 2000 or 2006 response criteria with OS among pts treated with HMA monotherapy or combinations were eligible for inclusion. Studies were excluded if they were (i) review or basic research articles, (ii) studies with <50% higher-risk MDS pts (inclusion of a minority of pts with MDS/MPN, oligoblastic AML, and lower-risk MDS was permitted), (iii) not published in English, and (iv) had insufficient reporting of the primary endpoint. The primary endpoint was the hazard ratio (HR) for OS for patients achieving an IWG-defined response (complete remission [CR], marrow CR, partial remission, hematologic improvement [HI]) compared to patients not achieving a response. Random-effects models were used to pool the HRs for death. Cochran Q and I2 indices were used to assess heterogeneity across included studies. Study heterogeneity was graded based on I2 indices as low (I2 <30%), moderate (I2 =30-60%), or high (I2 >60%). Comprehensive Meta-Analysis (CMA version 2.2, Biostat) was used for all analyses. Results: Our search strategy identified 7023 studies after duplicate removal. Following abstract and title review to identify clinical trials and large cohort studies reporting IWG response and OS among MDS pts treated with HMA, 195 studies were assessed for eligibility as full texts. Among these 185 studies were excluded for the following reasons: insufficient reporting of the primary outcome of OS and IWG response (n=114), duplicate publications from the same pt cohort (n=42), <50% higher-risk MDS pts (n=13), cohort studies with <100 pts (n=6), not on HMA therapy (n=4), ongoing clinical trials without published results (n=3), transplant (n=2), and review article (n=1). The final set of studies included 3896 MDS pts treated with azacitidine, decitabine, guadecitabine, or HMA-combination in 9, 4, 1, and 2 studies, respectively. Among the 5 available studies with data on the impact of CR on OS, the HR for death was 0.365 (95% CI: 0.311-0.430) for pts who achieved a CR compared to pts without a CR. Study heterogeneity was low (Cochran's Q=0.5; I2=0%; Figure A). Six studies reported the impact of HI on OS. Pts who achieved HI had favorable outcomes compared to pts without HI (HR: 0.419; 95% CI: 0.299-0.585) but with high heterogeneity across studies (Cochran's Q=14.34; I2=65.13%; Figure B). The prognostic impact of other response categories (e.g., marrow CR, partial remission) was only reported by 1 study each, precluding a meta-analysis. Conclusion: Achieving CR as defined by the IWG MDS response criteria is associated with improved OS among higher-risk MDS pts treated with HMA-based regimens. HI was also associated with OS, but with high study heterogeneity. The strong and consistent association of CR with OS supports its use as an outcome in clinical trials in MDS. The prognostic implications of other response categories as such CR with partial hematologic recovery (CRh) especially with novel combination therapies require additional studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Intravenous Efgartigimod in Adults with Primary Immune Thrombocytopenia: Results of a Phase 3, Multicenter, Double-Blinded, Placebo-Controlled, Randomized Clinical Trial (ADVANCE IV)

Background: In immune thrombocytopenia (ITP), immunoglobulin G (IgG) platelet autoantibodies accelerate platelet clearance and impair platelet production. IgG homeostasis is regulated by the neonatal Fc receptor (FcRn). Efgartigimod (EFG), a human IgG1 Fc-fragment, is a natural ligand of FcRn engineered to competitively bind to FcRn with high affinity and prevent recycling of endogenous IgG, but not albumin, thereby reducing IgG levels including IgG autoantibody levels. Methods: The efficacy and safety of intravenous (IV) EFG were evaluated in ADVANCE, a phase 3, multicenter, randomized, double-blinded, placebo (PBO)-controlled trial (NCT04188379) in adults with persistent or chronic ITP. Participants with an average of 2 platelet counts (PLTs) of <30×109/L during screening were randomized 2:1 to receive 10 mg/kg EFG or PBO for 24 weeks. Concurrent oral corticosteroids, oral immunosuppressants, dapsone, danazol, fostamatinib, and oral thrombopoietin receptor agonists (not romiplostim) were permitted but required to remain at the entry dosage and frequency. Participants received weekly dosing (weeks 1-4) followed by response-dependent weekly or every 2 weeks (q2w) dosing (weeks 5-16) and then maintained their dosing regimen from weeks 17-24. The primary and key secondary endpoints were tested in hierarchical order. The primary endpoint was the proportion of chronic ITP participants with a sustained PLT response (PLT of ≥50×109/L in ≥4 of 6 visits between weeks 19 and 24 without intercurrent events, e.g., rescue therapy at week 12 or later). Key secondary endpoints included extent of disease control (cumulative weeks with PLTs of ≥50×109/L) in the chronic population, proportion of participants in the overall population (chronic and persistent) with sustained PLT response, incidence of bleeding events, and a durable sustained platelet response (PLT of ≥50×109/L in ≥6 of 8 visits between weeks 17 and 24) in the overall population. Safety and pharmacodynamic measures were also evaluated. Results: 131 participants (118 chronic ITP, 13 persistent ITP; 86 EFG, 45 PBO) were randomized. Participants had long-standing, severe ITP (median time since diagnosis of 4.57 years; baseline median PLT of 17×109/L) and were heavily pretreated (67.2% had ≥3 prior ITP therapies). In chronic ITP participants, sustained PLT response was reached in more EFG-treated participants (21.8%; 17/78) than PBO (5.0%; 2/40; p=0.0316). EFG achieved all PLT-related secondary endpoints (Table1). Model-based mean changes from baseline in PLT levels over time showed a clear differentiation from PBO as of week 1, indicating an early onset of PLT response in the EFG group. A sustained PLT response was achieved in 90% (9/10) of participants who reached and maintained the q2w fixed dosing. EFG-treated participants responded better than PBO regardless of age, sex, severity of disease, time since diagnosis, prior ITP treatment, or background medication (Figure1). International working group (IWG) response (consecutive visits ≥7 days apart with PLTs of ≥30×109/L and 2-fold increase from baseline in the absence of bleeding events) was seen in 51.2% (44/86) of EFG treated participants compared to 20.0% (9/45) in the PBO group. Mean IgG levels in EFG-treated participants decreased steadily over the first 4 weeks of treatment, after which the mean maximum reductions from baseline remained greater than 60% throughout the trial. Mean IgG levels were similar in the group on q2w treatment. Adverse events (AEs) were reported in 93.0% (80/86) of participants in the EFG group and 95.6% (43/45) in the PBO group. Most frequent AEs included bruising, headache, hematuria, and petechiae. Serious AEs were reported in 8.1% (7/86) of participants in the EFG group and in 15.6% (7/45) in the PBO group, and none were treatment related. These included bleeding or events related to bleeding (n=5), infections (n=4), and worsening primary ITP (n=3). No deaths or increased risk of infection were observed. Conclusions: Compared to PBO, EFG showed an early PLT increase, higher sustained PLT response, and more weeks with PLT ≥50×109/L. EFG achieved the primary and all PLT-related secondary endpoints and also showed that 51.2% of participants on EFG achieved IWG response criteria versus 20% on PBO. EFG was well tolerated with no new safety signals. Long-term efficacy and safety data are being evaluated in the open-label extension trial (ADVANCE+; NCT04225156). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venetoclax (Ven) with Azacitidine (Aza) for Untreated Elderly Acute Myeloid Leukemia (AML) Patients (Pts) Unfit for Induction Chemotherapy: Single Center Clinical Experience and Mechanistic Insights from Correlative Studies

Introduction: There is no effective standard of care for older AML pts who are unfit for induction. We explored the combination of the BCL-2 inhibitor venetoclax (ven) with azacitidine (aza) for this population in a multi center phase 1b study (NCT02203773), and report clinical results from our center, as well as mechanistic insights regarding the activity of this regimen derived from correlative studies performed with our pt samples.Methods: The dose escalation/expansion trial combined aza or decitabine, at the standard dose and schedule, with ven daily in older AML pts unfit for induction. Our institution enrolled into the aza arm. Pts were eligible if ≥65 and with adequate organ function. Response assessments employed International Working Group (IWG) criteria; if a morphologic remission was achieved without count recovery, delay of the subsequent cycle by up to 14 days was permitted, with growth factors per institutional guidelines, and best response was upgraded if counts improved in this timeframe. Minimal residual disease (MRD) testing was performed by digital droplet PCR (ddPCR) with a sensitivity of 0.01%. Mass cytometry was performed using CyTOF.Results: 33 pts enrolled and received at least 1 day of therapy. 23 received 400 mg venetoclax, 9 received 800 and 1 received 1200 (Table 1). 2 elected to come off study after <7 days; both died of AML. Median follow up time using reverse Kaplan-Meier was 351 days (95% CI 146, 468). The overall response rate (ORR), defined as complete response (CR) + CR with incomplete count recovery (CRi) + partial response (PR) + morphologic leukemia free state (MLFS), was 30/33 (91%); 19 (58%) had a CR, 9 (27%) had a CRi, 1 had a PR and 1 had a MLFS. Only 1 pt who completed >1 week of therapy did not respond (resistant disease). No variables tested predicted outcomes in the 31 pts who had >1 week of therapy (Table 2); 5/5 with monosomal karyotype, 5/5 with FLT3 and 2/2 with TP 53 responded. 3 proceeded to transplant; none have relapsed after 14, 8 and 4 months. 4/33 (12%) relapsed; only 1 relapse occurred in a patient who continued on therapy, after 13 months. 3/4 relapsed after coming off study for a hip fracture (N=1), personal decision (N=1) and development of mastocytosis (N=1). The median response duration has not occurred; mean is 484 days (std error 44). Median progression free survival (PFS) has not occurred; mean is 294 days. Median overall survival (OS) has not occurred; mean is 376 days (Figure 1).We used ddPCR to measure MRD in all pts with amenable mutations (N=18). Of these, 14 have completed ≥1 cycle with ≥3 months of follow-up, and were analyzed for MRD. 3 achieved MRD negativity; 1 who remains on therapy (cycle 16, 453 days), and surprisingly, 2 who discontinued therapy, for personal reasons and cytopenias, after 1 and 6 cycles. They remain in MRD negative CR and CRi after 24 and 16 months. Another who achieved a CR and discontinued therapy after 3 cycles for personal reasons has also had no further therapy for 25 months and continues to be in CR with borderline MRD detectability (0.024%).Detailed temporal analysis of 2 pts who achieved a CR and CRi using CyTOF and single cell RNA-seq methods showed rapid and extensive targeting of primitive AML cell types (Figure 2, not all data shown). This data indicates effective targeting of the AML stem cell population. Ongoing functional studies using xenograft models will corroborate direct targeting of AML stem cells.Conclusion: Ven with aza is a highly active regimen for untreated elderly AML pts who are not candidates for induction chemotherapy; all but 1 pt who stayed on study for >1 week achieved an IWG response, primarily CR/CRi. There were no serious adverse events related to ven and very few significant related adverse events. Responses were durable with few relapses, particularly for pts who remained on treatment; 3 pts who elected to stop all therapy have had no recurrence with considerable follow up. MRD detection with ddPCR reveals the depth of response possible with aza+ven; several pts in long term follow up have achieved MRD negative remissions, including 2 who discontinued all therapy after 6 months or less with no subsequent treatment for 24 and 16 months. Median PFS and OS were not reached with median follow up time of nearly 1 year. The universality, depth and durability of responses, coupled with the CyTOF and single cell RNA-seq data, suggest this regimen effectively targets the leukemia stem cell population. [Display omitted] DisclosuresPollyea:Agios, Pfizer: Research Funding; Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis: Membership on an entity's Board of Directors or advisory committees.

The potential treatment of antroquinonol in adult patients with relapsed acute myeloid leukemia (AML).

e19001 Background: The prognosis of relapsed acute myeloid leukemia (R/R AML) remains poor and the management is challenging. Despite the increasing availability of targeted agents, the lower responses still represent a major obstacle to overcome. Antroquinonol is an isoprenyltransferase inhibitor with antitumor activity in vitro and xenograft models of AML. Our aim is to evaluate hematopoietic recovery with Antroquinonol in this phase IIa study. Here, the results from our phase IIa trial demonstrate the safety, tolerability, and activity of Antroquinonol in patients with relapsed AML. Methods: GHAML-2-001 is a phase IIa, open-label study in adult patients with relapsed acute myeloid leukemia or at initial diagnosis when no intensive treatment is possible. Antroquinonol 200 mg BID was administered in a 28-day cycle (up to six cycles). The primary endpoint is hematologic response rate. Secondary endpoints consist of 4-week survival, 24-week survival, duration of hematologic response and transfusion independence, and the response rates. Therapy was continued for as long as tolerated and there was continuing evidence of therapeutic benefit in the opinion of the investigator. Treatment response was assessed by the International Working Group (IWG) response criteria after each cycle. Results: Twelve eligible patients had a median age of 62.5 years (range, 42-69; 6 males, 6 females) and the whole process was conducted between March 2019 and February 2020. Of the two patients who did not complete the therapy period were due to the patient's decision to withdraw: One patient withdrew on day 7 and the other one withdrew on day 49. Among other ten patients who finished all six cycles (168 days), Antroquinonol showed excellent safety and favorable tolerability. At the end of the treatment, the rate of complete remission (CR/CRi) after 6-completed cycles was 50% (5/10) and the 24-week survival rate was 100%. Transfusion independence was achieved in 8 (80%) of 10 transfusion independence evaluable patients at the end of the 6th cycle treatment. Conclusions: In high-risk relapsed AML patients, orally administered Antroquinonol induced CRs and was well tolerated. This significant result suggests the potential of Antroquinonol for the therapy of this underserved population. Clinical trial information: NCT03823352. Clinical trial information: NCT03823352.

Eltanexor (KPT-8602), a Second-Generation Selective Inhibitor of Nuclear Export (SINE) Compound, in Patients with Higher-Risk Myelodysplastic Syndrome

Background: Overexpression of exportin 1 (XPO1) in malignant cells increases the nuclear export/inactivation of tumor suppressor proteins (e.g. p53, IκB), and promotes the translation of eIF4E-bound mRNAs coding oncoproteins (e.g. c-MYC, BCL-2, AR). Selinexor plus low dose dexamethasone (Sel-dex) was recently approved in the United States based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. Eltanexor (elta), a second-generation SINE compound, has demonstrated reduced brain penetration and improved tolerability compared to selinexor in non-clinical animal models, and preliminary anti-tumor activity in clinical trials of hematologic and solid tumor malignancies. The primary objective of this study was to assess the safety, tolerability and anti-tumor activity of elta in patients (pts) with higher risk (HR)-Myelodysplastic Syndrome (MDS). Methods: This is part of a Phase 1/2 study (NCT02649790) to determine the safety, tolerability and anti-tumor activity of elta in advance malignancies. This trial planned to evaluate single agent activity of elta in an expansion cohort of 20 pts with HR-MDS (intermediate-2 [Int-2] or high-risk by the International Prognostic Scoring System [IPSS]). Other key eligibility criteria included: age ≥18, ECOG ≥1, adequate organ function, and documented evidence of progressive disease as defined by the 2006 International Working Group (IWG) Response Criteria for MDS, which includes hypomethylating agent (HMA) failure. The dose levels evaluated in the MDS cohort were 10 and 20 mg elta taken orally once daily for 5 consecutive days per week in a 28-day cycle. A key efficacy endpoint is overall response rate (ORR) which includes complete response (CR), partial response (PR), marrow CR (mCR), and hematologic improvement (HI) using the 2006 IWG Response Criteria for MDS. Results: Twenty pts (median age 77 years-old; range 62-89; 55% male) were enrolled as of 15 July 2018 (n=15 at 20 mg and n=5 at 10 mg). All pts were refractory to HMA with a median of 2 prior therapies (range 1 - 5) and 90% high risk via IPSS (11 pts high, 7 pts Int-2, 2 pts Int-1 [IPSS-R high]). Fourteen of 20 pts were evaluable for response, 2 are pending disease reassessment and 4 were not evaluable (NE). Preliminary efficacy demonstrated best responses of 4 mCR (29%) and 6 stable disease (SD; 43%) and 4 progressive disease (PD; 29%). The disease control rate (mCR + SD) was 71%. The median time on treatment for all pts was 69 days (range 5+ - 379) with a median time on study of 115 days (range 5+ - 400). The most frequent (≥3 pts) treatment-related adverse events (TRAEs) any grade (Gr) included nausea (53%), decreased appetite (33%), diarrhea (27%), thrombocytopenia, anemia, neutropenia, vomiting and dysgeusia (20% each). The most frequent Gr≥3 TRAEs included thrombocytopenia and anemia which are expected in this immune compromised patient population. All AEs were reversible and manageable by supportive care and dose modification. The 4 pts NE for response were pts who discontinued from treatment before having the first disease response reassessment due to: Gr3 diarrhea related to eltanexor, Gr5 sepsis not related per investigator, Gr3 pneumonia not related, and withdrawal by pt. Conclusion: Oral eltanexor demonstrated preliminary anti-tumor activity as a single agent in elderly pts with HMA-refractory HR-MDS, including mCRs or disease stabilization, and a manageable tolerability profile. Further evaluation of efficacy and safety in HR-MDS is on-going. Disclosures Lee: Helsinn: Consultancy; Jazz Pharmaceuticals, Inc: Consultancy; Roche Molecular Systems: Consultancy; AstraZeneca Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Ai Therapeutics: Research Funding. Bhatnagar:Karyopharm Therapeutics: Other: Research support; Novartis and Astellas: Consultancy, Honoraria; Cell Therapeutics, Inc.: Other: Research support. Senapedis:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Patents &amp; Royalties. Baloglu:Karyopharm Therapeutics Inc: Equity Ownership, Patents &amp; Royalties; resTORbio: Employment. Wang:Karyopharm Therapeutics Inc: Employment. Shah:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents &amp; Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Preliminary Results from a Phase II Study of the Combination of Pevonedistat and Azacitidine in the Treatment of MDS and MDS/MPN after Failure of DNA Methyltransferase Inhibition

Preliminary Results from a Phase II Study of the Combination of Pevonedistat and Azacitidine in the Treatment of MDS and MDS/MPN after Failure of DNA Methyltransferase Inhibition

Relationship of bone marrow blast (BMBL) response to overall survival (OS) in a multicenter study of rigosertib (Rigo) in patients (pts) with myelodysplastic syndrome (MDS) with excess blasts progressing on or after treatment with a hypomethylating agent (HMA).

7056 Background: No therapies are approved for MDS after HMA failure. 04-24 was a single-arm study to evaluate best BMBL response as a potential surrogate for OS in higher-risk (HR) MDS pts who progressed on or after an HMA. Rigo is a Ras-mimetic that inhibits the RAS-RAF-MEK pathway, which is frequently activated in HR MDS (Athuluri-Divakar Cell 2016; Gil-Bazo Cancer Biol Ther 2016). Methods: Eligible MDS pts had 5-30% BMBL confirmed within 6 wks pre-study and progression per International Working Group (IWG) 2006 criteria on or after HMAs within 2 yrs. Rigo 1800 mg/24 hrs was continuously infused over 72 hrs q 2 wks × 8 cycles, then q 4 wks until progression or unacceptable toxicity. Primary endpoint was relationship of best BMBL IWG response to OS by Kaplan Meier method. Results: 64 pts were treated (median 5 cycles, range 1-32+), with 61% male, median age 73 (range 47-87), median prior HMA duration 10.8 mos (range 1.2-70.2). Revised International Prognostic Scoring System scores were low 2%, intermediate 11%, high 27%, very high 53%, and unknown 8%. ≥Grade 3 adverse events in ≥10% of pts were anemia 19%, thrombocytopenia 19%, and febrile neutropenia 16%. At the analysis time 40 pts (63%) had died. Best BMBL IWG response was marrow complete response (mCR) 14 pts (22%), stable disease (SD) 30 (47%), progressive disease (PD) 15 (23%), and failure (early death/withdrawal) 5 (8%); 2 mCR pts had transplant. Median OS was 7.0 mos (95% confidence interval 4.8-10.8). Landmark median OS (from day of best BMBL response) was mCR not reached; SD 6.3 mos; PD 3.3 mos. Median OS of mCR+SD was 8.5 mos, with log-rank p = 0.011 (mCR+SD OS to PD OS). Conclusions: BMBL response is a predictor of survival for MDS pts receiving Rigo after HMA failure, confirming findings in earlier Phase 1/2 studies (Silverman ASCO 2015 Abstr 7017). Based on earlier results identifying an MDS subset benefitting from Rigo (Garcia-Manero Lancet Oncol 2016; ASCO 2016 Abstr 165681), a randomized Phase 3 trial of Rigo vs physician’s choice (INSPIRE) is ongoing to determine if Rigo improves survival after HMA failure within 9 cycles. Clinical trial information: NCTO 1928537.

A Phase II Study of AT7519M, a CDK Inhibitor, in Patients with Chronic Lymphocytic Leukemia: NCIC CTG Trial IND.193

Introduction: The prognosis of patients (pts) with relapsed or refractory (rel/ref) Chronic Lymphocytic Leukemia (CLL) is poor. AT7519M is a small molecule inhibitor of cyclin-dependent kinases (CDKs) 1, 2, 4, 5 and 9 with lower potency against CDKs 3, 6 and 7. AT7519 has potent anti-proliferative activity against peripheral blood mononuclear cells isolated from CLL patients. Exposure of CLL cells to AT7519 results in cell cycle arrest and, ultimately, cell death by apoptosis. Based on the results of a NCIC CTG phase I study in advanced malignancies, the recommended phase II dose (RP2D) was 27 mg/m2 given as a 1 hour infusion twice weekly for 2 out of every 3 weeks. Using this schedule, Tumor Lysis Syndrome (TLS) and QTc prolongation were not observed.Methods: In a phase II clinical trial, we evaluated the clinical and pharmacodynamic effects of AT7519 using the RP2D schedule in pts with rel/ref CLL. Eligible patients were those with documented CLL with at least one prior systemic treatment regimen and either lymphocyte count > 10 x 109/L or at least one measurable lymph node > 2 cm x 2 cm. The primary objective was complete or partial remission (CR/PR) as defined by the 2008 International Working Group (IWG) Guidelines. We used a Fleming Phase II design, aiming for a total of 30 subjects, assuming an HA of >0.20. Cycle 1, dose 1 was administered as an in-patient with prophylaxis and monitoring for TLS.Results: Seven pts were accrued over 16 months. As a result, the trial was prematurely closed. Reasons for slow accrual included concerns about the risk of TLS, the need for in-patient care during cycle 1, and the relative stringency of eligibility criteria regarding baseline hematopoietic and renal function. All seven pts were male, with median age 70 years (range 47-81). Median number of previous regimens was 3 (range 1-4). Two pts had 11q- and one had 17p-. A total of 21 cycles were administered (median 4 cycles) with 71% of patients receiving > 90% of the planned dose intensity. Two pts required a dose reduction due to thrombocytopenia and one of these patients came off study early due to hypoxia and fever. The most common non-hematologic adverse events that were at least possibly related were grade 1 and 3 fatigue, grade 1 nausea (57%), grade 1 diarrhea and grade1/2 anorexia (43%) and grade1/2 fever (29%). Hematologic toxicities were primarily grade 1 and 2. One pt developed grade 4 neutropenia and grade 3 thrombocytopenia on cycle 1 day 2; a second patient developed grade 3 thrombocytopenia on C1D2. Both required dose reductions and counts recovered. Biochemical toxicity was minimal; all grade 1 except one pt with transient grade 2 bilirubin and 2 pts with grade 2 hypophosphatemia. According to the protocol defined 2008 IWG response assessment criteria, there were no responses observed. Four pts had stable disease (SD), two pts had progressive disease (PD) and one pt was inevaluable (came off due to toxicity after 2 doses). However, updated response criteria for CLL recommend that lymphocytosis alone should not be considered evidence of progressive disease in clinical trials testing novel agents that affect cellular migration and adhesion. Based on these new criteria, 1 of 7 patients developed PD, 3 demonstrated tumor shrinkage at time of coming off protocol therapy including 2 with corresponding improvement in blood counts although none achieved objective partial response (see Table).Conclusion: The CDK inhibitor, AT7519M was safely administered to pts with rel/ref CLL. While some patients had tumor shrinkage, there were no objective responses over the course of this study. Unfortunately, the small sample size of this trial precluded any other definitive conclusions. [Display omitted] DisclosuresToguchi:Astex Pharmaceuticals, Ltd: Employment. Lyons:Astex Pharmaceuticals: Employment.

Whole-body DWI in patients with lymphoma: imaging findings, pitfalls, and limitations

Whole body (WB) imaging plays an essential role in the management of lymphoma patients, including defining the full extent of the disease at baseline, allowing for an accurate staging and therefore an adapted treatment strategy, assessing treatment response and detecting relapse. Contrast-enhanced computed tomography (CT) has long been the imaging technique most commonly used for staging and follow up of malignant lymphoma, using International Working Group (IWG) criteria [1]. However, CT lacks functional and metabolic information, compromising identification of disease in non-enlarged lymph nodes or other organs, as well as sufficient contrast in certain organs as for example the spleen or bone marrow. In 2007, IWG response criteria were revised, incorporating Positron Emission Tomography (PET) with 18-fluorodeoxyglucose (FDG) information [2], thus combining metabolic information and anatomical data of the CT resulting in a higher accuracy than the both imaging modalities taken separately [3]. Diffusion Weighted Magnetic Resonance Imaging (DW-MRI) probes noninvasively the random microscopic motion of water molecules in the body, reflecting cellularity and cell membrane integrity. Because of their high cellularity and high nuclear-to-cytoplasm ratio, lymphomas have a lower apparent diffusion coefficient (ADC) than other tumors [4]. WB-DW-MRI allows both anatomical information, as well as functional and quantitative evaluation of tumor sites, thanks to the extraction of the apparent diffusion coefficient (ADC). At staging, lymphoma lesions have low ADC value except necrotic areas. Recent studies comparing whole-body DWI to PET-CT have demonstrated the potential role of whole-body DWI in routine lymphoma patient care but included only a small number of patients. Using the DWIBS technique (diffusion weighted imaging with background body signal suppression), Abdulqadhr et al. compared whole-body DWI and PET/CT at staging with an agreement in the Ann Arbor stage for 90.3% of patients [5]. Based on ADC analysis, Lin et al showed an agreement at baseline in 93% of patients [4]. Response assessment is necessary during therapy to readapt treatment strategy if necessary, and to document a complete remission at the end of treatment. After treatment, an increase in ADC value of residual masses has been demonstrated [6]. Recent technical breakthroughs in MRI technology such as echo-planar imaging (EPI), high gradient amplitudes, combined phased-array surface coils covering the patient, and parallel imaging, have drastically improved patient comfort and acceptance for whole body MRI [7,8], making this technique feasible in clinical routine, illustrating the need for radiologists to get familiar with this technique. As a result, WB-DW-MRI with ADC mapping has become a promising tool for lymphoma staging and re-staging, and response assessment. Based on our 4-years experience with WB-DW-MRI applied in Hodgkin and diffuse large B-cell lymphoma patients together with 18FDG-PET/CT, our objective is to offer radiologists the information required to optimize acquisition whole body DWI parameters on both 1.5 and 3T MR systems. We will expose the spectrum of imaging findings and discuss the pitfalls, limitations, and potential challenges of WB-DW-MRI in caring for lymphoma patients.

Maitake Mushroom Extract in Myelodysplastic Syndrome (MDS): A Phase II Study

Abstract 5043 Background:MDS is a heterogeneous group of hematologic diseases characterized by ineffective erythropoiesis and an increased risk of AML. MDS-related deaths are commonly due to infection resulting from impaired immunity, including quantitative and functional neutrophil defects. Maitake extract is from the fruit body of Grifola frondosa mushroom and is widely used in Asia as an adjunctive treatment for malignant diseases. This hot water extract is composed of a central beta 1,6-glucan core surrounded by beta 1,3-branches. Maitake extract enhances hematopoiesis by increasing G-CSF production with subsequent stem cell proliferation and differentiation of granulocyte-monocyte colony forming cells. Maitake also activates macrophages through Dectin-1 receptor binding, increases the weight and number of nucleated cells in the spleen and improves innate immune response in animal and human models. Activated macrophages may reduce iron stores. Compared to G-CSF, maitake may have fewer side-effects, is less costly, and may produce a comparable improvement in granulocyte function. Materials and Methods:MDS patients with IPSS Low and Int-1 risk disease and ANC>500, plts >20K were enrolled. Following double baseline measurements, patients received the maitake extract at 3mg/kg PO BID for 12 weeks. Primary endpoints include change in neutrophil counts and alterations in granulocyte function as measured by the respiratory burst test. The respiratory burst test is a highly sensitive and quantitative flow cytometric assay of granulocyte and monocyte function to assess the production of spontaneous reactive oxygen species (ROS) and stimulated response to 3 activators: opsonized E. coli, phorbol ester and the chemotactic peptide N-formylmethiolyl-leucyl-phenylalanine (fMLP). Results were compared to age-matched normal healthy volunteers. Responses were assessed using the modified International Working Group (IWG) MDS response criteria.Secondary endpoints include serial assessment of hemoglobin and platelet levels, reticulocyte count, monocyte function, and GM-CSF and G-CSF levels. Iron studies were assessed throughout treatment to determine whether the maitake indirectly alters iron stores potentially decreasing iron overload. Results:14 eligible patients (pts) (8M, 6F; median age 69, range 52–83 yrs) received the maitake extract. IPSS risk categories included: Low-risk, n=7; Int-1, n=7. WHO Stage: RA=2; RARS=1; RCMD=6; RCMD-RS=1; RCUD=1; MDS-U=1; CMML-1=2. Two pts received prior 5-azacytidine therapy.Mean fMLP-stimulated granulocyte function in pts at baseline was lower than control values. Monocyte baseline response to E. coli was significantly reduced (p<0.01); ROS production to phorbol ester was also lower than in controls.No patients met criteria for response using the modified IWG response criteria. Preliminary analyses showed that ROS responses to E. coli stimulation increased by weeks 7–9 in pts who were deficient at baseline. Monocyte ROS production increased in 2 pts by 2–6 fold at week 7. There was a 2–15 fold increase in the neutrophil response to fMLP by week 7 and a 2–35 fold increase in monocyte response to fMLP at week 9. Monocyte response to E. coli increased between 3–10 fold in 2 pts with peak values during weeks 7–9. The two pts with the most pronounced response by fMLP and ROS production also had eosinophilia, which resolved following study participation.The most common toxicities were diarrhea (grade 1) in 6 pts, eosinophilia (2–2.8 × normal) in 3 pts, increases in AST (grade 1) and ALT (grade 1) in 4 pts and nausea (grade 1) in 1 patient. Two pts were removed from the study, one for diarrhea possibly related to study medication and one for disease progression. Conclusion:Maitake mushroom extract is well tolerated without evidence of clinically significant adverse hepatic, renal or metabolic abnormalities. No clinical responses were seen. Based on our preliminary data, the maitake extract appears to enhance ROS in both unstimulated and stimulated cells, confirming preclinical data. The improvement in granulocyte and monocyte function in our in vitro studies suggests that maitake may enhance immune responses in MDS pts. Eosinophilia was noted but the significance remains uncertain at this time. The study is ongoing. Updated results will be presented. Disclosures:No relevant conflicts of interest to declare.

Lack of Efficacy of Pyridoxine (Vitamin B6) Treatment In Acquired Idiopathic Sideroblastic Anemia, Including Refractory Anemia with Ring Sideroblasts

AbstractAbstract 2919 Background:Sideroblastic anemias can be either hereditary due to congenital mutations in factors critical for iron processing or heme biosynthesis, or acquired; acquired sideroblastic anemias may be induced by alcohol or medications, but are usually idiopathic. Pyridoxine, a form of vitamin B6, plays a critical role in heme synthesis as a cofactor for δ-aminolevulinic acid synthetase (ALAS). Some subtypes of congenital sideroblastic anemia, such as those associated with mutations in the ALAS2 gene encoding the erythrocyte-expressed isoform of ALAS, may respond to pyridoxine therapy at doses ranging from 5–500 mg/day. Anecdotal reports of improvement with pyridoxine therapy in cases of acquired idiopathic sideroblastic anemia (AISA) have led to widespread clinical use of this agent in patients with refractory anemia with ring(ed) sideroblasts (RARS) and refractory cytopenia with multilineage dysplasia associated with ring sideroblasts (RCMD-RS). However, there are no systematic studies of the effectiveness of pyridoxine in AISA. Methods:We reviewed clinical and laboratory data from 231 adult patients with marrow aspirate-proven AISA (i.e., RARS or RCMD-RS, based on 2001 WHO criteria) evaluated at our institution between 1994 and 2007. Responses to pyridoxine were assessed using 2006 International Working Group (IWG) standardized criteria for MDS (erythroid response with hemoglobin increase by '1.5 mg/dl). The relationship between response to pyridoxine and disease subtype or International Prognostic Scoring System (IPSS) stratification was assessed using χ2 test, using a p-value limit of <0.05 for statistical significance. Results:86 of the 231 patients (42%) were treated with pyridoxine for an average of 19 months (range 1–114 months) at a mean dose of 167 mg/day (range 50–600 mg/day). Sufficient follow-up data to allow response evaluation were available from 74 (86%) of the 86 patients who received pyridoxine. Only 5/86 patients (6.8%) receiving pyridoxine met IWG response criteria for hematological improvement, but 3 of these 5 patients also received erythropoetin and 1 also received prednisone concomitantly with pyridoxine therapy. Therefore, only 1/86 (1.4%) patient's improvement in hemoglobin could be attributed to pyridoxine monotherapy. ALAS2 genotype data were not available from these 5 patients. The dose of pyridoxine was not associated with response to therapy (187.5 mg daily in responders vs. 157 mg daily in non-responders (p=0.60).Patients with RCMD-RS were more likely to be treated with vitamin B6 compared to patients with RARS (p=<0.001), possibly because of more severe anemia, but response to pyridoxine did not differ significantly between subtypes (3/49 vs. 2/25, response in RARS vs. RCMD-RS; p=0.76). Among the 74 evaluable patients, 3/46 patients in the low IPSS risk group responded to pyridoxine, compared to 2/24 of patients in the Intermediate-1 risk group and 0/4 in the Intermediate-2 risk group (p=0.82). Adverse effects associated with pyridoxine included new onset of irreversible symptomatic peripheral neuropathy in 2/86 patients (2.3%). Conclusions:Pyridoxine is commonly prescribed to patients with AISA in clinical practice, and this agent is often continued for a long period of time despite lack of evidence of objective response. Pyridoxine is an ineffective therapy in AISA that induces symptomatic peripheral neuropathy in some patients. Therefore, pyridoxine therapy should be limited to patients with known or suspected congenital mutations that confer pyridoxine responsiveness, and therapeutic trials should be brief to avoid adverse effects. Disclosures:No relevant conflicts of interest to declare.

Revised Lymphoma Response Criteria

In recent years, considerable improvements have been made in therapy and treatment outcomes among patients with non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL), and researchers in many ongoing clinical trials are testing additional novel agents and regimens. The International Working Group (IWG) response criteria that were first proposed in 1999 (J Clin Oncol …

A Phase II Trial of Combination Therapy with Arsenic Trioxide (ATO) and Gemtuzumab Ozogamicin (GO) in Patients with High-Risk Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML) Arising from MDS.

Background: Bone marrow findings in high-risk MDS are similar to those found in AML. MDS-associated myeloblasts are just as likely to express CD33 as AML myeloblasts, and cytogenetic abnormalities are similar to those of older AML patients (pts). Therapies effective in AML may also have activity in advanced MDS. GO is an anti-CD33 monoclonal antibody covalently linked to calicheamicin, a cytotoxic agent. ATO works through apoptotic and pro-differentiating mechanisms, and may allow for enhanced GO cytotoxicity.Methods: We conducted a multicenter trial in pts with high-risk MDS (IPSS score >1.5, or FAB or WHO classification with >5% CD33+ myeloblasts) or AML arising from MDS (with CD33+ myeloblasts) who had not received previous induction therapy, from 2/04 – 6/06. Pts received ATO (0.25mg/kg IV d1–5 during week 1, then twice weekly weeks 2–12) and GO (3mg/m2 on day 8) for 1 or 2 12-week cycles. Pts who had stable disease or improvement on a week 12 bone marrow biopsy received a second 12-week cycle, and then another week 24 biopsy. The primary endpoint was response as defined by the Modified International Working Group (IWG) criteria for MDS or, for AML patients, the IWG response criteria for AML.Results: Twenty-two pts have been enrolled; 21 are evaluable for response. The median age was 69 years. Fourteen pts (64%) had MDS (4 RAEB-1, 8 RAEB-2, 2 CMML-2,) with IPSS cytogenetic risk groups of good (2), intermediate (6), poor (4) and no growth (2), and IPSS classifications of high (5), Int-2 (5), and Int-1 (2). Eight pts (36%) had AML with cytogenetic risk groups as defined by CALGB 8461: intermediate (4), adverse (3), and unknown (1). Fifteen pts received prior therapies, including growth factors (10), 5-azacytidine (5), hydroxyurea (3), prednisone (1), anagrelide (1), thalidomide (1), and lenalidomide (1). Pts had a median of 15% blasts: 11.5% for MDS pts; 43.5% for AML pts. Of the 21 pts, 11 (52%) completed 1 cycle of therapy; an additional 5 (24%) completed 2 cycles. Reasons for discontinuing therapy included: withdrawing consent (5), progressive disease (7), and toxicity (4). Responses occurred in 8 patients (38%): 8 (38%) by the IWG MDS criteria; 2 of 8 AML pts (25%) by the IWG AML criteria; and 2 (9%) by both criteria. Using the modified IWG MDS criteria, 2 patients had a partial remission, 3 had a neutrophil response, 2 had a platelet response, and 1 had both platelet and neutrophil response. Using the IWG AML Criteria, 2 AML pts achieved a partial remission. Grade3/4 non-hematologic toxicities included neutropenic fever or infection (6), fatigue (4), pulmonary complications (3), hepatotoxicity (1), renal failure (1), prolonged QTc (1), nausea (1), epistaxis (1), hypoxia (1). Of 20 pts evaluable for 6 month survival, 15 (75%) were alive, 7 (47%) of whom responded to treatment. Of 12 patients evaluable for 1-year survival, 4 (33%) were alive, 2 of whom responded to treatment. Pts who completed two cycles of therapy spent a median of 13 days in the hospital.Conclusion: The combination of ATO + GO is well-tolerated and yields hematologic responses, particularly in neutrophils and platelets. This combination may be a viable alternative to high-dose, inpatient therapy in pts with high-risk MDS or secondary AML.

Quality of Life and Myelodysplasia.

The myelodysplastic syndromes (MDSs) are heterogeneous hematopoietic diseases associated with bone marrow failure, peripheral cytopenias, and a propensity for progression to acute myeloid leukemia (AML). In 2000, an International Working Group (IWG) of investigators proposed standardized response criteria which included quality of life as an important treatment goal. Quality of life becomes important when we are presented with a patient who is not a candidate for intensive curative therapy for myelodysplasia. The purpose of this literature review is to determine what quality of life instruments are optimal for this disease process and review is to examine the types of quality of life tools that have been used in published phase II and III studies of myelodysplasia. The focus is on adult hematology, and excludes studies with curative intent such as bone marrow transplantation, as well as phase I studies. Clinical trials from 1996—2006 were reviewed. 80 clinical trials were analyzed for the presence of attention to quality of life data. 7 trials used a quality of life instrument. All of the studies which used a quality of life instrument were published after 2003. Types of quality of life instruments used were the (EORTC) QLQ-C30 FACT-An along with the Geriatric Depression Scale (GDS) Short Form-12 (SF-12). The most common tool was the FACT-An. This was used in 5/7 studies that had quality of life tools. Of the 7 studies, 4 included the effect of therapy in all domains. The remainder focused on fatigue and/or anemia symptoms and their relation to quality of life. Conclusion: While the IWG response criteria have prompted consideration of quality of life as response criteria, there must be better uniformity in quality of life assessment, as well as determination of the optimal tool to use. A disease specific quality of life instrument should be considered one solution to this problem.

The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all‐trans retinoic acid in patients with acute myeloid leukemia

Valproic acid (VPA) inhibits histone deacetylase activity and, synergizing with all-trans retinoic acid (ATRA), achieves differentiation induction of myeloid blast cells in vitro. We used VPA in 58 patients with acute myeloid leukemia (AML) who were too old and/or medically unfit to receive intensive chemotherapy (32 AML secondary to myelodysplastic syndrome [MDS], 22 de novo AML, 4 AML secondary to myeloproliferative syndrome). VPA serum concentrations were 50-100 mug/mL. Thirty-one patients received VPA monotherapy. ATRA was added later in 13 patients who did not respond or who relapsed. Another 27 patients received VPA plus ATRA from the start. Median treatment duration was 93 days for VPA and 88 days for ATRA. The response rate was only 5% according to International Working Group (IWG) criteria for AML but was 16% when IWG response criteria for MDS were used, which capture hematologic improvement and stabilization of the disease. These endpoints, which are not necessarily correlated with diminishing blast counts, are relevant for the patients' quality of life. Among 23 patients with a peripheral blast count > 5%, 6 (26%) showed a diminishing blast count, and 5 of these had a complete peripheral blast clearance. Future trials should combine VPA with chemotherapy or demethylating agents.