PURPOSE OF REVIEWAcute lymphoblastic leukemia (ALL) is a heterogeneous disease, for which treatment guidelines are still evolving. Allogeneic hematopoietic cell transplantation (allo-HCT) is a ...potentially curative therapeutic modality for ALL, and this review describes the recent studies and current practice patterns concerning the who, when, and how of allo-HCT in the management of ALL.
RECENT FINDINGSAllogeneic stem cell transplantation is the treatment of choice for patients with ALL after first relapse and is also recommended for high-risk patients in first complete remission (CR1). Minimal residual disease evaluation and monitoring is developing as an important prognostic factor and could guide physicians in determining which patients, especially those with standard risk, might require transplant. Tyrosine kinase inhibitor (TKI) therapy allows a much higher proportion of Philadelphia-chromosome-positive ALL patients to attain remission and proceed to transplant with improved results; posttransplant TKI maintenance therapy may also provide survival benefit. Reduced-intensity conditioning regimens are a reasonable alternative for patients who would otherwise be ineligible for transplant because of age or comorbidity.
SUMMARYFor patients with high-risk features, there is general agreement that allo-HCT in CR1 is a potentially curative option; however, there is no consensus on early transplant for standard-risk patients.
Abstract Posttransplantation thrombotic microangiopathy (TMA) is a multifactorial complication of allogeneic hematopoietic cell transplantation (allo-HCT) whose incidence is increased with the use of ...a sirolimus plus tacrolimus (SIR/TAC) regimen for acute graft-versus-host disease (aGVHD) prophylaxis. We evaluated the incidence and possible risk factors for TMA in a case series of 177 patients who received allo-HCT using SIR/TAC-based GVHD prophylaxis. The patients received either a sibling donor graft (n = 82) or a matched unrelated donor graft (n = 95). Within the first 100 days post-HCT, 30 patients (17%) were diagnosed with TMA, and an additional 9 patients (5%) were classified as probable TMA cases. The median time to onset of TMA was 4.6 weeks (range, 1.6-10.6 weeks). Thirty-four patients developed both TMA and aGVHD, with the majority (81%) developing aGVHD first. Multivariate analysis identified the following factors as associated with increased risk of TMA: day 14 serum sirolimus level ≥9.9 ng/mL (hazard ratio HR, 2.19; 95% confidence interval CI, 1.13-4.27; P = .02), presence of previous aGVHD grade II-IV (HR, 3.04; 95% CI, 1.38-6.71; P < .01), and fully myeloablative conditioning (HR, 3.47; 95% CI, 1.60-7.53; P < .01). These risk factors for TMA suggest that when using a SIR/TAC regimen for GVHD prophylaxis, careful monitoring and adjustment of the sirolimus dosage is critical, particularly in patients with active aGVHD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Allelic variants of genes implicated in drug absorption, distribution, metabolism, and excretion (ADME) determine the pharmacokinetic variability of many medications and are increasingly ...recognized as important factors determining the success or failure of medical treatments. Both tacrolimus and sirolimus have narrow therapeutic ranges maintained by therapeutic drug monitoring (TDM). Using an ADME panel that covers >99% of the PharmaADME working group core list (188 single nucleotide polymorphism SNP and 12 copy number variant CNV assays in 36 pharmacogenetically relevant genes), we studied 177 patients who underwent allogeneic hematopoietic cell transplantation (HCT) using tacrolimus/sirolimus–based graft-versus-host disease (GVHD) prophylaxis. We tested for possible associations between ADME variants and tacrolimus/sirolimus drug levels, concentration/dose (C/D) ratio, and clinical endpoints, including acute GVHD. A total of 62 SNP and 6 CNV assays were evaluable after removing the variants, which were homozygous in (nearly) all samples. For sirolimus, rs2032582 (ABCB1) T-carriers versus non–T-carriers were associated with higher blood levels ( P = .01), with similar results for C/D ratio. Generalized estimating equation analysis supported these findings. For tacrolimus, rs776746 CYP3A5*3/*3 and CYP3A5*3/*1 were associated with higher blood levels than CYP3A5*1/*1 ( P = .002). By multivariable analysis, rs776746 CYP3A5*3/*3 and CYP3A5*3/*1 were independently associated with decreased acute GVHD compared with CYP3A5*1/*1 , after adjustment for conditioning, donor type, race/ethnicity, and age. We demonstrated association of specific ADME genetic polymorphisms with blood levels of tacrolimus/sirolimus, and incidence of acute GVHD after HCT, in spite of TDM and dose adjustment. A larger ongoing study will determine whether these associations have clinical utility beyond TDM.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction:
Higher risk MDS is a serious disease associated with poor survival with hypomethylating agents (HMAs) the standard of care in patients ineligible for stem cell transplantation. ...Unfortunately, HMAs are only effective in 30-40% of patients with duration of response typically shorter than 1.5 years (Fenaux, Lancet Oncol 2009) leading to evaluation of combination therapies to improve outcomes in higher risk MDS. Inhibition of both histone deacetylation and DNA hypermethylation has been shown to induce re-expression of silenced genes in myeloid malignancies in a synergistic fashion. Studies have evaluated HMAs in combination with HDACi but the results have been disappointing due to increased toxicity and early discontinuations. Pracinostat, a potent oral Class I, II, IV HDAC inhibitor, has been studied in combination with standard dose azacitidine in a prior Phase 2 study in 102 patients with untreated IPSS intermediate-2/high risk MDS (Garcia-Manero, Cancer 2017). Pracinostat was administered at 60 mg/day on 3 alternate days/week for 3 weeks/month, with step down dose to 45 mg in case of poor tolerability. Toxicity, primarily cytopenias, nausea, vomiting and fatigue resulted in early discontinuations and insufficient treatment exposure, potentially leading to diminished efficacy and no observed benefit of the pracinostat/azacitidine combination. This follow-up study is evaluating a lower dose of pracinostat (25% reduction) in combination with standard dose azacitidine with the goal of reducing toxicity, decreasing early discontinuations, and improving outcomes.
Methods:
The primary objective of this Phase 2, two-stage study at 24 sites is to determine the safety/tolerability and efficacy of the pracinostat/azacitidine combination in patients with IPSS-R high-/very high-risk MDS previously untreated with HMAs. Up to 40 subjects were to enroll in Stage 1, treated with pracinostat at 45 mg, 3 days each week for 3 consecutive weeks, followed by 1 week of rest, along with azacitidine at the standard dose of 75 mg/m2 for 7 days of each 28-day cycle. Study drugs are to be administered until disease progression or intolerable toxicity, avoiding early discontinuation (<6 months) due to lack of response. Response evaluation is performed after 2 and 6 cycles of therapy, and then every 6 months or as clinically indicated; analyses are descriptive. At a planned interim analysis, a pre-defined discontinuation rate due to adverse events (AEs) of ≤10% in the first 3 cycles (“early discontinuations”), a rate comparable to that observed with azacitidine alone in the prior study, and an overall response rate (ORR) of ≥20% were deemed desirable and would support expansion into Stage 2, wherein approximately 20 additional patients will be treated for a total of 60 evaluable patients. The study Independent Data Monitoring Committee (IDMC) in conjunction with the study Sponsor was to determine whether the study would expand based on the discontinuation rate.
Results:
At the time of the interim analysis (25 May 2018), 39 patients had received ≥1 dose of study treatment and 20 were evaluable for assessment of early discontinuations. Median age was 67 years, 69% were male, and 59% had high-risk MDS. Of the 20 evaluable patients, 2 patients (10%) discontinued prior to the end of Cycle 3 due to AEs (1 febrile neutropenia, Day 45 and 1 fungal infection, Day 90). In 18 subjects evaluated for response at the end of Cycle ≥2, the ORR was 28% (1 complete response, 4 partial responses). Most common Grade ≥3 AEs in the 33 patients with >1 week follow-up were decreased neutrophil count (33%), anemia (30%), febrile neutropenia (27%), and dyspnea (12%). Non-hematologic AEs of fatigue and gastrointestinal events were reduced in this initial group of patients relative to that seen in the prior study.
Conclusions:
The interim analysis of this study evaluating the efficacy and safety of pracinostat + azacitidine in patients with IPSS-R high-/very high-risk MDS revealed a discontinuation rate and an efficacy response rate meeting the predefined thresholds to allow for expansion of the study. These findings suggest that a reduced dose of pracinostat may allow patients to remain on treatment longer, thus increasing the likelihood of a treatment response. Based on these data, the study IDMC approved expansion of this study to enroll 60 evaluable patients. Updated data, including 6 months efficacy data on the initial cohort, will be presented.
Khaled:Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy; Juno: Other: Travel Funding. Ramies:MEI Pharma, Inc: Employment. Mappa:Helsinn Healthcare: Employment. Atallah:Jazz: Consultancy; BMS: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy; Novartis: Consultancy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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Background: Hypomethylating agents (HMA), such as azacitidine (AZA), are the standard of care for patients (pts) with higher-risk myelodysplastic syndromes (MDS). However, overall ...response rate (ORR=CR+PR) with HMA alone is approximately 30%, with a 2-year overall survival (OS) rate of 50.8%. Preclinical studies show that pracinostat (PRAN), an oral histone deacetylase inhibitor, synergizes with HMA. A study in pts with untreated IPSS intermediate-2/high-risk MDS receiving 60 mg PRAN plus AZA resulted in early discontinuations, mainly due to adverse events (AE), potentially leading to diminished clinical benefit. This follow-up phase II study evaluates a lower dose of PRAN (25% reduction) in combination with AZA in order to reduce toxicity, decrease early discontinuations, and improve outcomes. An interim analysis showed low discontinuation rate and promising efficacy, allowing trial expansion. Herein, we report preliminary safety and efficacy in the overall population. Methods: Open-label, II-stage, phase II trial (NCT03151304) in pts (≥18 years) naive to HMA therapy and with IPSS-R of high/very high-risk MDS. Planned enrollment was 60 pts. Pts received 45 mg PRAN 3 days/week for 3 consecutive weeks plus standard AZA dose for 7 days of each 28-day cycle. Primary objectives were to define the safety/tolerability of the combination and to assess the ORR (CR+PR). OS was a secondary endpoint. Results: Sixty-four pts were enrolled and received ≥1 dose of treatment. Most pts were male (67%), median age was 68 years (range 47–89), and the proportion of pts with high/very high-risk MDS was similar. After 17.6 months’ median follow-up, 31% of pts remain on treatment; 69% of pts discontinued treatment due to stem cell transplant (25%), disease progression (17%), AEs (11%), consent withdrawal (3%), pt noncompliance (3%), death (3%), lost to follow-up (2%), and other (5%). Most common nonhematologic AEs were constipation (55%), nausea (52%), fatigue (45%), decreased appetite (39%), peripheral edema (36%), diarrhea, and dyspnea (31% each). Frequent hematologic AEs were decreased neutrophil count (50%), anemia (39%), decreased platelet count (38%), febrile neutropenia (36%), and thrombocytopenia (30%). ORR was 33% (95% CI 22-46), with 33% achieving CR; 34% of pts had marrow CR. Median OS was 23.5 months (95% CI 16.4-nc), with an estimated 1-year OS of 77%. Conclusions: In pts with high/very high-risk MDS, a lower dose of pracinostat in combination with AZA demonstrated a tolerable safety profile and promising efficacy. Clinical trial information: NCT03151304 .
Introduction:
Treatment of adults with relapsed/refractory (R/R) B-ALL using CD19-targeted chimeric antigen receptor (CAR) T cells has achieved remarkable remission rates, both in pediatric and adult ...populations. There are multiple CAR constructs and T cell manufacturing platforms in use, and both aspects of the therapy may impact efficacy and toxicity. Park et al. report that 83% of adult patients (pts) achieve complete response (CR) to their CD19 CAR T cells with a CD28 costimulatory domain (NEJM; 3785: 449), using an unselected peripheral blood (PBMC) manufacturing platform. Unfortunately, therapy-associated toxicities in adult and pediatric ALL pts are problematic, with grade 3/4 cytokine release syndrome (CRS) ranging from 26-49 % and neurotoxicity 18-42%. Here we report preliminary data from one arm of a phase 1 clinical trial (NCT02146924) in adult pts with R/R B-ALL testing a memory-enriched T cell starting population engineered to express a CD19-specific, CD28-costimulatory CAR (CD19:28z-CAR). All pts achieved CR or CRi with a low incidence of severe cytokine release syndrome (CRS) and neurotoxicity.
Unique to this study is our Tn/mem-enriched manufacturing platform, a naïve/memory T cell-enriched T cell product that is lentivirally transduced to express our CD19:28z-CAR. The manufacturing process starts with patient PBMC, depletes the CD14+ monocytes and CD25+ Tregs, and selects for CD62L+ T cells. The resultant T cell population for CAR transduction includes both the central memory and stem cell memory populations along with naïve T cells. Preclinical studies in mice had suggested that using a more uniform T cell product with a less-differentiated T cell phenotype improved antitumor activity. This Tn/mem manufacturing platform is the same as our Tcm-derived platform (Blood;127:2980) except that CD45RA depletion was omitted.
Patients and Methods:
This phase I study used the activity constrained for toxicity (ACT) design, an extension of the toxicity equivalence range (TEQR) design of Blanchard and Longmate (Contemp Clin Trials; 32:114), that dose escalates based on lack of activity, while constraining the dose for toxicity. The primary objectives of this study were to test the safety and activity of Tn/mem-enriched CD19:28z CAR T cells, and to determine the phase 2 recommended dose. The primary endpoints were toxicity and disease response.
Sixteen pts were consented and received a lymphodepleting regimen (LDR) of 1.5-3 gm/m2 cyclophosphamide over 2-3 days and 25-30 mg/m2 fludarabine for 3 days. Three pts received LDR, but did not receive T cells due to infection or lack of CD19+ disease. Patients received a flat dose of 200 million (M) CD19:28z-CAR T cells: 11 autologous and 2 allogeneic donor products. Of the 13 that received 200 M CAR+ T cells, 2 pts were deemed ineligible for dose escalation / disease response evaluation, as 1 received <80% of the prescribed dose (100 M) and the other had CD19-negative extramedullary disease.
The median age of the 13 CAR T cell treated pts was 33 years (24-72). All pts had active bone marrow (BM) disease at the time of LDR: 8 pts (62%) had high disease burden (15-91% BM blasts) and 5 had low disease burden (</= 5% BM blasts). Patients were heavily pretreated, with a median of 5 (2-6), prior regimens. Six pts received prior allogeneic transplant (HSCT), 9 had prior blinatumomab, and 1 had prior CD19 CAR T cells.
Results:
Toxicity: Table 1 describes the major toxicities of the 13 CAR-treated pts, stratified based on disease burden. There were no DLTs, and T-cell therapy attributed (>/=possibly) toxicities were typically mild and reversible. Eight pts had grade 2 CRS, and 2 had grade 3 CRS. Three pts had grade 2 neurotoxicity and 2 had grade 3.
Response: Eleven pts were evaluable for response, with best response of 4 CRs (MRD- by flow) and 7 CRi (6 MRD-, 1 not tested). Median response duration at last contact or HSCT start was 81 days (39-286); 8 pts proceeded to HSCT (in CR or CRi) at a median of 69 days post-CAR infusion (39-103).
Conclusions:
Our ongoing phase 1 trial demonstrates a 100% response rate to Tn/mem-enriched CD19:28z-CAR T cell therapy in adults with relapsed/refractory (R/R) B-ALL. Although the numbers are small, the unanimous response, combined with a tolerable and reversible toxicity profile in pts with both low and high disease burden is remarkable and suggests promise for this Tn/mem manufacturing platform for CD19 and other CAR targets.
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Khaled:Juno: Other: Travel Funding; Daiichi: Consultancy; Alexion: Consultancy, Speakers Bureau. Wang:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Brown:Mustang Therapeutics: Consultancy, Other: Licensing Agreement, Patents & Royalties, Research Funding. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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Introduction: In the phase 3 QuANTUM-R trial, once-daily, oral, highly potent and selective FLT3 inhibitor Q improved clinical benefits vs SC (median overall survival mOS, 6.2 vs 4.7 mo HR, 0.76 ...(95% CI, 0.58-0.98); P = .02; composite complete remission CRc, 48% vs 27%; median duration of CRc, 12.1 vs 5.0 wk) in 367 pts with R/R FLT3-ITD AML (Cortes et al. Lancet Oncol, 2019; NCT02039726). Prior to randomization, 25% (Q) and 23% (SC) of pts had 1 prior HSCT. An OS sensitivity analysis, with censoring at the time of any subsequent HSCT during QuANTUM-R, was supportive (mOS, 5.7 vs 4.6 mo HR, 0.79 (95% CI, 0.59-1.05); P = .05). Post hoc analyses of characteristics and clinical outcomes in pts who underwent subsequent HSCT in QuANTUM-R are reported.
Methods: Pts aged ≥ 18 y with FLT3-ITD R/R AML receiving Q (60 mg 30-mg lead-in) or 1 of 3 prespecified high- or low-intensity SC regimens and underwent subsequent HSCT as part of the open-label, randomized QuANTUM-R trial were analyzed. Pts receiving HSCT in the Q arm could resume maintenance Q 30-100 days after HSCT. Decisions to proceed to HSCT and resume Q after HSCT were made per investigator discretion/institutional policies.
Results: Of 367 randomized pts, 85 in the Q arm underwent any subsequent HSCT (allogenic HSCT allo-HSCT, 84 6 with and 78 w/o additional AML therapy; autologous HSCT, 1) and 19 in the SC arm underwent any HSCT (5 with and 14 w/o additional AML therapy). Median age (range) was lower in pts with any HSCT (Q, 49 19-71 y; SC, 44 23-67 y) vs pts w/o (Q, 58 19-81 y; SC, 59 18-78 y).
Q + SC pooled data showed a longer mOS (95% CI) in 104 pts with any HSCT vs 263 w/o (12.2 10.0-24.1 vs 4.4 4.1-4.9 mo; P < .0001; Fig 1); 1-year OS probabilities (95% CI) were 50% (40%-60%) vs 13% (9%-18%). Among pts preselected for high-intensity therapy (Q n = 188 + SC n = 93), mOS in the pooled high-intensity group was 11.9 (10.0-24.0) mo with any HSCT vs 4.6 (4.1-5.4) mo w/o. Among pts preselected for low-intensity therapy, 13/57 in the Q arm and 0/29 in the SC arm underwent any HSCT; mOS in the pooled low-intensity group was 32.4 (6.2-NA) mo with any HSCT vs 4.1 (2.7-4.6) mo w/o.
In pts with CRc (last recorded response prior to allo-HSCT), mean time (range) to allo-HSCT was 13.3 (5.9-26.9) wk with Q and 12.1 (6.3-28.6) wk with SC. Q + SC pooled data showed that mOS (95% CI) was longer in pts with a CRc prior to allo-HSCT vs pts w/o CRc (20.1 11.7-NA vs 8.8 7.0-11.4 mo).
Survival outcomes by treatment were similar regardless of study treatment, with longer mOS in pts with any HSCT vs pts w/o (Q, 11.9 10.2-25.1 vs 4.5 4.1-5.4 mo; SC, 12.7 6.1-NA vs 4.0 2.7-5.0 mo); respective 1-year OS probabilities (95% CI) were 50% (39%-60%) vs 13% (8%-20%) and 51% (26%-70%) vs 12% (6%-21%). In the Q arm, mOS (95% CI) was longer in pts with a best response of CRc who resumed Q after allo-HSCT (27.1 18.2-NA mo) vs pts not resuming Q (5.4 4.7-11.4 mo; Fig 2).
In 48 pts (62%) in the Q arm resuming Q after allo-HSCT, median time (range) from allo-HSCT to Q resumption was 65 (30-106) d. Four pts (5%) in the Q arm died < 30 days after allo-HSCT. As of 2/22/2018, 46 of 78 pts in the Q arm (59%) and 9 of 14 pts in the SC arm (64%) with allo-HSCT w/o additional AML therapy died, primarily due to AML disease progression (Q, 31 40%; SC, 7 50%). The frequency of treatment-emergent adverse events (TEAEs) was mostly lower in pts resuming Q after allo-HSCT than in the overall Q population (Table 1); TEAEs of interest were similar. Long-term survivor data will be presented.
Conclusions: Independent of HSCT, Q improved survival vs SC in pts with FLT3-ITD R/R AML in QuANTUM-R. Q + SC pooled analyses showed longer survival in pts with HSCT vs pts w/o and in pts with CRc prior to allo-HSCT. Importantly, survival post-HSCT was similar in the Q and SC arms, indicating that pts eligible for HSCT were appropriately transplanted, and the higher HSCT rate in the Q arm was beneficial to pts. More pts treated with Q underwent HSCT, likely due to a higher rate and duration of CRc with Q vs SC and better overall fitness. In pts preselected for low-intensity SC at study entry, 13 were able to undergo HSCT after Q treatment. Resumption of Q after HSCT was associated with better survival outcomes and was tolerable. These data illustrate the value of using Q to target the FLT3-ITD mutation as a part of the overall treatment sequence in pts with FLT3-ITD R/R AML.
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Ganguly:Seattle Genetics: Speakers Bureau; Janssen: Honoraria, Other: Advisory Board; Kite Pharma: Honoraria, Other: Advisory Board; Daiichi Sankyo: Research Funding. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; BiolineRx: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Merus: Consultancy, Honoraria, Research Funding. Krämer:Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Bayer: Research Funding. Levis:Amgen: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Daiichi Sankyo Inc: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Menarini: Consultancy, Honoraria; FUJIFILM: Consultancy, Research Funding. Martinelli:Daiichi Sankyo: Consultancy, Honoraria; Pfizer: Consultancy, Other: trial grant; Celgene: Consultancy, Honoraria, Other: trial grant; Janssen: Consultancy, Other: trial grant; Incyte: Consultancy, Other: trial grant; Amgen: Consultancy, Other: trial grant; Abbvie: Consultancy, Honoraria, Other: trial grant; Novartis: Consultancy, Other: trial grant; Roche: Consultancy, Other: trial grant; Ariad: Consultancy, Other: trial grant. Perl:Novartis: Honoraria, Other: Advisory board, Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of the data., Research Funding; Bayer: Research Funding; BioMed Valley Discoveries: Research Funding; FujiFilm: Research Funding; Takeda: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Astellas: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of trial data., Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Other, Research Funding; Arog: Consultancy, Other: Non-financial support included travel costs for advisory board meetings.; AbbVie: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Actinium Pharmaceuticals: Consultancy, Honoraria, Other: Clinical Advisory Board member, Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Non-financial support included travel costs for advisory board meetings.; Jazz: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; NewLink Genetics: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.. Russell:Astellas: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau. Arunachalam:Daiichi Sankyo: Employment. Gammon:Daiichi Sankyo: Consultancy. Lesegretain:Daiichi-Sankyo Inc.: Employment, Equity Ownership. Mires:Daiichi Sankyo: Employment. Namuyinga:Daiichi Sankyo: Employment. Zhang:Daiichi Sankyo: Employment. Khaled:Omeros: Consultancy; Daiichi Sankyo: Other: Travel support; Alexion: Consultancy, Speakers Bureau.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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Introduction: Patients (pts) with relapsed/refractory (R/R) acute myeloid leukemia (AML) with FLT3-ITD mutations have a dismal prognosis and limited treatment options. Given the aggressiveness of ...FLT3-ITD AML, therapies that produce rapid and sustained disease control are needed. Quizartinib (Q), a once-daily, oral, highly potent and selective FLT3 inhibitor, demonstrated a clinically meaningful overall survival (OS) benefit in pts with R/R FLT3-ITD AML vs salvage chemotherapy (SC; 6.2 vs 4.7 mo HR, 0.76 (95% CI, 0.58-0.98); P = .02) in the phase 3 QuANTUM-R trial (NCT02039726; Cortes et al. Lancet Oncol, 2019). In this post hoc analysis, we characterize clinical outcomes in pts who achieved a composite complete remission (CRc) in QuANTUM-R, including pts with CR with incomplete hematologic recovery (CRi) and transfusion independence.
Methods: Pts aged ≥ 18 years with FLT3-ITD AML R/R after standard AML therapy, with or without hematopoietic stem cell transplant (HSCT), were randomized 2:1 to Q (60 mg 30-mg lead-in) or 1 of 3 prespecified SC regimens. Pts receiving HSCT in the Q arm could resume Q after HSCT. Response was assessed per modified International Working Group criteria (Table 1). Transfusion dependence at baseline (BL) was defined as any platelet (PLT) or red blood cell (RBC) transfusion within 28 days of first dose. Post-BL transfusion independence was defined as no PLT or RBC transfusions for any consecutive 56-day period on treatment.
Results: Of 367 randomized pts, 245 and 122 were randomized to Q and SC, respectively. Median duration of treatment was 97 days with Q (including post-HSCT resumption) and ranged from 5 to 10 days with SC depending on the regimen. Median follow-up was 23.5 mo.
In the intent-to-treat population, CRc was consistent across prespecified subgroups (eg, sex, response to prior therapy, FLT3-ITD variant allele frequency). Median time to CRc was 1.1 mo with Q and 0.9 mo with SC; median duration of CRc was 2.8 mo with Q and 1.2 mo with SC (Table 2). Most responses in both arms were CRi, achieved in 99 pts (40%) in the Q arm and 32 pts (26%) in the SC arm. Peripheral blood counts in pts who achieved CRi are shown in Table 3. Of pts with CRi, 45 (Q) and 13 (SC) underwent HSCT. Outcomes with HSCT included engraftment failure in 11% (Q), rejection in 2% (Q), relapse in 33% (Q) and 46% (SC), and successful transplant in 47% (Q) and 46% (SC) and were unknown in 7% (Q) and 8% (SC).
Of the 205 pts in the Q arm who were transfusion dependent at BL, 46 (22%) became transfusion independent post-BL (29 with HSCT; 17 without). Mean (SD) duration of post-BL transfusion independence was 255 (216.6) days. By response, 24 of 91 pts (26%) with CRi, 7 of 48 (15%) with a partial response (PR), and 4 of 47 (9%) with no response (NR) became transfusion independent post-BL; respective mean (SD) durations were 297.6 (268.3), 84.6 (21.7), and 211.3 (111.9) days. Of the 36 pts in the Q arm who were transfusion independent at BL, 20 (55.6%) maintained transfusion independence post-BL (12 with HSCT; 8 without; mean SD duration, 208 203.1 days). Transfusion independence could not be assessed in the SC arm. Transfusion data was not collected after the end of treatment, and most pts in the SC arm were treated for < 56 days.
In the Q arm, median OS (95% CI) was longer in pts with CRi (7.5 5.4-9.9 mo) vs pts with PR (6.1 5.1-7.2 mo) or NR (4.1 3.3-5.9 mo) (Figure 1); respective medians in the SC arm were 8.8 (6.3-20.8), 7.8 (5.4-28.2), and 3.8 (2.7-4.7) mo. In the 34 pts in the Q arm with a last response of CRi prior to allogeneic HSCT, median OS (95% CI) was 25.1 (9.9-NA) mo; in the SC arm (n = 9), median OS (95% CI) was 20.1 (4.3-NA) mo. In the Q arm, median OS (95% CI) was longer in pts with CRi who became transfusion independent post-BL vs pts who did not (27.1 10.4-NA vs 5.3 4.6-6.4 mo); similarly, median OS (95% CI) was longer in pts who maintained transfusion independence vs pts who did not (25.1 11.4-NA vs 9.6 4.6-NA mo).
Conclusions: Q induced rapid, durable, and consistent tumor control in pts with FLT3-ITD R/R AML irrespective of prior therapy, including HSCT. A high proportion of pts with CRi became eligible for HSCT, the only potential curative treatment option. Moreover, a high proportion achieved durable transfusion independence regardless of HSCT, which is also associated with clinical benefit. These data highlight the clinical benefit of achieving CRi with Q in pts with FLT3-ITD R/R AML, a population with a high unmet need.
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Levis:Novartis: Consultancy, Research Funding; Daiichi Sankyo Inc: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; FUJIFILM: Consultancy, Research Funding; Menarini: Consultancy, Honoraria. Ganguly:Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau; Kite Pharma: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board. Khaled:Alexion: Consultancy, Speakers Bureau; Daiichi Sankyo: Other: Travel support; Omeros: Consultancy. Krämer:BMS: Research Funding; Bayer: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees. Martinelli:Novartis: Consultancy, Other: trial grant; Pfizer: Consultancy, Other: trial grant; Roche: Consultancy, Other: trial grant; Incyte: Consultancy, Other: trial grant; Ariad: Consultancy, Other: trial grant; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: trial grant; Amgen: Consultancy, Other: trial grant; Abbvie: Consultancy, Honoraria, Other: trial grant; Janssen: Consultancy, Other: trial grant. Perl:BioMed Valley Discoveries: Research Funding; FujiFilm: Research Funding; Novartis: Honoraria, Other: Advisory board, Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of the data., Research Funding; Takeda: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Bayer: Research Funding; NewLink Genetics: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Actinium Pharmaceuticals: Consultancy, Honoraria, Other: Clinical Advisory Board member, Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Non-financial support included travel costs for advisory board meetings.; Jazz: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Astellas: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of trial data., Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Other, Research Funding; Arog: Consultancy, Other: Non-financial support included travel costs for advisory board meetings.; AbbVie: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.. Russell:Astellas: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau. Choi:Daiichi Sankyo: Employment. Lesegretain:Daiichi-Sankyo Inc.: Employment, Equity Ownership. Mendell:Daiichi Sankyo, Inc.: Employment. Mires:Daiichi Sankyo: Employment. Zhang:Daiichi Sankyo: Employment. Cortes:Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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