Introduction.NPM1mut MRD assessment has been established as an independent prognostic marker in AML. The magnitude of NPM1mut MRD reduction post chemotherapy is associated with clinical outcome. At the Alfred and Austin Hospitals (Melbourne, Australia), high-dose cytarabine (HiDAC)-based induction was employed in favor of standard-dose cytarabine (SDAC) "7+3" induction until 2017. We hypothesized that HiDAC-based AML induction would result in greater reduction in NPM1mut MRD compared to SDAC-based induction and be associated with improved clinical outcome. Methods. Consecutive patients (pts) with newly diagnosed NPM1 mutated AML were retrospectively identified from 2 institutions if NPM1mut MRD results were available after achieving morphologic remission. This study was approved by the Alfred HREC (460/17). The HiDAC cohort received either high (HDAC+3, 3 g/m2 BD d1,3,5,7, from 2012 to 2014) or intermediate dose cytarabine (IDAC+3, 1.5 g/m2 BD d1,3,5,7, from 2014 to 2017), in combination with idarubicin (12 mg/m2 d1-3). The SDAC cohort received 7+3 (from 2017 to March 2020). Planned consolidation chemotherapy for the HiDAC cohort consisted of 2 cycles of IcE (idarubicin 9 mg/m2 d1-2, cytarabine 100 mg/m2 d1-5, and etoposide 75 mg/m2 d1-5), whereas in the SDAC induction cohort, either 2 cycles of IDAC+2 (cytarabine 1 g/m2 x6 doses and idarubicin 12 mg/m2 d1-2), or 4 cycles of HiDAC (cytarabine 1-3 g/m2 x6 doses) was administered. Midostaurin was available as standard of care since December 2018 in Australia. NPM1mut bone marrow copy numbers by RT-qPCR are expressed per 105ABL1 copies. Results. A total of 66 pts with NPM1mut AML were included in this study and summarized in Table. Majority had intermediate risk (95%) or normal karyotype (82%) and 38% had FLT3-ITD. The HiDAC cohort (n=28) was younger than the SDAC cohort (n=38) (median 47 vs 62 years) and more commonly underwent allogeneic HSCT in first remission (29% vs 5%). Among the HiDAC cohort, 54% completed the planned 2 cycles of consolidation chemotherapy, whereas 74% in the SDAC cohort completed at least 2 cycles of consolidation. Midostaurin was received by 9 pts, all from the SDAC cohort (24%). Baseline NPM1mut copy numbers were similar between both cohorts (Figure). Following course 1, the HiDAC cohort achieved a lower NPM1mut MRD level than the SDAC cohort: median 10 vs 82 copy numbers (p<0.001), 4.5 vs 3.4-log10 reduction (p<0.001), and 20% vs 0% with negative MRD (p=0.01). These differences narrowed after course 2: 1.9 vs 7.9 copies (p=0.05), 5.2 vs 4.4-log10 reduction (p=0.01), and 33% vs 10% with negative MRD (p=0.1). Similar findings were observed after course 3. The MRD levels at end of therapy (EOT) were similar between HiDAC and SDAC cohorts: 1.1 vs 3.8 copies (p=0.15), 5.2 vs 4.7-log10 reduction (p=0.09), and 41% (9/22) vs 22% (8/36) with negative MRD (p=0.15) (Figure). Survivors were followed up for a median of 30 months: 18 pts had relapsed AML, 12 died, and median RFS and OS were both not reached. Early death (<60 days) was observed in only 1 pt (SDAC cohort). Estimated 3-year RFS and OS were 64% and 79%, respectively, without significant differences between the HiDAC vs SDAC induction cohorts: 3-year RFS 64% vs 66% and OS 80% vs 78%. Significant prognostic factors from univariate analyses were age (for RFS only), FLT3-ITD and MRD levels. Sensitivity analysis excluding the 9 pts who received midostaurin did not affect the results. Next, we analyzed the prognostic significance of NPM1mut MRD response within each cohort of induction chemotherapy intensity. In the HiDAC cohort, NPM1mut MRD levels post course 1 (and 2), but not at EOT, were significantly associated with both risks of relapse (HR 0.31, 95% CI 0.15-0.67) and death (HR 0.31, 95% CI 0.14-0.70). Among the SDAC cohort, the log reduction at EOT, but not post course 1 and 2, was significantly associated with relapse (HR 0.47, 95% CI 0.26-0.84) and death (HR 0.45, 95% CI 0.22-0.89). Peripheral blood NPM1mut MRD levels were not available for comparison. Conclusions. Intensified induction chemotherapy resulted in more rapid early NPM1mut MRD reduction but did not have significant impact on EOT MRD levels or survival outcomes. The clinical significance of MRD reduction at various time points should be interpreted in the context of selected therapeutic regimens. Moreover, MRD thresholds should be re-validated in the context of regimens incorporating novel targeted therapies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

BACKGROUND/AIMS:We sought to determine factors associated with the overall survival from relapse (OSR) of acute myeloid leukaemia (AML) after allogeneic haemopoietic stem cell transplantation (alloHSCT) and the effect of first salvage therapy and subsequent graft-versus-host disease (GVHD) on OSR.METHODS:Data on 386 patients from nine Australian centres with relapsed AML post-alloHSCT were collected retrospectively. OSR was calculated using the Kaplan-Meier method. Univariate and multivariate analyses were conducted using the log-rank test and proportional hazards modelling, respectively and a prognostic index for OSR was derived from multivariate modelling.RESULTS:On multivariate analysis, relapse within 6 months (hazard ratio (HR) 2.4, P < 0.001) and grade 3-4 acute GVHD preceding relapse (HR 2.0, P = 0.004), were associated with inferior OSR. Patients with 1-2 factors had inferior OSR compared to those with zero factors (all patients: HR 2.3, P < 0.001, patients given salvage: HR 1.8, P < 0.001). The first salvage therapy used post-relapse was donor cell therapy (DCT) (second alloHSCT or donor lymphocyte infusion) in 75, re-induction chemotherapy (CT) in 103, radiotherapy in 8 and interferon-α in 6. Although re-induction CT death rate was low (2%), survival after CT was inferior to DCT (HR 1.9, P < 0.001). No survival benefit was seen for patients who developed GVHD following salvage therapy (P = 0.405).CONCLUSION:Patients with AML who relapse beyond 6 months from alloHSCT without prior grade 3-4 acute GVHD have a better outcome from salvage therapy. Salvage treatments employing DCT as the initial treatment of AML relapse confer a survival advantage over CT.

Background The utility of high-dose cytarabine during induction chemotherapy for adult acute myeloid leukemia (AML) remains contentious. Intermediate-dose cytarabine may maintain a high first-cycle complete remission (CR) rate, whilst reducing treatment-related toxicity. Aim We examined the outcomes of adult AML patients treated with idarubicin (12 mg/m2 days 1-3) in combination with high-dose (3 g/m2; HDAC3) or intermediate-dose cytarabine (1.5 g/m2; IDAC3) given twice daily on days 1, 3, 5, and 7. Methods Consecutive AML patients aged ≤60 years at 2 major tertiary referral centers, the Alfred and Austin Hospitals, were treated with sequential protocols of HDAC3 (n=52; 2010-2014) and then IDAC3 (n=58; 2014-2017). Planned consolidation chemotherapy consisted of up to 2 cycles of idarubicin 9 mg/m2 days 1-2, cytarabine 100 mg/m2 days 1-5, and etoposide 75 mg/m2 days 1-5 (IcE). Favorable-risk karyotype was excluded from this analysis. We assessed treatment responses (2017 European LeukaemiaNet recommendations), 30 and 60-day mortality, ability to deliver consolidation therapy (number of cycles and days from induction to first consolidation chemotherapy), rates of allogeneic hematopoietic stem cell transplant (allo-HSCT) in first remission (CR1), rates of total parenteral nutrition (TPN) usage, haematologic toxicities (days to platelet and neutrophil recovery), and relapse-free (RFS) and overall survival (OS) censored for allo-HSCT or loss to follow-up. Statistical analysis was performed using R version 3.3.2. Results IDAC3-treated patients were younger than those receiving HDAC3 (median 44 vs 48 years) but had a higher frequency of secondary AML (16% vs 4%); (Table 1). Other baseline characteristics were balanced between both groups. No significant differences were observed for any outcome (Table 2), except the use of TPN which is most likely a result of change in practice over time rather than a true reflection of mucositis. Response rates including CR or CR with incomplete haematologic recovery (CRi) were similar: 79% (HDAC3) vs 83% (IDAC3) after 1 cycle of induction. There was no death at 30 days and only 1 death at 60 days. Allo-HSCT in CR1 was similar; among patients with adverse-risk karyotype, allo-HSCT in CR1 was performed for 9/15 (60%) after IDAC3 and 7/11 (64%) after HDAC3. Days to neutrophil and platelet recovery were also similar. Delivery of consolidation chemotherapy was similar between both groups. After excluding treatment failure and partial remission (PR), 94 patients were eligible for first consolidation chemotherapy (3 patients with PR were considered near CR), of which 14 (15%) did not receive further consolidation therapy with the following reasons: allo-HSCT in CR1 (n=10); prolonged cytopenias (n=3); and maintenance clinical trial (n=1). Twenty-nine patients (31%) received only 1 consolidation therapy due to the following reasons: allo-HSCT in CR1 (n=14); prolonged cytopenias (n=10); non-hematologic toxicities (n=2); relapse (n=2); and unknown (n=1). IcE chemotherapy was administered in all except 2 cases: one received high-dose cytarabine for 1 cycle, and another had reduced idarubicin dose for 1 cycle. Survivors were followed up for a median of 8 (IDAC3) and 37 months (HDAC3), respectively. Median OS were 11.5 and 18.6 months for IDAC3 and HDAC3 (p=0.3), respectively (Figure 1A), and the corresponding median RFS were 8.4 and 9.4 months (p=0.5), respectively (Figure 1B). Overall, the median OS for adverse-risk karyotype remained significantly inferior compared to intermediate-risk (5.6 vs 20.9 months, p=0.009 by log-rank test); among adverse-risk karyotype, this was 5.1 vs 6.5 months for IDAC3 and HDAC3, respectively. Similarly, patients with FLT3 -ITDpos/ NPM1 WT had inferior median OS (n=7, 6.1 months) when compared with FLT3 -ITDneg/ NPM1 WT (n=55, 15.9 months), FLT3 -ITDpos/ NPM1 MUT (n=14, 20.9 months), and FLT3 -ITDneg/ NPM1 MUT (n=16, 40.6 months, p=0.06 by log-rank test). Conclusion IDAC3 and HDAC3 were both well tolerated in adult patients with AML with high first-cycle CR/CRi rates observed and low early mortality. No significant differences in hematopoietic recovery or delivery of post-remission therapy was apparent. With the caveat of limited sample size and follow-up duration, survival outcomes appeared equivalent. Download : Download high-res image (302KB) Download : Download full-size image Disclosures Grigg: Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees. Wei: AbbVie, Celgene, Servier: Research Funding; AbbVie, Celgene, Novartis, Amgen, Servier: Membership on an entity's Board of Directors or advisory committees; AbbVie, Celgene, Novartis, Amgen, Servier: Honoraria.

We retrospectively analysed 386 cases of relapsed acute myeloid leukaemia (AML) from 1336 allogeneic haematopoietic stem cell transplants (alloHSCT) performed between 2000-2011, with two aims: 1. To find and validate factors available at time of relapse that would predict for overall survival from relapse (OS). 2. To determine the effect of first salvage therapy and subsequent GVHD on OS. Aim 1: 349 analysable patients were randomly split into training (n = 233) and validation (n = 116) cohorts. The cohorts were comparable; the only significant difference was more HLA-matched recipients in the validation cohort (P= .002). Factors predicting inferior OS on univariate analysis were: relapse within 6 months, relapse within 12 months, grade 3-4 acute GVHD prior to relapse, FLT3-ITD mutation, prior induction failure, marrow blasts > 30% at relapse, use of a T cell replete graft, and absence of chronic GVHD prior to relapse. On multivariate analysis, only relapse within 6 months (HR 2.3, P < .001), and grade 3-4 acute GVHD prior to relapse (HR 2.0, P = .004), remained significant. These two factors were combined into a prognostic index and validated; in the validation cohort, patients with 1-2 factors had inferior OS compared to those with 0 factors (HR 2.5, P < .001). This effect remained significant when analysis was limited to the validation cohort patients given salvage (HR 2.3, P = .002). Aim 2: Of 333 analysable patients, 134 patients were not given salvage; their median survival was 33.5 days. 199 patients given salvage had 5y OS of 14%. First salvage therapy was second alloHSCT (ie conditioning plus donor cell infusion) in 55; donor lymphocyte infusion (DLI) (ie donor cell infusion without conditioning) in 16; reinduction chemotherapy (CT) without planned cell infusion in 75; radiotherapy in 8, interferon in 6, and unknown in 7. We defined donor cell therapy (DCT) as second alloHSCT or DLI. Characteristics of patients receiving DCT as first salvage, and patients receiving CT as first salvage, were similar, although CT recipients had shorter median follow-up of survivors (11.2 vs 36.7 months, P = .017). CT as first salvage was inferior to patients receiving DCT as first salvage (5y OS 5% vs 23%, HR 1.8, P < .001). For patients given DCT first, there was no difference in OS between second alloHSCT and DLI (HR 1.1 for second alloHSCT, P = .697). We were unable to demonstrate a benefit in OS for patients with post-relapse GVHD (HR 0.8 for presence of GVHD, P = .405). Our findings underscore the poor prognosis of relapsed AML post alloHSCT and provide useful baseline data for future interventional studies. Patients with relapse beyond 6 months from alloHSCT and without prior grade 3-4 acute GVHD may expect better OS with salvage compared to those with either or both factors. Overall, better outcomes for OS were with DCT as initial treatment.