Acute Myeloid Leukemia Induction Research Articles

Synergy between FLT3-ITD and p53 Haploinsufficiency or Loss in the Development of Acute Myeloid Leukemia

FLT3-ITD (internal tandem duplication) is a late event in the pathogenesis of acute myeloid leukemia (AML). Identification of early cooperating events for FLT3 mutations may improve our understanding of the pathogenesis of AML and lead to a more efficient treatment and improved outcome for AML patients. p53 alteration can be found in up to 70% of AML patients with complex karyotypes, while studies from our group and others show a relatively low incidence of p53 mutation (generally around 10%) in other AML patients. Dysfunction of p53 pathway resulting from overexpressed MDM2/MDM4 is more often found than p53 mutations in patients with de novo AML. An early mouse study identified the FLT3 gene to be preferentially mutated by insertional mutagenesis in p53 knock-out but not in p53 wild-type tumors. Importantly, p53 mutation appears to be an early event in the pathogenesis of AML. In this study, we investigated whether p53 haploinsufficiency or loss cooperates with FLT3-ITD in the induction of AML.To this end, we crossed FLT3-ITD knock-in mice with p53 knockout mice to generate mice harboring both ITD/ITD and p53 knockout mutations. ITD/ITD; p53+/- (FLT3-ITD homozygous and p53 heterozygous) mice became moribund much faster than mice with ITD/ITD alone or p53+/- alone. The median survival of ITD/ITD;p53+/- mice (n=69) was 313 days, which was significantly shorter than that of ITD/ITD mice (littermates of ITD/ITD; p53+/- mice, 583 days, n=16), p53+/- mice (521 days, n=30), and WT mice (862 days, n=10) (p<0.0001). Interestingly, the median survival ITD/ITD;p53-/- mice (FLT3-ITD homozygous and p53 homozygous, littermates of ITD/ITD; p53+/- mice, n=11) was further reduced (125 days), and significantly shorter than ITD/ITD; p53+/- mice and p53-/- mice (148 days, n=15) (p<0.05). Moreover, cooperation of FLT3-ITD and p53 inactivation also significantly altered disease spectrum in mice. While AML was observed only in 25% ITD/ITD mice and p53+/- mice mainly developed solid tumors, 88% ITD/ITD; p53+/- mice developed acute leukemia including AML (58%). The incidence of AML was further increased in ITD/ITD; p53-/- mice (73%, 8/11). All ITD/ITD; p53-/- mice developed acute leukemia, while 72% p53-/- mice developed lymphoma/lymphoblastic leukemia. Interestingly, >50% ITD/ITD; p53-/- mice and ITD/ITD; p53+/- mice with acute leukemia demonstrated a bi-clone disease, with co-existence of AML and ALL. Unexpectedly, all analyzed murine AMLs with complete or heterozygous loss of p53 (n=9) showed normal karyotypes. p53 haploinsufficiency or loss did not increase self-renewal of hematopoietic stem/progenitor cells as defined by serial replanting assays in vitro and limiting dilution transplantation of leukemic cells in vivo. However, animals with only AML in the ITD/ITD; p53+/- group showed a significant increase of CMPs in comparison with ITD/ITD mice with CMML, P53+/- and WT mice, e.g. a 66-fold increase of CMPs in #1376 mouse compared with WT mice. This suggests that the block of differentiation from CMPs to GMPs may have contributed to the development of AML.P53 haploinsufficiency or loss reduced the sensitivity of murine FLT3-ITD leukemia to crenolanib in vitro (IC50: 313.3nM, 461.4nM, and 185.8nM for ITD/ITD;p53+/-, ITD/ITD;p53-/-, and ITD/ITD leukemia, respectively), but not their sensitivity to midostaurin (IC50: 117.3nM, 110.2nM, and 201.3nM). To develop an efficient therapy for p53-mutated AML, we firstly tried to combine FLT3 inhibitors and MDM2 antagonist idasanutlin, FLT3 inhibitor and Bcl2 inhibitor venetoclax. Unfortunately, these did not enhance induction of apoptosis in leukemic cells from ITD/ITD;p53+/- mice. However, exposure to the proteasome inhibitor carfilzomib had a strong cytotoxic effect against ITD/ITD; p53+/- and ITD/ITD;p53-/-, leukemic cells (IC50: 5.2nM and 17.1nM vs. 6.8nM for ITD/ITD leukemia). In addition, the combination of carfilzomib with midostaurin showed an additive cytotoxicity in murine ITD/ITD; p53+/- leukemia as well as in primary leukemic cells from most patients with AML (n=10).Taken together, our data indicate a strong cooperating effect of FLT3-ITD and p53 haploinsufficiency or loss in the induction of AML and ALL. Our data emphasize more careful analysis of p53 deregulation in AML. Targeting FLT3 in combination with drugs working independently of p53 status, such as proteasome inhibitor carfilzomib, might improve outcomes of AML patients. DisclosuresGanser:Novartis: Membership on an entity's Board of Directors or advisory committees.

Final Results from a Phase I Trial Combining Selinexor with High-Dose Cytarabine (HiDAC) and Mitoxantrone (Mito) for Remission Induction in Acute Myeloid Leukemia (AML)

Final Results from a Phase I Trial Combining Selinexor with High-Dose Cytarabine (HiDAC) and Mitoxantrone (Mito) for Remission Induction in Acute Myeloid Leukemia (AML)

Molecular Predictors and Current Management of Minimal Residual Disease (MRD) Following Induction Chemotherapy for Acute Myeloid Leukemia (AML)

▪Background: MRD is a powerful prognostic factor in AML. Emerging data indicate that allogeneic stem cell transplant (alloSCT) with MRD results in outcomes equivalently poor to alloSCT with morphologic AML (Araki et al., JCO 2016). Genomic predictors of MRD are unclear, and relative efficacy of therapies for MRD remains elusive.Objectives: Here we provide an integrated analysis of responses for 163 patients (pts) who underwent induction chemotherapy with baseline next-generation sequencing (NGS) followed by serial immunophenotypic monitoring for MRD.Methods:163 patients starting in April 2014 who underwent induction chemotherapy at Memorial Sloan Kettering Cancer Center were retrospectively studied. All received anthracycline + cytarabine, with or without investigational agents. Immunophenotypic MRD was identified in bone marrow aspirates (BMA) by multiparameter flow cytometry. Any level of residual disease was considered MRD+. Molecular analysis was obtained from pre-induction BMA by NGS using 28 or 49 gene panels. Cytogenetics/FISH were performed using standard techniques.Results: Patient characteristics are in Table 1. 7/163 (4.9%) died within 30 days of induction.153 pts had BM biopsy after induction prior to further therapy. 124/153 underwent flow after induction. 65/124 (52.4%) achieved CR/CRi after induction alone, 31/124 (25%) MRD+CR/CRi, and 34/124 (27.4%) MRD-CR/CRi. Pre-induction molecular analysis from 126 suggests that certain cytogenetic and molecular abnormalities correlate with achievement of MRD-CR. (Figure 1) Only 2/25 (8%) with RUNX1, 0/13 with SF3B1, and 0/11 with TP53 mutations achieved MRD-CR/CRi as best response after 1 cycle of induction. Only 3 additional RUNX1, 2 SF3B1, and 0/11 TP53 achieved MRD-CR/CRi as best response after a second cycle of therapy. In contrast, 7/8 with CBF AML (inv16 and no KIT mutation, n=4) or (t(8;21), n=3) achieved MRD-CR/CRi (n=5) or CR without flow (n=2) after 1 cycle of induction. 91/163 (55.8%) underwent alloSCT following induction or additional therapy. Post-alloSCT follow-up indicates potential value in converting MRD+ to MRD-. 84/91 were evaluable for MRD with flow cytometry prior to alloSCT. 41/84 (48.8%) were MRD-, 30/84 (35.7%) MRD+, and 13/84 (15.4%) persistent AML. 13/41 (31.7%) MRD-pre-alloSCT were MRD- post-induction. 28/41 (68.2%) MRD+ or persistent AML converted to MRD- prior to alloSCT following additional therapy. 23/29 MRD+CR/CRi pts after induction were intermediate/unfavorable and therefore transplant candidates. 19/23 MRD+CR/CRi intermediate/unfavorable underwent transplant (9 without post-induction therapy, 10 after consolidation), while 4 did not proceed to transplant due to relapse after induction (n=1), relapse after consolidation (n=2), and patient preference. There was no significant difference in post-transplant OS between early MRD-CR immediately following induction and later conversion to MRD-CR prior to alloSCT (Figure 1B). Post-transplant analysis reveals that most pts who enter transplant with persistent AML (n=13) or MRD+ (n=30) clear MRD (30/43, 69.7%) by the first post-transplant BM (median 32 days, Figure 1C). Despite initial post-transplant MRD clearance, pts who entered alloSCT with persistent AML or MRD+ had poorer post-transplant OS compared to pts who entered alloSCT with MRD- (p=0.02, Figure 1D).Conclusion: Our data show that AML pts with specific molecular mutations (RUNX1, SF3B1, and TP53) are unlikely to achieve MRD-CR/CRi after induction chemotherapy. We further show that additional therapy such as consolidation may be advantageous for some MRD+ pts to achieve MRD-CR prior to alloSCT, although others remain resistant to MRD clearance. Post-transplant OS is improved in pts who are MRD- at time of transplant, regardless of whether they required additional therapy beyond induction to achieve this state. Our results suggest that development of MRD-eradicating therapies after AML induction has the potential to improve post-transplant outcomes. [Display omitted] DisclosuresGoldberg:AROG: Research Funding; Pfizer: Research Funding; Celgene: Consultancy. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Perales:Takeda: Other: Personal fees; Merck: Other: Personal fees; Abbvie: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Novartis: Other: Personal fees. Tallman:ADC Therapeutics: Research Funding; Daiichi-Sankyo: Other: Advisory board; Orsenix: Other: Advisory board; Cellerant: Research Funding; BioSight: Other: Advisory board; AROG: Research Funding; AbbVie: Research Funding.

Clinical Characteristics and Outcomes of 82 Patients with Mixed-Phenotype Acute Leukemia

Objectives: Mixed-phenotype acute leukemia(MPAL) is a rare disease and comprises 2% to 5% of all acute leukemia. Outcomes for MPAL are worse than both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).The complex phenotype exhibited by this type of leukemia resulted in a myriad of treatment approaches.In our study, we retrospective analysis 82 patients in clinical trail, treatment strategy and prognosis.Method: eighty-two patients diagnosed with MPAL at Nan fang hospital from 2006 to 2017 using either EGIL or 2008 WHO criteria were analyzed. Comparison the treatment effect and outcomes between different therapy types.Result: eighty-two patients, including 60 males and 22 females with a median age of 29 years (range, 2 months-72 years), were studied. 61 patients (77%) were older than 18years, 73patients met the criteria for MPAL via EGIL, 68via WHO2008, and 59of these were reported to satisfy both definitions. fifty one of these cases (62.2%) had a B/myeloid phenotype, Twenty four of these cases (29.3%) had a T/myeloid phenotype. The other cases (8.5%) showed immunophenotypic evidence of a B, T, and myeloid lineage in one blast population. Among the 82 cases, 57 cases with successful cytogenetic studies, 20(35.1%) had normal karyotypes and 37patients(64.9%) had abnormal karyotypes. Twelve patients (21.05%) translocation between chromosomes 9 and 22, five (8.8%) patients had 11q23/MLL translocations. Twelve patients (21.05%) had a complex karyotype and eight patients (14%) had other karyotype. The rarity of this disease and the fact that patients with MPAL are excluded from most AML and ALL clinical trials further complicates guidance about therapy. Of the 82 cases, 75 patients underwent the complete first course of treatment and complete remission rate was 49.8%. treatment approaches utilizing therapy for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and so-called “hybrid” therapy mixing elements of both are 51.9%, 16.7% and 66.7% respectively (P=0.003).OS and EFS with hybrid induction therapy and ALL like induction were not significantly different than those with AML induction by either definition (P>0.05). A total of 60 patients received consolidation treatment, 21 patients received the chemotherapy while 39 patients received stem cell transplant (HSC). The total Median EFS was 21months, in Chemotherapy group and HSC group, the Median EFS was 6 months and 40 months respectively, The 3-year EFS was 26.1% and 55.6% respectively (P=0.038). The total Median OS was 21 months, Median OS showed a significant survival benefit for starting with chemotherapy as compared to HSC( 12 months and 43 months respectively (P=0.001)), The 3-year OS was 19.1% and 57.7% respectively.Conclusion: In this study, ALL like induction therapy or “hybrid” therapy was associated with a more than three-fold greater CR rate than AML therapy. SCT therapy showed a trend for an association with higher OS and EFS for MPAL .Key words: MPAL, Immunophenotype,Treatment strategyFundingKey Sci-Tech Research Projects of Guangdong Province (2014A02021102). DisclosuresFan:National Natural Science Foundation of China (No. 81600141, No. 81770190) and Natural Science Foundation of Guangdong Province (No. 2016A030310390): Research Funding.

Midostaurin in Combination with Idarubicin and Cytarabine (3+7) Induction for FLT3 Positive AML - Very High Complete Response Rates and Transition to Allogeneic Transplantation

Background:The CALGB 10603 RATIFY trial demonstrated that midostaurin, a multi-targeted small molecule FLT3 inhibitor, when given in combination with standard 3+7 induction consisting of daunorubicin 60mg/m2 for 3 doses and cytarabine 200mg/m2/day for 7 days significantly prolonged overall survival (OS) compared to placebo plus standard induction in FLT3 positive acute myeloid leukemia (AML) patients. The safety and efficacy of the other anthracycline commonly utilized in standard AML induction, idarubicin, has not been evaluated to date.Methods:A single-center retrospective review from May 2017 to July 2018 was performed. Patients were included if they had a diagnosis of FLT3 positive AML and received induction chemotherapy with idarubicin. The primary outcome was incidence of adverse effects attributed to midostaurin. Grading of adverse effects was in accordance with the Common Terminology and Criteria of Adverse Effects (CTCAE) version 5. Additional outcomes included OS, relapse-free survival (RFS), similar as in the Ratify trial, as well as detection of FLT3 on subsequent bone marrow biopsies.Results:Ten patients were included. All patients received induction therapy with idarubicin 12mg/m2 for 3 doses and cytarabine 100mg/m2/day for 7 days. Median age was 53 years (range: 33 to 66) and 6/10 were male. Eight of 10 patients exhibited internal tandem duplication (ITD) on diagnosis; two had FLT3 tyrosine kinase domain (TKD) D835. Eight patients had diploid cytogenetics; the other two patients had core-binding factor AML. Midostaurin was initiated on day 8 of induction in all but 2 patients, who started on day 11 and 12, respectively.Nine of ten patients completed all 28 planned doses of midostaurin. All patients received antifungal prophylaxis with micafungin throughout the course of midostaurin. The median time from day 1 of induction to neutrophil (>500/µl) and platelet (>100,000/µl) recovery was 23 days and 26 days, respectively. Granulocyte colony stimulating factor (G-CSF) was initiated for all patients after day 14 bone marrow biopsy, as per institutional procedure. Four of 10 patients experienced an adverse event attributed to midostaurin. Maculopapular rash was observed in 3 patients a median of 5 days after midostaurin initiation: 2 of 3 patients had a grade 2 rash and continued therapy with topical steroids; one patient had a grade 3 rash and discontinued midostaurin after 17 of 28 planned doses. A grade 1 drug fever was attributed to midostaurin in a fourth patient. Fevers persisted despite neutrophil recovery and subsequently dissipated after completion of the final midostaurin dose.Persistent FLT3 mutation was detected in 4/9 (1 not reported) day 14 bone marrow biopsies but was negative in 9/10 pts on day 28. The lone positive FLT3 result on day 28 occurred in a patient with refractory disease (>5% blasts) necessitating salvage therapy. Notably, this patient only completed 17 of 28 planned doses. All other patients exhibited a complete response (CR) on day 28.The median follow-up time was 243 days (range: 57 to 394). Nine patients are alive at the time of reporting. Six patients proceeded to allogeneic transplantation -one death was attributed to transplant-related complications, occurring in the same patient needing salvage and reduced duration midostaurin. Two patients relapsed a median of 184 days after start of induction -both FLT3-ITD positive and neither having undergone allogeneic transplant prior to relapse.Conclusions:Midostaurin in combination with idarubicin-based induction 3+7 therapy in this first case series appears to be safe. While the incidence of rash was higher (30%) than reported in RATIFY, this only resulted in discontinuation of therapy in one patient. Although patient numbers are limited, 90% achieved a FLT3 negative CR after completion of induction therapy and six patients proceeded to allogeneic transplantation. A confounding variable includes the routine use of G-CSF, which likely contributed to the shorter duration from induction to neutrophil recovery observed compared to RATIFY (23 days vs 26 days). The influence of G-CSF use on outcome is uncertain, however represents an interesting observation. A randomized, prospective trial comparing midostaurin in combination with idarubicin versus daunorubicin at both 60mg/m2 and 90mg/m2 is warranted to establish the optimal anthracycline induction therapy for FLT3 mutated AML patients. DisclosuresAl-Homsi:Celyad: Membership on an entity's Board of Directors or advisory committees. Diefenbach:Denovo: Research Funding; Merck: Consultancy, Research Funding; Acerta: Research Funding; Incyte: Research Funding; Trillium: Research Funding; Millenium/Takeda: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy; Seattle Genetics: Consultancy, Research Funding.

Transcriptomic Profile Identified a Specific Signature in Children with Acute Myeloid Leukemia (AML) and Primary Induction Failure (PIF): Preliminary Data and Future Perspectives

Background. Acute Myeloid Leukemia is a heterogeneous disease, characterized by the uncontrolled proliferation of hematopoietic precursor cells. AML accounts for 15% of acute leukemias in children, with a cure rate of 55-60% as overall survival (Pession A Blood 2013). Complete remission (CR) is achieved in 80-85% of children with AML. Current protocol defines CR by morphological evaluation (blasts <5%) and cytofluorimetric analyses (blasts <0,1%), after two cycles of high-dose chemotherapy. Around 10-15% of children and 30% of adults do not achieve remission and are defined as Primary Induction Failure (PIF). The majority of these cases are addressed to other form of high-dose chemotherapy blocks, experimental therapies or directly to hematopoietic stem cell transplantation (HSCT) as salvage treatment, showing a very poor prognosis (Quarello P et al. British Journal of Haematology 2015). Strong efforts to generate biological data in order to define this subtype of AML are needed for early identification and for target therapy design.Aim. Our study aims to characterize a specific gene-expression profile in children with PIF-AML in order to early detect peculiar genetic aberrations and to identify potential targets to new compounds.Materials and Methods. We analyzed diagnostic samples from 4 children with PIF-AML, diagnosed and treated in our Center, from 2013 to 2016. All cases were female and 3 had more than 10 years of age. One presented with a monosomy of chromosome 11; two with complex karyotype (one with NUP98-NSD1 rearrangement) and one with no cytogenetic and molecular markers. After two cycles of Induction phase, one case showed complete blast regeneration (>60%); in the other three cases we detected, by flow-cytometry, a blast rate between 10-20%. In the attempt to compare these cases with those presenting with very high-risk (VHR) features but achieving CR after induction (Primary Induction Responder, PIR), we included in our analyses 8 children with VHR-PIR-AML, diagnosed and treated in our Center: 2 with FLT3-ITD and NUP98-NSD1 fusion genes; 2 with FLT3-ITD and complex karyotype; 2 with DEK-CAN fusion genes (1 with FLT3-ITD); 2 with NUP98 rearrangements and complex karyotype. We performed whole transcriptome analyses using Human Transcriptome Array 2.0 (Affymetrix). Then we compared our analyses with a recently published data set, including a large population of children with AML (Bisio V Leukemia 2017). Based on transcriptomic findings, we determined the expression of specific genes, by Real-time PCR using gene-specific probes (UPL probes by Roche Merck, Germany), applying a QuantStudio7 Flex System technology (Applied Biosystem, California, USA) and the relative quantification method (the comparative 2-ΔΔCt method). We applied a t-student test, for statistical analyses among different subgroups.Results. A direct comparison of PIF-AML vs PIR-AML subgroups revealed 919 protein-coding and 8 pri-miRNA overexpressed genes (fold-change >3, FDR adjusted p value <0.05) and 18 protein coding and 43 pri-miRNA down-regulated genes (fold-change >-3, FDR adjusted p value <0.05). Marked differences were observed in cancer-related genes such as KIT, PTEN, FLT3 and POU4F1, and in cell-cycle related genes such as cyclin transcripts (CNNG1, CCNA1, CCND2, CCNJ, CCNC, CCNY). Moreover some genes that discriminate PIF from PIR subgroups are also differentially expressed between cases with NUP98-negative and NUP98-positive AML (PDGFD, CCNA1). The latter group is considered as a VHR-AML subtype. Based on these findings, we selected several genes including HOX-B3, HOX-B5, CEBP-D, CCNA1, PDGF-D and performed a Real-Time PCR with specific-gene probes. Comparing gene expression data of our 4 PIF-AML cases with 8 VHR-PIR-AML cases, we observed a strong statistically significant different expression in CCNA1 (p<0.0001) and PDGF-D (p<0.0001).Conclusions. Our findings defined a characteristic profile of PIF-AML, highlighting the overexpression of cell-cycle related genes (CCNG1, CCNA1) and several potential targets (KIT, FLT3, PDGF-D) to be considered for an alternative treatment in this very poor-prognostic subgroup of patients. In conclusion our results suggest that PIF-AML samples bear a specific gene expression profile, not overlapping with those of known molecular and karyotype AML subgroups. However, a larger population study is needed to confirm our preliminary data. DisclosuresNo relevant conflicts of interest to declare.

Evaluation of Prognostic Factors after Induction Chemotherapy for Acute Myeloid Leukemia

Purpose: Recent studies have shown that dose escalation of daunorubicin from 45mg/m2 to 90mg/m2 during acute myeloid leukemia (AML) induction showed response benefit and overall survival in patients <=65 years. Yet, the further management of patients with persistent disease based on the evaluation of D14 bone marrow has often been questioned due to lack of data. The primary purpose of this study is to evaluate the overall remission rates of patients with a positive D14 bone marrow compared with those who had a negative D14 results, and to determine if blast % on the D14 bone marrow aspirate is a prognostic indicator for remission and survival in acute leukemia patients who underwent induction chemotherapy. We aim to investigate the relevance of the D14 bone marrow result by dividing the result into blast percent categories and investigate if the there is a correlation between D14 blast % and CR.Patients/Methods: This was an IRB approved retrospective chart review conducted at North Shore University Hospital. Adult patients with AML who received standard induction 7 + 3 Daunorubicin and Cytarabine from 2010 to 2015 were included. 150 patients were reviewed and those that were eligible were evaluated for various factors (D14 blast %, initial marrow blast %, gender, age, cytogenetic risk profile, initial WBC, initial hemoglobin, initial platelets and initial LDH levels, along with those lab values at D14) for tests of association with CR. These patients' D14 blast % biopsies were divided into blast percent categories as followed: (Chemotherapeutic/<1%, 1-10%, 10-30%, 30-60% and > 60%). Complete remission (CR) was defined as patients having <5% blasts on their day 28 bone marrow or day 63 and corresponding neutrophil count >1,000 and platelet count >100 k. Fisher's exact test was used to compare the proportion of patients who reached CR among the D14 blast % categories, and on other categorical data. The Wilcoxon test was utilized to compare CR on continuous variables. Results were considered statistically significant if p < 0.05.Results: 115 patients were analyzed and we found no significant association between D14 blast % and CR status. However, initial blast % was found to be significantly associated with CR status (p=0.009), specifically, those with >60% initially had the greatest CR rate. D14 hemoglobin, D14 platelets or D14 LDH levels were not significantly associated with CR status (p=0.67, p=0.33, and p=0.13, respectively). Similarly, initial WBC, hemoglobin, platelets and LDH levels were each not significantly associated with CR (p=0.99, p=0.51, p=0.47 and p=0.36, respectively). Results did provide evidence to suggest that D14 WBC was significantly associated with CR (p=0.02), but when both D14 WBC and initial blasts % were included in a multiple logistic model, WBC was no longer a significant predictor of outcome. As such, only initial blast percent (at time of diagnosis or initial visit) was deemed predictive of CR response day at D63 (p=0.0142); patients with initial blast >60% had the greatest rate of CR compared with <20% blasts initially.Conclusion: The data suggests that there is no statistical difference between the blast % on the D14 bone marrow and the achievement of CR during induction chemotherapy for AML. Secondary outcomes showed that the initial blast % was associated with CR especially in patients with an initial blast % >60%. Also, D14 WBC might be associated with remission. Prospective studies are required to confirm these findings. DisclosuresNo relevant conflicts of interest to declare.

The Odyssee Study: Prevention of Dysbiosis Complications with Autologous Fecal Microbiota Transfer (FMT) in Acute Myeloid Leukemia (AML) Patients Undergoing Intensive Treatment: Results of a Prospective Multicenter Trial

▪Introduction. AML standard intensive induction chemotherapy (“3+7” or equivalent) combined with wide spectrum antibiotics can dramatically alter the composition of the gut microbiota, leading to dysbiosis which is characterized by loss of microbial diversity. Such dysbiosis status can promote a pathological condition involving uncontrolled local immune responses, systemic inflammation and increased incidence of adverse events. The development of FMT-based drugs to restore microbial communities could offer novel therapeutic possibilities to reduce such adverse events and potentially improve outcomes in AML. We therefore conducted this single arm prospective phase I/II multicenter trial (NCT02928523) to evaluate the use of a FMT-based drug in association with AML induction treatment to restore the gut microbiota diversity.Patients and methods. A total of 62 consecutive patients aged between 24 and 69 years old with a diagnosis of de novo AML were screened in 7 French sites. At time of admission and AML diagnosis (Step 1=S1), patients' faeces were collected, rigorously screened, prepared following a standardized process, and stored at -80°C until later administration. The drug was administered as an enema after hematopoietic recovery (S2) and before consolidation chemotherapy (Conso). The primary endpoint was the recovery of at least 70% of microbiota diversity (based on the Simpson index) after drug administration and the reduction of multidrug resistant bacteria carriage. Blood and feces samples were collected at S1, S2, and around 10 days post-FMT before Conso (S3). Microbiome diversity restoration was assessed by metagenomics analysis through Illumina HiSeq shotgun sequencing. Antibiotic resistance gene carriage (ARGC, also known as resistome) was evaluated through mapping of readouts on the MEGARES database. Secondary objectives included safety and analysis of host response with assessment of blood and fecal markers by ELISA and Luminex.Results. Overall, 25 patients were actually treated with FMT, and 20 were included in the per-protocol population. Induction Chemotherapy (IC) induced a dramatic shift in microbial communities, with a significant 42.3% decrease of mean α-diversity Simpson index between S1 and S2 at species level (0.85 to 0.50; p<0.001). Ten days after FMT administration (S3), the Simpson index returned to its initial baseline level (0.50 to 0.86; p<0.001). In addition to variations of the diversity, we demonstrated using the Bray-Curtis dissimilarity index (BC) a profound shift in the microbial communities following IC (mean BC S1-S2: 0.76) and the restoration of the initial microbial profile after FMT (mean BC S1-S3: 0.40). Moreover, IC and associated antibiotic treatments induced a significant increase in the mean number of readouts mapped against antibioresistance genes at S2 (167546 to 371466 reads, p<0.01) that reflect ARGC. Then, a significant reduction of 43% of the mean number of reads mapped was observed at S3 after FMT (211128 reads, p<0.001).No serious adverse events (SAE) were observed within 30 days after FMT and all post FMT SAEs were not related to the FMT procedure. Moreover, FMT did not induce any local or systemic inflammatory reaction as measured by fecal and blood markers (fecal neopterin and IgA; plasmatic CRP, IL-6 and sCD14). Interestingly, restoration of the microbiome diversity was associated with a significant reduction of CRP and fecal neopterin levels, suggesting a potential anti-inflammatory impact of FMT.Overall, FMT was well tolerated and had an excellent safety profile. The one-year overall survival estimate in the whole cohort was 84% (4 deaths among 25, none of which were related to FMT: 2 multiple organ failures, 1 heart attack and 1 grade IV resistant GVHD). The median time to death from the second FMT was 182.5 days (113-225 days).Conclusions. This is the first prospective trial testing the safety and efficacy of FMT in AML patients receiving intensive induction chemotherapy. The trial achieved its primary endpoint and established the capacity of FMT to restore a diverse microbiome with high levels of similarity to baseline, as well as reducing ARGC and intestinal inflammation. A controlled randomized trial with repeated FMT administrations is currently planned to further evaluate the impact of FMT on clinical outcomes and long-term survival. (This trial was funded by MaaT Pharma whose product was tested in this protocol). DisclosuresMohty:MaaT Pharma: Consultancy, Honoraria. Doré:MaaT Pharma: Consultancy, Honoraria.

Compared the Effect of Mitroxantrone ( MA) with Idarubicine (IA) for Acute Myeloid Leukemia Induction Therapy

Background: Treatment for acute myeloid leukemia (AML) has remained relatively unchanged over the past few decades. Standard-dose cytarabine and idarubicin (7+3 IA) or daunorubicin (7+3 DA) induction regimen have been recommended for AML induction therapy by global guidelines. Mitroxantrone, a type II topoisomerase inhibitor, disrupts DNA synthesis and DNA repair, has been recommended as a salvage treatment for refractory/relapsed AML or induction therapy for elderly patients. Objective: To compare the the clinical response and adverse events of Idarubicin regimen ( IA) with mitoxantrone and cytarabine (MA) in the treatment of newly acute myeloid leukemia (AML) . Methods: This retrospective study evaluated 164 patients with newly diagnosed AML who received either IA (idarubicin 10mg/M2, d1-3; cytarabine 200mg/d, d1-7) or MA regimen (mitoxantrone 10mg/M2, d1-d3; cytarabine 200mg/d, d1-7) as induction therapy from September 2010 to November 2017 at Guangdong General Hospital. The primary end point of this study was complete response and complete response with incomplete blood count recovery (CR/CRi), with secondary end points were adverse event rates and days of granulocyte and platelet recovery. Results: A total of 164 patients , 90 patients were males and 74 females, the median age was 41 (range:14~64) years old. There were 88 patients received IA regimen and 76 patients received MA regimen. There was no significant difference in clinical features and molecular biological characteristics in two groups (P>0.05). The CR/CRi rate was 72.3% and 64.0% (P=0.263) in IA and MA group after the first induction regimen, respectively. And the accumulated CR/CRi rate was 85.9% and 75.7% in two group, respectively (P=0.109). The common adverse reactions in the two groups were myelosuppression and infection , but with no statistical difference (P>0.05) in the incidence and grade of serious. The grade 4 and grade 5 neutropenia were 95.3% vs.98.7% and 4.7% vs. 1.3%, P>0.05 in IA and MA group respectively. And thrombocytpenia were 72.9% vs.63.2% and 4.7% vs. 1.3%, P>0.05. There was no significant difference in the incidence and severity of gastrointestinal, cardiovascular, respiratory, skin, liver and kidney injury between the two groups (P>0.05). The median days of intravenous antibiotics (including antifungal drugs), neutrophil recovery, platelet recovery and the units of platelet and red blood cell suspension transfusion had no statistical difference in two groups (P>0.05). Conclusion: This retrospective study implied mitoxantrone with standard-dose cytarabine (3+7 MA) regimen has similar efficacy and outcome to the idarubicin with standard-dose cytarabine (3+7 IA) regimen for newly diagnosed AML, without increasing the incidence of adverse event rates. DisclosuresNo relevant conflicts of interest to declare.

Indoximod Combined with Standard Induction Chemotherapy Is Well Tolerated and Induces a High Rate of Complete Remission with MRD-Negativity in Patients with Newly Diagnosed AML: Results from a Phase 1 Trial

▪BackgroundSuccessful allogeneic stem cell transplantation (HSCT) in treatment of patients (pts) with acute myeloid leukemia (AML) is dependent upon graft-versus-leukemia, suggesting that intact immune surveillance is essential for eradicating minimal residual disease. Myeloblast-induced T-cell tolerance through overexpression of indoleamine 2,3-dioxygenase (IDO) is thought to play a significant role in immune evasion through upregulation of tryptophan (Trp) catabolism and kynurenine production, resulting in a Trp-poor environment that leads to immune system suppression. Indoximod is a small-molecule inhibitor of the IDO pathway that acts directly on immune cells to reverse IDO pathway-mediated suppression. We are assessing the safety and preliminary efficacy of indoximod in combination with standard induction chemotherapy in patients (pts) with newly diagnosed AML.MethodsIn this open-label, multicenter, phase 1 study (NCT02835729), eligible pts with newly diagnosed AML were treated with indoximod in combination with induction chemotherapy (idarubicin 12 mg/m2/d x3 days with cytarabine 100 mg/m2/d x7 days). Using a “3+3” design, indoximod (600 mg [dose level 0], 1000 mg [dose level 1], 1200 mg [dose level 2]) was given orally every 8 hours (Q8h) starting on day 9 of induction. Regimen limiting toxicity (RLT) was defined as any ≥ grade 3 non-hematologic adverse event (AE) that was not incontrovertibly related to the underlying AML or cytarabine or idarubicin. After induction, pts received up to 4 cycles of high dose cytarabine (HiDAC) consolidation while continuing indoximod. Patients continued on maintenance indoximod for up to 6 months from completion of consolidation therapy. Indoximod was discontinued 4 weeks prior to HSCT in eligible patients and not restarted as maintenance post-HSCT.ResultsAs of July 15, 2018, 31 pts were enrolled (median age 55 years, range 18-78; 77% male). Six patients did not proceed with study therapy due to a diagnosis of acute promyelocytic leukemia, issues with medical insurance coverage, consent withdrawal, critical illness, and intestinal myeloid sarcoma preventing oral intake. Pts who received ≥1 dose of indoximod were included in the intention-to-treat (ITT) analysis (n=25), and pts who received ≥80% of their scheduled indoximod doses were included in the per-protocol (PP) analysis (n=19). Reasons for not completing ≥80% of indoximod doses were: consent withdrawal (n=3), inability to swallow (n=2) and physician decision (n=1). Of the 19 PP patients, 16 (84%) had either unfavorable karyotype or adverse mutation profile and 3 (16%) had secondary AML (s-AML). Indoximod combined with induction chemotherapy was well tolerated; no RLT was observed. The most frequent grade ≥3 non-hematologic treatment-emergent AEs in the ITT population, regardless of attribution, were febrile neutropenia (60%), hypoxia (16%), atrial fibrillation (12%), pneumonia (12%), hypocalcemia (12%), and hypotension (12%). Among 25 ITT pts, 21 (84%) achieved a remission (CR/CRh/CRi/CRp), and 15 of 19 (79%) in the PP analysis achieved remission. Among 12 pts with measurable residual disease (MRD) available in remission, 10 (83%) had MRD <0.02% (MRD-neg). Eleven of 19 pts (58%) received ≥1 cycle of HiDAC and 5 (26%) received maintenance indoximod. All 11 patients who received HiDAC #1 became MRD-neg. Median relapse-free and overall survival have not been reached. IDO Composite Scores in bone marrow were calculated by multiplying percentage of stained mononuclear cells by grade of staining intensity determined by 3 independent pathologists. Median composite IDO1 score in tested pt samples (n=11) was 0.76 (range, 0.1-2.2). Expression of IDO1 mRNA at baseline varied significantly among patient samples analyzed (fold changes (FC) range: 0.1-84, normalized to β-Actin expression). IDO1 mRNA was significantly upregulated in post-induction samples compared to baseline (FC range: 1.7-248) in 10 out of 12 paired samples.ConclusionsIndoximod is well tolerated in combination with standard AML induction therapy. Rates of morphologic response and of MRD-neg status are very promising. The recommended phase 2 dose (RP2D) was 1200 mg oral Q8h and a placebo-controlled randomized phase 2 study is under development. DisclosuresEmadi:NewLink Genetics: Research Funding. Loken:Hematologics, Inc: Employment, Equity Ownership. Kennedy:NewLink Genetics: Employment, Equity Ownership. Link:NewLink Genetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Munn:NewLink Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Patterns of Infection and Mortality Associated with Intensive AML Induction Therapy: 10 Year Experience from a Tertiary Cancer Centre in India

Introduction: The treatment of acute myeloid leukaemia (AML) with intensive induction regimens remains a challenge in low and middle incomes countries. Early induction related deaths particularly due to infectious complications are a major problem. This is in stark contrast to high-income countries where induction mortality has declined significantly over the last 2 decades with improved antibiotic use and supportive care. In this study we assess induction mortality (all cause and infection related) in AML patients who received intensive induction therapy in a tertiary cancer centre in India over a 10-year period (2008-2017).Methods: We included patients with newly diagnosed AML treated at Cancer Institute, Chennai in South India who received intensive induction therapy. Intensive therapy was defined as use of any anthracycline with cytarabine (3+7/ADE/others). We assessed baseline demographics including age, gender, cytogenetic risk status, and type of induction regimen used. We also assessed key clinical outcomes including patterns of antimicrobial prophylaxis and treatment, infectious complications, cause of death, ICU stay, and length of hospital stay. Induction mortality was defined as deaths occurring within 45 days of initiating treatment for AML or start of 2nd induction.Results: Between January 2008 and December 2017, 510 patients with AML were evaluated at Cancer Institute, Chennai and accepted for treatment. Excluding 51 patients with APML and 55 patients who were unfit for intensive induction, 404 patients received treatment with an intensive induction regimen. Median age was 23 years (Range: 1-74 years) and 219 (54.2%) were male patients. 165(40.8%) patients were less than 18 years of age. Among those who had cytogenetic and/ molecular data for risk stratification [N=341 (84.7%)], 101 (29.6%) were low risk, 166 (48.7%) intermediate risk and 74 (21.7%) high risk. Therapy details: 318 (78.7%) patients received daunorubicin and cytarabine (‘3+7‘), 52 (12.9%) received ADE, and 38 (8.4%) received other combinations ofdaunorubicin and cytarabine.87(21.5%) of the cases had infection at the time of presentation. 389(96.8%) had an episode of febrile neutropenia with 184(45.5%) requiring management in Intensive Care Unit (ICU). Focus of infection could be identified in 294(72.7%) of the patients with 207(51.2%) having a positive culture.The overall incidence of induction mortality over the entire study period was 15.6%(n=63)and 14.8% for the most recent year included (2017). The majority of the deaths (n=53; 84.1%) were due to infectious complications (fig1). Median time to death from start of induction was 19 days. The incidence of fungal pneumonia significantly reduced since 2012 when thethe antifungal prophylaxis was switched from fluconazole to voriconazole (p=0.03). Starting in 2012, an increase in the incidence of multi-drug resistance (MDR) gram negative septicaemia and mortality (MDR: carbapenem resistant enterobacteriaceasensitive only to colistin and tigecycline) was noted. This led to proactive use of colistin in patients with febrile neutropenia and septic shock, a GI focus or baseline stool colonisation by MDR gram negative organisms.Despite this, during the last 4 years(2014-2017), there has been a significant rise in the incidence of sepsis and death due to MDR gram negative organisms (fig2). The proportion of deaths attributable to MDR sepsis is 23.8%. The early use of colistin, tigecycline and carbapenems did not significantly decrease the mortality.Conclusions: The induction mortality remains high at 15.6% and is in contrast to the declining induction mortality in high-income countries. While the morbidity and mortality due to specific infections (specifically fungal pneumonia) have changed over time, there is no signfiicant decline in infectious or all cause induction mortality over the 10 years. In the last four years, MDR gram negative sepsis has been a major cause of morbidity and mortality. The early and increased use of broad spectrum antibiotics like tigecycline, colistin and carbapenems has not led to a decrease in MDR gram negative sepsis. Overall, despite improvements in supportive care and early use of broad spectrum antimicrobial agents, infection related morbidity and mortality remains a substantial challenge in treating acute myeloid leukaemia in low- and middle-income countries. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Response Rate, Event-Free Survival (EFS), and Overall Survival (OS) in Newly-Diagnosed Acute Myeloid Leukemia (AML): U.S. Food and Drug Administration (FDA) Trial-Level and Patient-Level Analyses

Background: Several novel therapeutics are being developed for AML with demonstrable effects on response rates (e.g. complete remission [CR], CR with incomplete hematologic recovery [CRi], CR with incomplete platelet recovery [CRp], overall response rate [ORR = CR+CRi/CRp]), and EFS. Improvement in EFS recently served as the basis of approval of gemtuzumab ozogamicin (GO) for the treatment of newly-diagnosed CD33-positive AML in adults (Jen et al. Clin Cancer Res 2018). The relationship between response rate, EFS, and OS in newly-diagnosed AML has not been conclusively established. Therefore, we conducted trial-level and patient-level meta-analyses of newly-diagnosed AML trials submitted to the FDA.Methods: We searched for trials submitted with Biologics License or New Drug Applications for treatment of newly-diagnosed AML between 2007 and 2017. Criteria for inclusion were randomized, active-controlled, multicenter trials of intensive AML induction and consolidation chemotherapy. The estimated odd ratios (OR - ratio of odds of response in treatment to odds of response in controls) of CR and ORR and hazard ratios (HR - ratio of hazard of treatment versus control) for EFS and OS were calculated for each study. EFS was defined as time from randomization to treatment failure (defined as date of randomization for patients who failed to achieve CR following induction), disease relapse following CR, or death. Associations between treatment effects at the trial-level were evaluated using weighted least square (WLS) regression analyses on the log-scale (weighted by sample size of each randomized comparison). Coefficient of determination (R2) and 95% confidence interval (CI) were calculated to measure the strength of associations. Individual patient data for OS were plotted against EFS to explore their relationship. An exploratory patient-level responder analysis was performed to compare OS between responders and non-responders, regardless of treatment assignment in the pooled dataset. We estimated HRs of OS from Cox proportional hazards models. OS estimates by response were obtained based on the Kaplan-Meier method.Results: We identified 8 trials with a total of 4482 patients and 3 experimental agents (GO, n=5; [daunorubicin and cytarabine] liposome injection, n=2; midostaurin, n=1) for treatment of newly-diagnosed AML. Two trials tested therapy in defined patient populations (FLT3 mutant = 1 and secondary AML = 1). The association between OS HR and CR OR at the trial-level was moderate (R2 = 0.67, 95% CI: 0.16 - 0.94; Figure 1), whereas the association between OS HR and ORR OR was weak (R2 = 0.43, 95% CI: 0.03 - 0.98). For the OS vs. EFS HR analysis, a weaker than expected association was observed (data to be presented at the meeting). Individual patient level data scatter plots suggested that one possible reason for the lack of a strong association between EFS and OS was that early failures and relapses did not always result in worse OS (Figure 2). In the patient-level responder analysis, patients who achieved a CR response had better OS compared with CRi+CRp response and no response (Figure 3).Conclusions: On a trial level, the meta-analysis of randomized, active-controlled trials in newly-diagnosed AML suggests a moderate association between OS and CR rate, but not ORR. A strong association between EFS and OS is not established and may be confounded by improvements in salvage therapy, supportive care, hematopoietic stem cell transplantation, and/or differing censoring across trials. A patient-level responder analysis showed that CR responders have better OS compared with CRi+CRp responders and nonresponders. While our results are limited by the number of trials, they suggest that CR remains the response endpoint associated with greatest long-term benefit and that EFS, while clinically meaningful, is not a surrogate for OS. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Minimal Residual Disease (MRD) at Time of Complete Remission Is Commonly Detected in Acute Myeloid Leukemia (AML) Patients Age ≥60 Years and Significantly Impacts Outcome Based on Post-Remission Treatment Strategies: Prospective Analysis of ECOG-ACRIN (E-A) E2906 Phase III Trial

Minimal Residual Disease (MRD) at Time of Complete Remission Is Commonly Detected in Acute Myeloid Leukemia (AML) Patients Age ≥60 Years and Significantly Impacts Outcome Based on Post-Remission Treatment Strategies: Prospective Analysis of ECOG-ACRIN (E-A) E2906 Phase III Trial

Limitations to Receiving Allogeneic Hematopoietic Cell Transplantation for Treatment of Acute Myeloid Leukemia: A Large Multi-Center Prospective Longitudinal Observational Study

Introduction: Acute myeloid leukemia (AML) is most frequently diagnosed in older patients (pts), whose median survival is less than 1 year. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment. However, older pts often have significant comorbidities and other geriatric health problems, and the effect of these on the probability of receiving HCT is unknown. To this end, we designed a prospective, multi-center, longitudinal, observational study dating from first presentation of adult pts with AML to be treated at one of 13 different referral centers that provide both AML treatment and HCT. We examined the effects of different variables (see methods) on the probability to 1) survive long enough to receive HCT and 2) to receive HCT if such survival occurred. Methods: We enrolled 695 pts (Table 1). Data on demographics, AML status, cytogenetic risks per European Leukemia Network (ELN), and response; age; comorbidities per the HCT-comorbidity index (CI); function including instrumental activities of daily living (IADL) and activities of daily living (ADL); frailty including walk test; geriatric assessment (GA) including cognition; Karnofsky performance status (KPS); QOL including the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT), Euro-QOL 5-Dimension scale (EQ-5D), ENRICHD Social Support Instrument, Social Activity Log, and Patient Health Questionnaire 9-item Depression Scale (PHQ-9) were collected at enrollment and at 1, 3, 6, 9, 12, 18, and 24 months thereafter. High-risk myelodysplastic syndromes (MDS) receiving AML-like therapy were included. We used competing risk Cox regression analyses, treating HCT as the event of interest and death without HCT as a competing risk, with staggered entry (left truncation) at time of consent. Associations between variables were assessed both at enrollment and over time. Results: The overall rate of HCT at 9 months after enrollment was 43% (Figure 1) and 92% of pts who received HCT did so by the 9 month mark. In multivariate analyses, death without HCT (Table 2) was associated with augmented HCT-CI scores ≥5 (HR:2.11, p Among survivors (Table 3), low likelihood to receive HCT was associated with age ≥70 years (HR:0.40, p=0.0001), low ELN risk (HR:0.28, p Conclusions: In a prospective, observational, multi-center study, increasing age, comorbidity burden, ELN risk, low-intensity initial AML induction regimen, depression, and functional dependence increase risks of early mortality without HCT. In those who survived long enough to potentially receive HCT, age up to 69 years and/or multiple comorbidities were not found to be barriers to HCT, likely reflecting the widespread use of reduced-intensity conditioning regimens. However, the independent sharp decline in receipt of HCT in pts aged 70-80 years suggests continued bias, although pts in this age group have been shown to derive similar benefit from HCT as younger pts. Use of objective comorbidity and GA tools rather than age per se to decide on HCT is encouraged. The adverse impact of impairments in psychological health and function on survival and of impairments of cognition, geriatric health, and performance status on receipt of HCT emphasize the need for interventions that target these health limitations in conjunction with AML treatment to improve outcomes. Finally, the benefit of intensive vs. less-intensive induction therapies should be addressed with a randomized trial. Disclosures Gerds:Celgene: Consultancy; Apexx Oncology: Consultancy; Incyte: Consultancy; CTI Biopharma: Consultancy. Shami:Lone Star Biotherapies: Equity Ownership; Baston Biologics Company: Membership on an entity9s Board of Directors or advisory committees; JSK Therapeutics: Employment, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees; Pfizer: Consultancy. Rizzieri:Arog: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Novartis: Consultancy; Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Teva: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Wang:Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy; Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Faderl:Jazz Pharmaceuticals: Employment, Equity Ownership. Koprivnikar:Amgen: Speakers Bureau; Otsuka: Consultancy; Alexion: Consultancy, Speakers Bureau. Sekeres:Celgene: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees; Opsona: Membership on an entity9s Board of Directors or advisory committees; Opsona: Membership on an entity9s Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding.

Cladribine in the remission induction of adult acute myeloid leukemia: where do we stand?

The combination of cytarabine and an anthracycline has been the standard of care for the induction of remission in acute myeloid leukemia (AML). The response to treatment and survival of adult patients with AML are still variable and depend on multiple factors. Therefore, there have been many efforts to improve the response to treatment and survival rates by either increasing the cytarabine dose or adding a third agent to the standard induction chemotherapy regimen. Unfortunately, attempts to improve response and survival have been mostly unsuccessful. Recent clinical trials and retrospective studies explored the addition of cladribine to standard induction chemotherapy for AML. Some of these studies showed higher rates of complete remission, and one showed improved survival. In this review, we will discuss the antileukemic properties of cladribine and summarize the recent clinical data regarding its incorporation into the induction therapy for adult AML.

Comparison of Peripheral Blast Clearance and Day 14 Bone Marrow Biopsy in Predicting Remission Status and Survival After 7+3 Induction in Acute Myeloid Leukemia

IntroductionInduction chemotherapy with cytarabine and an anthracycline (7+3) remains the standard of care for acute myeloid leukemia (AML). Patients and MethodsWe retrospectively analyzed 183 newly diagnosed AML patients to compare the utility of rapid peripheral blast clearance (PBC), day of peripheral blast disappearance, residual blasts, and cellularity at day 14 bone marrow biopsy (D14BM) in predicting clinical response to 7+3 induction, overall survival (OS), and relapse-free survival (RFS). ResultsIn multivariable logistic regression analysis, day 2 PBC > 85% [P = .0016] was the only predictor of remission status, with sensitivity and specificity of 75%. Peripheral blast disappearance within 5 days after induction and < 10% cellularity in D14BM predicted superior OS and RFS in multivariate analysis. Median follow-up of patients was 28 months since diagnosis. Two-year OS and RFS for patients with ≤ 10% versus > 10% cellularity at D14BM was 60.6% [95% confidence interval (CI), 50.8%-72.2%] versus 32.5% [95% CI, 23.0%-45.8%], and 51.9% [95% CI, 41.9%-64.3%] versus 28.8% [95% CI, 19.1%-43.4%], respectively [P = .0003 for OS and .002 for RFS]. ConclusionRapid PBC after 7+3 induction showed a significant improvement in specificity compared with D14BM, with similar sensitivity. Neither of these methods were reliably specific tools for the decision of early reinduction, despite their prognostic value. Our findings indicate that morphological cellularity in D14BM is an independent prognostic factor for OS and RFS, regardless of blast percentage, and that ≤ 10% cellularity defines D14BM hypoplasia.

Sequential high-dose cytarabine and mitoxantrone (S-HAM) versus standard double induction in acute myeloid leukemia\u2014a phase 3 study

Dose-dense induction with the S-HAM regimen was compared to standard double induction therapy in adult patients with newly diagnosed acute myeloid leukemia. Patients were centrally randomized (1:1) between S-HAM (2nd chemotherapy cycle starting on day 8 = “dose-dense”) and double induction with TAD-HAM or HAM(-HAM) (2nd cycle starting on day 21 = “standard”). 387 evaluable patients were randomly assigned to S-HAM (N = 203) and to standard double induction (N = 184). The primary endpoint overall response rate (ORR) consisting of complete remission (CR) and incomplete remission (CRi) was not significantly different (P = 0.202) between S-HAM (77%) and double induction (72%). The median overall survival was 35 months after S-HAM and 25 months after double induction (P = 0.323). Duration of critical leukopenia was significantly reduced after S-HAM (median 29 days) versus double induction (median 44 days)—P < 0.001. This translated into a significantly shortened duration of hospitalization after S-HAM (median 37 days) as compared to standard induction (median 49 days)—P < 0.001. In conclusion, dose-dense induction therapy with the S-HAM regimen shows favorable trends but no significant differences in ORR and OS compared to standard double induction. S-HAM significantly shortens critical leukopenia and the duration of hospitalization by 2 weeks.

Efficacy and Toxicity of Idarubicin Versus High-dose Daunorubicin for Induction Chemotherapy in Adult Acute Myeloid Leukemia: A Systematic Review and Meta-analysis

BackgroundThe 2 main formulations of anthracycline used for acute myeloid leukemia (AML) induction therapy are idarubicin (IDA) and daunorubicin. Patients and MethodsThe present systematic review and meta-analysis compared the efficacy and toxicity between IDA and high-dose daunorubicin (HDD) for induction therapy for adult AML. Relevant studies reported before June 2018 were searched from the Medline and Embase databases. ResultsA total of 5 studies with 1809 participants (3 randomized controlled studies and 2 retrospective cohort studies) met the eligibility criteria and were included in the meta-analysis. The patients in the IDA arm for induction therapy had a significantly greater complete response rate after the first course of induction therapy compared with those in the HDD arm (66.7% vs. 61.1%, respectively; odds ratio, 1.23; P = .04; I2 = 0%). A significantly lower rate of refractory AML was also observed in the IDA group than in the HDD group (16.8% vs. 20.7%, respectively; odds ratio, 0.77; P = .04; I2 = 0%). However, no difference was found in the long-term overall survival between the 2 groups. Also, the induction mortality rate, febrile neutropenia rate, and cardiotoxicity rate were not significantly different between the 2 groups. The major limitation was the relatively small number of included studies, which could have limited the power of the meta-analysis to demonstrate significant long-term benefits. ConclusionThe complete response rate after the first course of induction therapy was significantly greater among adult patients with AML who had received IDA as part of induction therapy compared with those who had received HDD.

Myeloid sarcoma without circulating leukemia mimicking gastrointestinal malignancy and lymphoma.

We present an unusual case of myeloid sarcoma with ascites and abdominal pain in which initial clinical, laboratory, and imaging studies suggested a gastrointestinal malignancy or lymphoma. Subsequent detection of leukemic ascites and blasts in a gastric, small bowel, and skin biopsy supported a diagnosis of myeloid sarcoma. Bone marrow biopsy revealed 15% blasts, and cytogenetics with an inversion 16 rearrangement was diagnostic of acute myeloid leukemia (AML). Positron emission tomography-computed tomography performed at presentation to stage a presumptive lymphoma found later utility in following the burden of extramedullary disease. Standard AML induction chemotherapy resulted in complete remission and was followed by three rounds of high dose cytarabine consolidation. The patient unfortunately relapsed leading to re-induction followed by allogeneic stem cell transplantation. This report describes the presentation, assessment, and management of myeloid sarcoma.

Infectious complications in adults undergoing intensive chemotherapy for acute myeloid leukemia in 2001-2005 using the Japan Adult Leukemia Study Group AML201 protocols.

The Japan Adult Leukemia Study Group (JALSG) AML201 protocols are regimens for remission induction and consolidation chemotherapy of acute myeloid leukemia (AML) and have been widely accepted in Japan since 2001. Management of infectious complications during chemotherapy has a key role in the supportive care of AML patients. By using case report forms collected in December 2001 and December 2005, we retrospectively analyzed the infectious complications in adult patients treated by using the JALSG AML201 protocols against AML (excluding promyelocytic leukemia). Of 980 patients, 80.2% experienced febrile neutropenia (FN), 8.3% bacteremia/fungemia, and 10.3% pulmonary infection at least once during remission-induction chemotherapy. Gram-positive bacteremia accounted for 65.1% of bacteremia/fungemia in 2001-2005, compared with 38.2% in 1987-1991 and 45.9% in 1992-1995. Of 750 patients, 81.9% experienced FN, 21.9% bacteremia/fungemia, and 9.1% pulmonary infection at least once during consolidation chemotherapy. During consolidation chemotherapy, bacteremia/fungemia and pulmonary infection were significantly more frequent in the high-dose cytarabine (HDAC) arm than in the conventional multiagent arm (25.9 vs. 17.9% and 12.7 vs. 7.7%, respectively). Invasive pulmonary aspergillosis accounted for 15.8% of pulmonary infections during remission induction and 19.7% during consolidation chemotherapy. Our data suggest that patterns of infectious complications have changed between 1987 and 2005, possibly because of chemoprophylaxis with oral fluoroquinolones and improved diagnosis of invasive pulmonary aspergillosis by serum antigen analysis.