Acute Myeloid Leukemia Regimens Research Articles

Low Intensity Salvage Therapy after Failure of Standard (7 +3) Induction Regimen in Acute Myeloid Leukemia (AML). a Single Center Experience from United Arab Emirates

Hypomethylating agent (HMA) and venetoclaxR as salvage therapy for Acute Myeloid Leukemia (AML) failing intensive induction therapy. A single center experience from United Arab Emirates. Introduction: Patients with AML who are younger and fit for therapy are treated with intensive chemotherapy. Complete remissions (CRs) range from 40-80% (Kantarjian, Blood vol. 116,22 (2010): 4422-9). Non-CR patients can be treated with salvage therapy as a bridge to Allogeneic hematopoietic cell transplant (AlloHCT). Salvage regimens have included high dose cytarabine based therapies (FLAG, MEC, HAM) which can be more toxic limiting the use of AlloHCT. Lower intensity and more targeted therapy could decrease toxicity with improved responses. We describe our experience with a low intensity regimen as salvage treatment after failure of intensive induction therapy and bridge to AlloHCT. Methods: This is a retrospective analysis of AML patients treated at Tawam Hospital, UAE from 01/2019 to 06/2022. Patient data was collected from the medical records including: demographics, hemogram at presentation, bone marrow biopsies, karyotyping, treatment and response. Results: Eighty patients were diagnosed with AML during this period. The median age was 45 years (range 16-95 years). Fifty-seven patients received therapy while twenty-three patients refused or were not eligible due to comorbidities and / or performance status. Intensive chemotherapy (infusional cytarabine and idarubicin 7+3 or FLAG) was used for thirty-three patients. The median age was 35 years (range 16 - 63 years). Cytogenetics (Metaphase Karyotyping and FISH): normal, n=7; good risk n=6 (inv 16 or t (8;21), growth failure n=5, poor risk n=10 (Complex = 3, Del 7 = 3, 11q abnormalities = 3, trans 6;9 =1) other n=5. Molecular testing for NPMI, FLT3, IDH1 and IDH2 was not available. Three patients died during induction and are excluded from analysis. Fifteen patients attained CR after 1 cycle of induction (50%). Twelve patients not in CR received outpatient, low intensity salvage therapy with HMA (5 azacitidine 75 mg/m2 daily x 7 days subcutaneously with Venetoclax 100 mg orally daily x 21 days along with antimicrobial prophylaxis with azoles in 28 days cycles). Bone marrow was repeated after the second cycle. The median number of cycles is 3 (range 1-9). Eight (67 %) achieved CR1. There were no treatment related deaths. This is comparable to our report of FLAG salvage therapy (Hassan IB. Int J Hematol. 2018 Oct;108(4):390-401). Four of the eight patients who achieved remission went for AlloHCT while one is awaiting AlloHCT. One patient is unable to go for HCT and is in remission after 9 cycles of therapy. Two patients after achieving CR relapsed and died of disease progression. With a median follow up of 123 days (range 33 -1107 days) five patients are alive and in remission, one has been lost to follow-up while the other six have died from progressive disease and complications. Conclusion. Low Intensity therapy with HMA and Venetoclax is a reasonable and effective alternative to intensive chemotherapy as first line salvage with minimal morbidity and zero treatment related mortality. Treatment was well tolerated and no patients required hospitalization for complications. This regimen is easily administered as an outpatient, serving as a bridge to AlloHCT

Long-Term Follow-up of AML Patients Treated Intensively before the Era of Targeted Agents. a Big Data Analysis from the Harmony Collaboration

Background: Due to better understand of biology of acute myeloid leukemia (AML), in 2017 a new era of targeted therapy has began. Before that, since 1973 younger and fit patients were offered the 3+7 regimen (based on anthracyclines and cytarabine) followed by high-dose cytarabine and, generally allogeneic stem cell transplantation in first complete remission (alloHSCT). In 2008 azacytidine, a hypomethylating (HM) agent was approved in Europe for AML patients, who were not candidate for intensive therapy and alloHSCT. In 2010 the European LeukemiaNet (ELN), based on cytogenetic and molecular genetic characteristics, proposed a risk score classification to facilitate decisions, including indications for alloHSCT. In addition to these advances, improved supportive therapies over the last 25 years are thought to have lowered therapy associated mortality. Aims: We aimed to analyse changes in outcome of AML patients treated between 1997-2016 prior to the approval of novel drugs, in order to better understand important factors contributing to patient outcome that might also contribute to the efficacy novel treatment approaches. Methods: Quality controlled, Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) harmonized data of the HARMONY alliance database coming from 100 organisations in 18 European countries were used for this study. Out of all AML records, 5359 patients diagnosed and treated with intensive regimens between 1997-2016 were identified. Patients treated with intensive regimens were identified regardless from age by the type of chemotherapy (n=4287) or by the age ≤70 (n=1072) if there was no information concerning the therapy. Patients with acute promyelocytic leukemia and those treated with targeted therapy were excluded from the analysis. Patients were categorized into 4 calendar periods: 1997-2001 (gr1), 2002-2006 (gr2), 2007-2011 (gr3) and 2012-2016 (gr4). The main outcome parameters analyzed were patient characteristics, overall survival (OS) and relapse-free survival (RFS). OS and RFS were determined using Kaplan-Meier analysis. Results: 5359 AML patients were included into the analysis: 1127 in gr1, 1294 in gr2, 1821 in gr3 and 1117 in gr4. The median follow-up of all patients was of 1.9 [0-17.6] while of those who survived of 5.8 [0-17.6] years. 46.6% of patients were female. The median age of all patients was 53 years (18-85). There were 3745 patients <60, 1229 between 60-69 and 385 ≥70 years old. There were no differences in ELN risk between groups. Intensive regimens in ≥70 years AML, were less frequent through calendar period: 12% in gr1 vs 6% in gr2 vs 6% in gr3 vs 7% in gr4. AlloHSCT was performed in first remission in 1770 (33%) patients and according to calendar period: 24.1% in gr1, 37.5% in gr2, 39% in gr3, and 27% in gr4 (p<0.001). OS significantly improved over the time: 15.5 (95CI: 13.8-17.6) in gr1 vs 26.3 (23.7-31.6) in gr2 vs 39.3 (32.5-47.1) in gr3 vs 37.8 (31.6-49.2) months in gr4 (p<0.001). The OS improvement was observed for both sexes, across all 4 calendar periods, but mostly for women: 32.4 (28.8-37.8) vs 25.0 (22.5-27.7) months (p<0.001). A significant improvement in OS across the four groups was observed in AML with alloHSCT: 33 (26-56.8) vs 45.4 (34.1-65.6) vs 63 (46-not-reached) months, with group 4 not yet reaching median survival, Fig A. Interestingly, the median age to perform alloHSCT in group 1 was of 42.1 (18 - 71), while in group 2, 3 and 4 it was 46.9 (16 - 69) vs 49.9 (17 - 75) and 53 (18 - 77) years, respectively (p=0.028), Fig B. Conclusion: Here we report the results of a large cohort of AML patients intensively treated between 1997-2016. Improvement of survival was observed for patients treated between 2007-2016 vs 1997-2007 in parallel with performing alloHSCT at more advanced age, most likely due to better supportive care and a greater proportion of reduced-intensity conditioning alloHSCT. As the majority of AML patients are diagnosed at advanced age, alloHSCT should be considered a curative treatment option. Less frequency of intensive regimens in elder AML since 2002 could be related with introduction of HM agents. Less number of alloHSCT in gr4 most likely represents a bias of our data base or could be related to better patient's selection (ELN criteria) and need to be analysed in a further study. The better improvement in OS in women could be explained by the fact that globally, including AML, women live longer than men. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Targeted activation of GPER enhances the efficacy of venetoclax by boosting leukemic pyroptosis and CD8+ T cell immune function in acute myeloid leukemia

Acute myeloid leukemia (AML) is a rapidly progressing and often fatal hematopoietic malignancy. Venetoclax (VEN), a recent FDA-approved BCL-2 selective inhibitor, has high initial response rates in elderly AML patients, but the majority of patients eventually acquire resistance. Multiple studies have demonstrated that the female sex is associated with better outcomes in patients with AML, which are predominantly attributed to estrogen signaling. As a novel membrane estrogen receptor, G protein-coupled estrogen receptor (GPER)-mediated-rapid estrogen effects have attracted considerable attention. However, whether targeting GPER enhances the antileukemic activity of VEN is unknown. In this study, we first demonstrated that GPER expression was dramatically reduced in AML cells owing to promoter hypermethylation. Furthermore, pharmacological activation of GPER by G-1 combined with VEN resulted in synergistic antileukemic activity in vitro and in vivo. Mechanistically, G-1/VEN combination synergistically triggered concurrent mitochondria-related apoptosis and gasdermin E (GSDME)-dependent pyroptosis by activating p38-MAPK/myeloid cell leukemia 1 (MCL-1) axis. Importantly, leukemic pyroptosis heightened CD8+ T cell immune function by releasing interleukin (IL)-1β/18 into the tumor microenvironment. Our study corroborates that GPER activation shows a synergistic antileukemic effect with VEN, making it a promising therapeutic regimen for AML.

Two-drug versus three-drug induction chemotherapy in pediatric acute myeloid leukemia: a randomized controlled trial

The benefit of three-drug induction chemotherapy over a two-drug induction has not been evaluated in pediatric acute myeloid leukemia (AML). We, therefore, conducted a randomized controlled trial to ascertain the benefit of a three-drug induction regimen. Patients aged 1–18 years with newly diagnosed AML were randomized to two cycles of induction chemotherapy with daunorubicin and ara-C (DA) or two cycles of ara-C, daunorubicin, and etoposide (ADE). After induction, patients in both arms received consolidation with two cycles of high-dose ara-C. The study’s primary objective was to compare the event-free survival (EFS) between the two arms. The secondary objectives included comparing the composite complete remission (cCR) rates, overall survival (OS), and toxicities. The study randomized 149 patients, 77 in the DA and 72 in the ADE arm. The median age was 8.7 years, and 92 (62%) patients were males. The median follow-up was 50.9 months. The cCR rate in the DA and ADE arm were 82% and 79% (p = 0.68) after the second induction. There were 13 (17%) induction deaths in the DA arm and 12 (17%) in the ADE arm (p = 0.97). The 5-year EFS in the DA and ADE arm was 34.4% and 34.5%, respectively (p = 0.66). The 5-year OS in the DA and ADE arms was 41.4% and 42.09%, respectively (p = 0.74). There were no significant differences in toxicities between the regimens. There was no statistically significant difference in EFS, OS, CR, or toxicity between ADE and DA regimens in pediatric AML. The trial was registered with the Clinical Trial Registry of India (Reference number: CTRI/2014/11/005202).

Retrospective analysis of three induction chemotherapy regimens in acute myeloid leukemia including CPX-351, cytarabine/daunorubicin with and without the addition of cladribine

Recently new treatments for acute myeloid leukemia (AML) emerged, including regimens like CPX-351 and cladribine with cytarabine and daunorubicin (DA + C), demonstrating improved survival in patient subsets. This retrospective analysis is comparing the outcome of 124 patients treated with cytarabine and daunorubicin (DA; n = 54), CPX-351 (n = 26) and DA + C (n = 44). Complete response rate following one cycle of therapy was increased in DA + C (62%) compared to CPX-351 (42%) and DA (50%). CPX-351 demonstrated a significant increased survival post allogenic stem cell transplantation against DA (hazard ratio (HR): 4.9; 95% confidence interval (95%CI): 1.1–21, p = 0.03). Median survival was reached for DA (5.6 years) but not for DA + C or CPX-351. Subgroup analysis showed that AML with myelodysplasia-related changes and therapy-related AML treated with CPX-351 had increased survival compared to DA (HR: 5.2; 95%CI: 1.2–22; p = 0.03). Our findings point twoards a CPX-351 superiority. However, the use of DA + C should be further evaluated in comparative studies.

How I Diagnose Acute Leukemia of Ambiguous Lineage.

Classification of acute leukemia involves assigning lineage by resemblance to normal progenitor cells. This approach provides descriptive information about the blast cells that is useful for disease monitoring, provides clues to pathogenesis, and can help clinicians select effective chemotherapeutic regimens. Acute leukemias of ambiguous lineage (ALALs) are those leukemias that either fail to show evidence of myeloid, B-, or T-lymphoid lineage commitment or show evidence of commitment to more than 1 lineage. The different treatment regimens for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) make ALAL a challenge both diagnostically and therapeutically. Current classification criteria have reduced the reported incidence of mixed-lineage leukemias by emphasizing fewer markers and categorizing some biphenotypic leukemias with recurrent cytogenetic abnormalities as other entities. Several recent studies have explored the genomic and epigenetic landscape of mixed-phenotype acute leukemia (MPAL) and have suggested a further refinement of the World Health Organization classification to emphasize the genomic heterogeneity of MPAL. Genomic and expression profile data for MPAL reveal mutations commonly seen in both AML and ALL, with T-/myeloid MPAL showing overlapping features with early T-cell precursor lymphoblastic leukemia. Our review aimed to discuss the diagnostic challenges, recent genomic studies, and therapeutic strategies in this poorly understood disease.

A novel HNRNPH1::ERG rearrangement in aggressive acute myeloid leukemia.

FUS::ERG rearrangement is a recurrent abnormality seen in a subgroup of acute myeloid leukemia (AML) with a poor prognosis. We described here a novel HNRNPH1::ERG rearrangement in a de novo AML. The patient was unresponsive to routine chemotherapy and succumbed to the disease just 3 months after diagnosis. Two additional cases of AML with HNRNPH1::ERG rearrangement were discovered by searching a publicly available sequencing database. The three patients share several clinical phenotypes with the FUS::ERG rearranged AML, including high blast count at diagnosis, pediatric or young adult-onset, and poor overall survival. In addition, hnRNPH1 and FUS are both hnRNP family members, a group of RNA-binding proteins functioning in RNA metabolism and transport. Therefore, we suggest that patients with HNRNPH1::ERG or FUS::ERG rearrangement belong to the same distinct clinicopathologic subtype of AML, that is, AML with ERG rearrangement. Based on a previous study showing that FUS::ERG binds to the retinoic acid-responsive elements and that all-trans retinoic acid-induced cell differentiation of AML cells, we support the clinical evaluation of an APL-like therapeutic regimen for AML with ERG rearrangement.

Research Advance of Gene Mutation and Targeted Drug Therapy in Childhood Acute Myeloid Leukemia --Review

The clinical therapeutic regimen for acute myeloid leukemia (AML) is not significantly different between adults and children, which is mostly based on IA (idarubicin and cytosine arabinoside) induction chemotherapy. With the rapid development of sequencing technique, people's understandings towards the molecular and biological abnormalities of AML are increasing, diverse AML gene mutation-based targeted drugs have been rapidly developed and applied. In this review, several commonly gene mutations in AML (such as FLT3, NPM1 and C/EBPA) was described, and the therapeutic effects and differences of targeted drugs that used in clinical treatment or had been reported (like tyrosine kinase inhibitor, IDH1 mutation inhibitor and epigenetic modification inhibitor) in child and adult AML patients were summrized.

Chidamide and Decitabine in Combination with a HAG Priming Regimen for Acute Myeloid Leukemia with TP53 Mutation.

We analyzed the treatment effects of chidamide and decitabine in combination with a HAG (homoharringtonine, cytarabine, G-CSF) priming regimen (CDHAG) in acute myeloid leukemia (AML) patients with TP53 mutation. Seven TP53 mutated AML patients were treated with CDHAG. The treatment effects were assessed using hemogram detection and bone marrow aspirate. The possible side effects were evaluated based on both hematological and non-hematological toxicity. Four of the seven patients were classified as having achieved complete remission after CDHAG treatment; one patient was considered to have achieved partial remission, and the remaining two patients were considered in non-remission. The overall response rate (ORR) to CDHAG was 71.4%. Regarding the side effects, the hematological toxicity level of the seven patients ranged from level III to level IV, and infections that occurred at lung, blood, and skin were recorded. Nausea, vomiting, liver injury, and kidney injury were also detected. However, all side effects were attenuated by proper management. The CDHAG regimen clearly improved the ORR (71.4%) of TP53-mutated AML patients, with no severe side effects.

How We Incorporate Venetoclax in Treatment Regimens for Acute Myeloid Leukemia.

Venetoclax has transformed the therapeutic landscape of acute myeloid leukemia (AML). Hypomethylating agents with venetoclax (HMA-VEN) have significantly improved outcomes and have become the standard therapy for older/unfit patients with newly diagnosed AML and are comparable to intensive chemotherapy in salvage setting. Venetoclax with intensive chemotherapy have shown high response rates in both frontline and salvage setting in younger patients, and triplet combinations with HMA-VEN and FLT3 inhibitors have shown encouraging results in FLT3mut AML. While patients with NPM1mut, IDH1/2mut experience favorable outcomes, those with TP53mut and secondary AML may experience minimal benefit from the addition of venetoclax. Despite improved outcomes, severe cytopenias and infectious complications are common with venetoclax-based regimens. Early response evaluation, dose reductions, venetoclax interruptions, use of growth factors, and prophylactic antimicrobials may minimize such myelosuppression and risk of infections. Outcomes after failure of frontline HMA-VEN are dismal, and novel approaches are needed to abrogate primary and acquired resistance.

The "7+3" regimen in acute myeloid leukemia.

The "7+3" regimen in acute myeloid leukemia.

Combining Isocitrate Dehydrogenase Inhibitors With Existing Regimens in Acute Myeloid Leukemia: An Evolving Treatment Landscape.

Identification of recurrent mutations in isocitrate dehydrogenase genes (IDH1 and IDH2) in patients with acute myeloid leukemia (AML) coupled with an understanding of the pathologic role these mutant IDH isoforms impart in leukemogenesis resulted in the development of IDH1 and IDH2 inhibitors comprising a novel, molecularly defined class of targeted therapies for the treatment of AML. This review herein describes the unique cellular pathophysiology and vulnerabilities in IDH-mutated AML; the clinical development, efficacy, and known resistance mechanisms to first-generation IDH inhibitors; summarizes the literature surrounding combination therapies incorporating targeted or cytotoxic therapies with IDH inhibitors in patients with IDH-mutated AML; and identifies future challenges and areas of active ongoing investigation within this molecular subgroup.

The Prognostic Value of Early Measurable Residual Disease Assessment in Patients with Acute Myeloid Leukemia Treated with Intensive Chemotherapy - Preliminary Results of Polish Adult Leukemia Group PALG-AML1/2016 Study

Background: Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML). Among patients who achieve remission after standard chemotherapy, detection of MRD (MRD+) after two cycles of intensive chemotherapy, at the end of consolidation and before allogeneic stem cell transplantation (alloHSCT) is a strong prognostic factor for relapse and shorter overall survival (OS) (Short NJ, JAMA Oncol. 2020). The optimal time-points to asses MRD, and MRD cut-offs as well as whether eliminating of MRD due to further chemotherapy improves an outcome still remain open questions. PALG-AML1/2016 study aims to compare the safety and efficacy of two commonly used induction and salvage regimens in AML (NCT03257241). This is also the first international randomized trial in AML induction to prospectively evaluate the impact of MRD on overall survival, using multi-modality testing (flow-cytometry, FC; next-generation sequencing, NGS) of serial samples.Study Design: In this study, 582 adult patients with newly-diagnosed AML will be randomized to DA-90 or DAC induction. Patients with complete remission (CR) or CR with incomplete hematologic recovery (CRi) receive further post-remission therapy adjusted to predefined risk group. The serial samples for multimodal MRD evaluation are collected at D14 (MRD-1), at time of CR/CRi after single or two induction cycles (MRD-2), and after each consolidation cycle (MRD-3, -4, -5).Material and Methods. The aim of this preliminary analysis was to evaluate the prognostic value of bone marrow assessment at D14 both cytological and by FC (MRD-1) as well as the kinetics of MRD during post-remission treatment. Multivariable logistic regression models were developed with significant variables from univariate analyses, including MRD and blast count. The predictive power of the MRD level and blasts percentage at D14 was evaluated by receiver operating characteristics (ROC) and area under the curve (AUC) analysis to determine the ability of the biomarkers to accurately predict response to the induction treatment.Results: The study group consisted of 284 patients (mean age: 47.1 ± 10.9) recruited until the end of May 2021. MRD-1 by FC was reported in 225 patients. CR and CRi either after single or double induction were achieved in 175 (61.6%) and 48 (16.9%) patients, respectively leading to an overall CR/CRi rate 78.5%. In univariate analyses, the factors significantly associated with achieving CR/CRi were: ELN high-risk group (OR 0.12, 95% CI: 0.05-0.33, p<0.0001), percentage of blasts at D14 (OR 0.95, 95% CI: 0.93-0.97, p<0.0001) and MRD-1 level (OR 0.94, 95% CI: 0.92-0.96, p<0.0001). A ROC analysis showed that AUC for the blasts count (0.71, 95%CI: 0.61-0.80) was significantly lower (p=0.0028) than AUC for MRD-1 levels 0.81 (95%CI: 0.74-0.89). Furthermore, two multivariate models, including ELN high-risk group and blasts or MRD biomarker, were evaluated. The model with blast percentage had an AUC of 0.83 (95% CI: 0.76-0.91). The model with MRD-1 level yielded higher AUC (p=0.0039) of 0.90 (95% CI: 0.84-0.95) and had a lower Akaike information criterion (116.9 vs. 127.1), indicating a better-fit model. In the analyzed group MRD-2 <0.1% did not have a predictive value for OS.MRD-3 at the end of consolidation 1 was reported in 182 patients: MRD+ in 99 (54.4%) and MRD- in 83 (45.6%) patients. Results of MRD-4 at the end of consolidation 2 were available in 114 patients with 49 (43.0%) being MRD+ and 65 (57.0%) MRD-. Fifty-eight patients (35 MRD-2+ and 23 MRD-2-) were evaluated for MRD kinetics from the end of induction until the end of consolidation 3. Conversion rate from MRD- to MRD+ was 13% (n=3) and from MRD+ to MRD- 34%(n=12), respectively (p=0.038).Conclusions: Our preliminary results suggest that flow cytometric bone marrow assessment on D14 has a predictive value for CR/CRi achievement and a potential prognostic utility for overall survival. The kinetics of MRD during consolidation requires further studies to better evaluate its prognostic significance.

Differential Outcomes of Salvage with FLAG-IDA and Venetoclax-Based Regimens in Relapsed and Refractory Acute Myeloid Leukemia

Background: Sequencing and selection of salvage regimens for acute myeloid leukemia (AML) remains unclear. Venetoclax augmentation of a hypomethylating agent (HMA) backbone has joined the salvage armamentarium following impressive performance in the front-line setting. However, little is known about the outcomes with venetoclax in relapsed and refractory (R/R) AML. Survival and toxicity data remain scarce for venetoclax-based salvage, particularly when compared to intensive reinduction. This study characterizes outcomes between venetoclax-based salvage regimens and FLAG-IDA in the R/R setting.Patients & Methods: We retrospectively analyzed all patients with AML treated at Massey Cancer Center younger than 65 in the R/R setting with either FLAG-IDA (fludarabine, cytarabine, G-CSF, and idarubicin) or venetoclax in combination with decitabine, azacitidine, or low-dose cytarabine from June 2018 to December 2020. Baseline patient demographics and disease characteristics were obtained and recorded in RedCap. Statistical analyses using unpaired t-test with Welch's correction or the Mann-Whitney test, Fischer's exact test, and Kaplan-Meier survival analyses were computed and compared with log-rank tests using GraphPad Prism. The event for calculating the overall survival was the date of death with patients otherwise censored at the date of last contact.Results: Twenty-eight patients were identified meeting inclusion criteria: 19 underwent salvage with venetoclax-based regimens and 9 patients were treated with FLAG-IDA. Five patients (55.6%) in the FLAG-IDA cohort underwent salvage for refractory disease (primary induction failure), compared to only two (10.5%) in the venetoclax group, which was statistically significant (p = 0.019). The remaining patients in both cohorts were treated in the relapsed setting. There was no significant difference in sex (p = >0.999), ECOG performance status at diagnosis (p = 0.083), or Charlson Comorbidity Index (CCI) scores (p = 0.128). The median age of patients treated with FLAG-IDA was 39 (range: 24 - 62), the four most common molecular mutations in the FLAG-IDA cohort occurred at a frequency of 22.2% each: FLT3-ITD, NPM1, WT1, and biallelic CEBPA. Two patients (22.2%) had favorable cytogenetics at diagnosis, one (11.1%) had intermediate cytogenetics, five (55.6%) had adverse cytogenetics, and one was unknown. All were initially treated with a 7+3 backbone. The most common non-hematological toxicities were neutropenic fever (55.6%) and acute kidney injury (22.2%). Five (55.6%) achieved CR and one (11.1%) achieved CRi for an ORR of 66.7%. There were no deaths within 60 days of salvage. Five (55.6%) patients went on to receive allogeneic SCT. Median survival was not reached at a median follow-up of 430 days (14.1 months).In the venetoclax-based cohort of 19 patients, the median age was 58 (range: 23 - 65), At the time of initial diagnosis, the most common molecular aberrations were TP53 (26.3%), NPM1 (15.7%), followed by FLT3-TKD, RUNX1, and TET2 (10.5% each). Two (10.5%) patients had favorable cytogenetics at initial diagnosis, two (10.5%) had intermediate, 14 (73.7%) had adverse cytogenetics, and one patient had unknown cytogenetics. Seventeen (89.5%) patients were initially treated with 7+3, one (5.3%) was treated with azacitidine, and one (5.3%) was treated with CPX-351. The most common non-hematological toxicities were infection (42.1%), neutropenic fever (31.6%), and GI toxicity (15.8%). Two (10.5%) patients achieved CR and four (21.1%) achieved CRi for an ORR of 31.6%. There were 3 deaths in 30 days and 1 death within 60 days. Four (21.1%) went on to receive allogeneic SCT after venetoclax-based salvage. The median survival was 268 days (8.81 months) and was statistically significant from the FLAG-IDA cohort (p = 0.0029).Conclusion: Our results suggest the efficacy of FLAG-IDA compared to venetoclax-based regimens with respect to ORR, survival, toxicity, and progression to transplant in the R/R setting for presumable intensive induction candidates, as evidenced retrospectively by prior receipt of such regimens. These differences may be impacted by changes to disease biology between the relapsed and refractory settings and TP53 status. Larger prospective studies with separate analyses between the relapsed and refractory settings are needed to confirm these findings. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Outcomes of Transplant-Eligible Patients with Myelodysplastic Syndrome-Refractory Anemia with Excess Blasts Registered in a Prospective Observational Study: The JALSG-CS11-MDS-SCT

Outcomes of Transplant-Eligible Patients with Myelodysplastic Syndrome-Refractory Anemia with Excess Blasts Registered in a Prospective Observational Study: The JALSG-CS11-MDS-SCT

Venetoclax Plus Azacitidine (VEN-AZA) Vs. Intensive Chemotherapy (IC) As Induction for Patients with Acute Myeloid Leukemia (AML): Retrospective Analysis of an Electronic Medical Records (EMR) Database in the United States

Venetoclax Plus Azacitidine (VEN-AZA) Vs. Intensive Chemotherapy (IC) As Induction for Patients with Acute Myeloid Leukemia (AML): Retrospective Analysis of an Electronic Medical Records (EMR) Database in the United States

Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia with Hyperdiploid Complex Karyotype: A Study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Introduction: Cytogenetics remains one of the most important prognostic factors in acute myeloid leukemia (AML) patients, even for outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Complex karyotype (CK) constitutes a cytogenetic category with a very adverse prognosis in this setting. However, CK is a heterogenous and loosely defined category which comprises a high diversity of cytogenetic subtypes, which is highly enriched with specific cytogenetic subtypes characterized by losses of chromosomal material at critical regions known to confer a poor prognosis per se, such as monosomal karyotype, del(7q)/-7, del(5q)/-5 or abnormalities leading to 17p region loss. On the contrary, rare AML cases characterized with only multiple numerical abnormalities known as pure hyperdiploid karyotype (HDK), have a controversial prognosis. We hypothesized that pure complex HDK AML has a distinct and much better prognosis after allo-HCT compared to non-HDK, CK AML.Methods: We selected from the EBMT registry adult patients with AML and a full cytogenetic report. HDK was defined by the presence of 49 chromosomes or more. Patients were then stratified by pure HDK (pHDK) and HDK with other cytogenetic abnormalities (HDK+), characterized by HDK and the presence of a prognostic-defining cytogenetic abnormality such as del(5q)/-5, del(7q)/-7, del(17p)/-17/i(17q), inv(3q21-26)/t(3;3)(q21;q26) or t(9;22). We included only first allo-HCT from a sibling or unrelated donor (UD) performed between 2000 and 2018.Results: A total of 236 patients were identified as having HDK. There were 95 pHDK and 141 HDK+. Median age at transplantation was 53 years (range, 18-74) and median follow-up was 43 months (range, 35-56). A diagnosis of secondary AML was reported in 48 patients (20%). At the time of allo-HCT, 180 patients (76%) were in first remission (CR1), and 56 were beyond CR1 (24%). Eighty-five (39%) patients received an allo-HCT from a sibling donor, with more matched unrelated donors (MUD) in HDK+ patients (p=0.02). Most patients (70%) had a Karnofsky performance status (KPS) score of more than 90% at the time of transplantation. A myeloablative conditioning regimen was administered in 46% of the patients. In vivo T-cell depletion was part of the regimen in 66% of the patients. The most frequent trisomies were trisomy 8, 21, 13, and 22.The 2-year probability of non-relapse mortality (NRM) was 26% for the entire cohort. The 2-year probability of LFS was 50% for pHDK and 31% for HDK+ (p=0.003). The 2-year probability of overall survival (OS) was 57% for pHDK and 36% for HDK+ (p=0.007). The 2-year cumulative incidence of relapse (RI) was 22% for pHDK and 44% for HDK+ (p=0.001) (Figure 1). The cumulative incidence of grade II-IV acute graft-versus-host disease (GvHD) and chronic GvHD was 34% and 33%, respectively, for the entire cohort. Finally, the 2-year probability of GvHD and relapse-free survival (GRFS) was 36% for pHDK and 21% for HDK+ (p=0.01). On multivariate analysis, pHDK remained associated with significantly better LFS, OS and GRFS and higher RI (all p-values<0.004). Age was associated with lower OS (p=0.05). Being in remission at the time of allo-HCT was associated with better LFS, OS and GRFS, and lower NRM and RI (all p-values<0.02). Secondary AML, donor type, KPS, and conditioning regimen intensity were not associated with any outcome in multivariate analysis.Conclusions: AML with pHDK has a better outcome after allo-HCT in terms of RI, LFS, OS and GRFS. pHDK AML constitutes probably a distinct cytogenetic entity from HDK+ or other non-hyperdiploid CK AML. CK remains a strong indication for allo-HCT, but the type of abnormalities included in CK significantly influences the outcome and should guide how to manage patients after allo-HCT in terms of immunosuppression withdrawal or prophylactic/preemptive post-transplant interventions such as use of hypomethylating agents or donor lymphocyte infusions. [Display omitted] DisclosuresLabopin: Jazz Pharmaceuticals: Honoraria. Ganser: Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Socie: Alexion: Research Funding. Forcade: Novartis: Other: travel grant. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Esteve: Jazz: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Abbvie: Consultancy; Novartis: Consultancy, Research Funding; Astellas: Consultancy; Pfizer: Consultancy; Novartis: Research Funding. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

Aspacytarabine (BST-236) As Monotherapy Is Safe, Well-Tolerated and Effective for the Treatment of Adults with Newly Diagnosed Acute Myeloid Leukemia Unfit for Intensive Therapy. Results of a Phase 2 Study

Aspacytarabine (BST-236) As Monotherapy Is Safe, Well-Tolerated and Effective for the Treatment of Adults with Newly Diagnosed Acute Myeloid Leukemia Unfit for Intensive Therapy. Results of a Phase 2 Study

Retrospective Analysis of the Outcomes of Patients with Relapsed/Refractory Acute Myeloid Leukemia Included in a Patient Named Program of Gemtuzumab Ozogamicin

▪Introduction: In 2010 the French Health Agency opened a compassionate patient named program of gemtuzumab ozogamicin (GO, Mylotarg®) in relapsed/refractory (R/R) patients with acute myeloid leukemia (AML). Of note, since 2012, it was recommended to use GO at the dose of 3 or 6 mg/m 2 in addition to chemotherapy. We conducted a retrospective trial (NCT03287128) to evaluate the efficacy and the safety of GO-based regimen in R/R adult AML patients.Patients and methods: We retrospectively collected data of patients older than 18 years treated with GO-based regimen for AML in first relapse or for refractory AML, defined by failure after a prior standard intensive chemotherapy, in 18 French centers between December 15, 2011 and November 10, 2016. The primary objective was to assess the response to GO-based regimen. Patients were considered in response if reaching complete remission (CR), CR without platelet recovery (CRp) or CR with incomplete hematological recovery (CRi). Secondary objectives were the cumulative incidence of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the safety of the use of GO-based regimen.Results: Three hundred and thirty-five adult patients with R/R AML were included. Median age was 58 years (20 to 80 years). At diagnosis, cytogenetics was favorable in 50 (17%) patients, intermediate in 173 (59%) and adverse in 60 (20%). ELN distribution was favorable: 35%, intermediate: 42% and unfavorable: 23%. NPM1 mutation was present in 29% of patients and FLT3 mutation in 23%. Most patients had de novo AML (84%). Two hundred and thirty-eight patients (79%) were in first relapse and 65 (21%) had a refractory AML. The time between first diagnosis of AML and treatment with GO-based regimen was 4 to 16 months (median 9.4 months). Most patients (88%) received GO in combination with various intensive chemotherapy scheme including “7+3” with anthracycline/cytarabine (n=39 patients), intermediate and high-dose cytarabine (n=68), cytarabine in continuous intravenous infusion (n=78), mitoxantrone/cytarabine (n=49) and fludarabine/cytarabine and/or amsacrine and/or etoposide chemotherapy (n=35). Median follow-up time was 11 months.Among the 305 patients, 191 responded to GO-based regimen: 110 (36%) were in CR, 62 (20%) were in CRp and 19 (6%) in CRi for an overall response rate (CR+CRp+CRi, ORR) of 63%. In multivariate analysis, response was associated with age <50 years, de novo AML and relapse status. Among the 191 responders, 110 received additional courses of chemotherapy, 69 with GO. Main reason to not receive additional course (with or without GO) was allo-HSCT project. In the whole population, median overall survival (OS) after day 1 of treatment with GO was 11.2 months. In the population of responders, median OS after response was 20.4 months. In multivariate analysis, longer survival was associated with age < 50 years, de novo AML and favorable ELN group. Cumulative incidence of relapse at 24 months after response was 46%. One hundred and forty-seven patients received allo-HSCT, including 122 responders after GO-based regimen and 25 patients in treatment failure. Cumulative incidence of allo-HSCT at 18 months was 48%. Four-year OS was 48% in transplanted patients versus 19% in non-transplanted patients (Figure 1).Regarding safety of GO-based regimen, early deaths occurred within <30 days after the first dose of GO in 14 patients, and within <60 days in 35 patients. Myelosuppression was observed in all patients. Mean duration of thrombocytopenia <100 G/L was 35 days in responders. Bleeding grade 3 or more was observed in 22 patients (7%). Infection grade 3 or more was observed in 112 patients (30%). Sinusoidal obstruction syndrome (SOS) after GO treatment was reported in 6 patients, resolving in 4 of them. Four cases of fatal SOS were reported after allo-HSCT. Toxic deaths, i.e., not related to worsening leukemia, were reported in 20 patients after the first course of chemotherapy, 3 after additional courses and 33 after allo-HSCT.Conclusion. Our study is the first to report efficacy data in the real-world setting of R/R AML adult patients treated with GO-based regimen. In our cohort of 305 patients, response rate was 63% and GO-based regimen appears as a valuable bridge-to-transplant option. Safety analysis showed toxicities consistent with the known safety profile of GO and chemotherapy. [Display omitted] DisclosuresLambert: ASTELLAS: Consultancy; CELGENE/BMS: Consultancy. Pautas: PFIZER: Consultancy; ABBVIE: Consultancy. Raffoux: ASTELLAS: Consultancy; PFIZER: Consultancy; ABBVIE: Consultancy; CELGENE/BMS: Consultancy. Legrand: Servier: Consultancy. Gastaud: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; GSK: Consultancy. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Mathilde: SERVIER: Consultancy; ABBVIE: Consultancy. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Castaigne: PFIZER: Consultancy.

DJ4 Targets Rho-associated Protein Kinase Pathway and Attenuates Disease Progression in Pre-clinical Murine Models of Acute Myeloid Leukemia

Introduction: The poor prognosis of acute myeloid leukemia (AML) and the highly heterogenous nature of the diseasemotivates targeted gene therapeutic investigations. Rho-associated protein kinases (ROCKs) are crucial for variousactin cytoskeletal changes, which have established malignant consequences in various cancers, yet are still not beingsuccessfully utilized clinically towards cancer treatment. ROCK 1 and 2 overexpression has been linked to AML celllines and overall survival of AML patients. This work reports the considerable therapeutic efficacy of the ROCKinhibitor DJ4 in both in vitro and in vivo preclinical models of AML to highlight the potential of this class of inhibitors.Experimental Design: The cytotoxic and pro-apoptotic activities of DJ4 for primary human AML samples and humanAML cell lines was determined by cell viability (MTS), colony forming assays, and Annexin V assays. Immunoblotanalysis was used to detect phosphorylation of downstream substrates of ROCK. To assess the preclinical therapeuticefficacy, the luciferase-expressing human AML cell line OCIAML-3-YFP-Luc was injected subcutaneously (SC) andintravenously (IV) into NRG-S mice. Mice were treated through an intraperitoneal (IP) injection with either vehiclecontrol or DJ4 (10 mg/kg) for 3 weeks. Modified AML cell lines, OCI-AML3-YFP-Luc and MV4-11-Luc2-EGFP, werealso treated with their respective IC50 dose of DJ4 or with vehicle control for 24 h and then administered via IV intoNRG-S mice and the survival advantage was monitored over time without further treatment. Disease progression wastracked in mice studies by flow cytometry analysis and examining the survival, bioluminescent signal, tumor volume,and tumor weights of the animals over time.Results: DJ4 induced cytotoxic and pro-apoptotic effects, within the micromolar range and in a dose-dependentmanner, in human AML cell lines (IC50: 0.05-1.68 μM) and primary patient cells (IC50: 0.264-13.43 μM) that harboredvarious mutations; however, normal hematopoietic cells are largely spared (Figures A-C). Treatment of DJ4demonstrated ~5-fold selectivity towards AML patient samples relative to the CB-MNCs of healthy donors (IC50= 25μM, Figure B). Representative flow cytometry plots of the Annexin V assay with AML primary cells (Figure C) depictedthe increase in the apoptotic populations as a result of treatment with increasing concentrations of DJ4. ROCKinhibition by DJ4 disrupts the phosphorylation of downstream targets, myosin light chain (MLC2), and myosin bindingsubunit of MLC phosphatase (MYPT) in OCI-AML3 and MV4-11, yielding a potent yet selective treatment response atmicromolar concentrations, 0.02 to 1 μM (Figure D). Analysis of mice treated with DJ4 via IP for 2.5 weeks indicatedthat DJ4 was well-tolerated with comparable CBC with differential and chemistry values and tissue morphology fromcross-sections of the spleen, liver, lung, and kidney relative to the vehicle treated group. Mice that were IV or SCinjected with OCIAML3-YFP-Luc and treated via IP with DJ4 exhibited an increase in overall survival and reductionin disease progression relative to the vehicle treated control mice (Figure E). Towards the end of the study, theOCIAML3-YFP-Luc SC injected mice exhibited at least a 3-fold reduction in the bioluminescent signal, ~4-fold decreasein tumor volume, and the tumor weight was significantly reduced by ~3-fold among the DJ4 treated group relative tothe control (Figure E). Mice that were IV administered DJ4 pretreated AML cells also exhibited a decreasedbioluminescent signal, increased survival of 10 and 20 days, and a significant reduction in the percent of human CD45cells in the bone marrow or spleen, indicating a diminished tumor burden (Figure F).Conclusion:The observed potency of DJ4 towards various AML cell lines and primary samples with a diverse set of mutationssuggests that this is a promising candidate to be incorporated into the standard AML regimen to help many differentsubsets of AML patients. Therapeutics that induce apoptosis have been shown to be promising candidates towardovercoming chemoresistance and to work well with appropriate combinations of standard of care drugs. This workhighlights the potential of targeting the Rho-ROCK pathway to improve the prognosis of AML and the need for thefuture development of chemotherapeutics that are both less toxic and more effective. [Display omitted] DisclosuresClaxton: Astellas: Other: Clinical Trial; Novartis: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Daiichi Sankyo: Research Funding; Incyte: Research Funding.