Intensive Induction Chemotherapy versus Hypomethylating Agents in Combination with Venetoclax in NPM1-mutant AML.

While intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), data from older patients shows that hypomethylating agents + venetoclax (HMA/VEN) can lead to durable remissions among patients with NPM1 mutations. Whether IC or HMA/VEN is superior in patients ≥60 years-old with NPM1-mutant AML is unknown. To compare IC and HMA/VEN, we performed an international, multicenter retrospective cohort study of patients with newly diagnosed, NPM1-mutant AML.We included 221 patients (147 IC, 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR; defined as CR + CR with incomplete count recovery [CRi]) rate was similar for IC and HMA/VEN (cCR: 85% vs. 74%; p=0.067). While OS was favorable with IC in unselected patients compared to HMA/VEN (24-month OS 59% [95% CI: 52-69%] vs. 38% [95% CI 27-55%]; p=0.013), it was not statistically different among patients 60-75 years-old (60% [95% CI 52-70%] vs. 44% [95% CI 29-66%]; p=0.069) and patients who received an allogeneic stem cell transplant (70% [95% CI: 58-85%] vs. 66% [95% CI: 44-100%]; p=0.56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS with IC 65% [95% 56-74%] vs. 40% [95% CI: 26-60%] with HMA/VEN; p=0.009) and without FLT3-ITD mutations might benefit from IC compared with HMA/VEN (24-month OS: 68% [95% CI: 59-79%] vs. 43% [95% CI: 29-63%]; p=0.008). In multivariable analysis, OS was not statistically different for patients treated with IC and HMA/VEN (hazard ratio for death HMA/VEN vs. IC: 0.71; 95% CI: 0.40-1.27; p=0.25).

Prognostic impact of 'multi-hit' versus 'single hit' TP53 alteration in patients with acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases.

While there is clear evidence to suggest poorer outcome associated with multi-hit (MH) TP53 mutation compared to single-hit (SH) in lower-risk myelodysplastic syndrome (MDS), data are conflicting in both higher-risk MDS and acute myeloid leukemia (AML). We conducted an indepth analysis utilizing data from 10 US academic institutions to study differences in molecular characteristics and outcomes of SH (n= 139) versus MH (n= 243) TP53MTAML. Complex cytogenetics (CG) were more common in MH compared to SH TP53MT AML (p <0.001); whereas ASXL1 (p= <0.001), RAS (p<0.001), splicing factor (p= 0.003), IDH1/2 (p= 0.001), FLT3 ITD (p= <0.001) and NPM1 (p= 0.005) mutations significantly clustered with SH TP53MT AML. Survival after excluding patients who received best supportive care alone was dismal but not significantly different between SH and MH (event free survival [EFS]: 3.0 vs 2.20 months, p= 0.22/ overall survival [OS]: 8.50 vs 7.53 months, respectively, p= 0.13). In multivariable analysis, IDH1 mutation and allogeneic hematopoietic stem cell transplantation (allo-HCT) as a time-dependent covariate were associated with superior EFS (HR; 0.44, 95% CI: 0.19-1.01, p= 0.05/ HR; 0.34, 95% CI: 0.18-0.62, p<0.001) and OS (HR; 0.24, 95% CI: 0.08-0.71, p= 0.01/ HR; 0.28, 95% CI: 0.16-0.47, p<0.001). While complex CG (HR; 1.56, 95% CI: 1.01-2.40, p= 0.04) retained unfavorable significance for OS. Our analysis suggests that unlike in MDS, multihit TP53MT is less relevant in independently predicting outcomes in patients with AML.

Crenolanib and Intensive Chemotherapy in Adults With Newly Diagnosed FLT3-Mutated AML.

PURPOSE: Crenolanib is a second-generation tyrosine kinase inhibitor with activity against FLT3-ITD- and TKD-mutant AML. We conducted a trial of crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3-mutant AML. METHODS: Eligible patients were 18 years and older. Induction chemotherapy consisted of cytarabine (100 mg/m2) continuous infusion on days 1-7 and anthracycline (daunorubicin 60-90 mg/m2 or idarubicin 12 mg/m2, once daily) on days 1-3 followed by consolidation with high-dose cytarabine (1-3 g/m2 twice daily on days 1, 3, 5) and/or allogeneic transplant. Crenolanib (100 mg thrice a day) was given from day 9 until 72 hours before the next cycle, after consolidation, and for 12 months after consolidation or transplant. RESULTS: Forty-four patients (median age, 57; range, 19-75 years) were enrolled. Thirty-six had FLT3-ITD, and 11 had FLT3-TKD mutations. European LeukemiaNet 2017 disease risk was favorable in 34%, intermediate in 30%, and adverse in 36%. The overall response rate was 86% (complete remission [CR], 77%; CR with incomplete count recovery [CRi], 9%): 90% in patients 60 years and younger and 80% in older patients. Measurable residual disease-negative CR/CRi rates were 89% and 45%, respectively. With a 45-month follow-up, median overall survival has not been reached and the median event-free survival was 44.7 months. Among younger patients, the estimated 3-year survival was 71.4% with 15% cumulative incidence of relapse. Treatment-related serious adverse events included febrile neutropenia, diarrhea, and nausea. The median time to platelets ≥100,000/µL and absolute neutrophil count ≥1,000/µL during induction was 29 and 32 days, respectively. No new FLT3-mutant clones were detected at relapse in patients completing consolidation. CONCLUSION: Crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3-mutant AML results in high rate of deep responses and long-term survival with acceptable toxicity. A randomized trial of crenolanib versus midostaurin plus chemotherapy in younger patients is ongoing.

Hypomethylating agents plus venetoclax compared with intensive induction chemotherapy regimens in molecularly defined secondary AML.

Molecularly defined secondary acute myeloid leukemia is associated with a prior myeloid neoplasm and confers a worse prognosis. We compared outcomes of molecularly defined secondary AML patients (n = 395) treated with daunorubicin and cytarabine (7 + 3, n = 167), liposomal daunorubicin and cytarabine (CPX-351, n = 66) or hypomethylating agents (HMA) + venetoclax (VEN) (n = 162). Median overall survival (OS) was comparable between treatment groups among patients aged >60 years. In a multivariable model HMA + VEN vs. 7 + 3 was associated with better OS (hazard ratio [HR] 0.64 [95% confidence interval (CI) 0.42-0.98, p = 0.041]), whereas CPX-351 vs. 7 + 3 was not (HR 0.79 [CI 95% 0.50-1.25, p = 0.31]). Allogeneic hematopoietic stem cell transplantation, BCOR and IDH mutations were associated with improved OS; older age, prior myeloid disease, NRAS/KRAS mutations, EZH2 mutation, and monosomal karyotype were associated with worse OS. When analyzed in each treatment separately, the IDH co-mutations benefit was seen with 7 + 3 and the detrimental effect of NRAS/KRAS co-mutations with HMA + VEN and CPX-351. In pairwise comparisons adjusted for age, HMA + VEN was associated with improved OS vs. 7 + 3 in patients with SF3B1 mutation and improved OS vs. CPX-351 in those with RNA splicing factor mutations. In molecularly defined secondary AML treatment with HMA + VEN might be preferred but could further be guided by co-mutations.

Single-cell genotypic and phenotypic analysis of measurable residual disease in acute myeloid leukemia.

Measurable residual disease (MRD), defined as the population of cancer cells that persist following therapy, serves as the critical reservoir for disease relapse in acute myeloid leukemia and other malignancies. Understanding the biology enabling MRD clones to resist therapy is necessary to guide the development of more effective curative treatments. Discriminating between residual leukemic clones, preleukemic clones, and normal precursors remains a challenge with current MRD tools. Here, we developed a single-cell MRD (scMRD) assay by combining flow cytometric enrichment of the targeted precursor/blast population with integrated single-cell DNA sequencing and immunophenotyping. Our scMRD assay shows high sensitivity of approximately 0.01%, deconvolutes clonal architecture, and provides clone-specific immunophenotypic data. In summary, our scMRD assay enhances MRD detection and simultaneously illuminates the clonal architecture of clonal hematopoiesis/preleukemic and leukemic cells surviving acute myeloid leukemia therapy.

Efficient line shape estimation by ghost spectroscopy.

Recovering the original spectral line shapes from data obtained by instruments with extended transmission profiles is a basic tenet in spectroscopy. By using the moments of the measured lines as basic variables, we turn the problem into a linear inversion. However, when only a finite number of these moments are relevant, the rest of them act as nuisance parameters. These can be taken into account with a semiparametric model, which allows us to establish the ultimate bounds on the precision attainable in the estimation of the moments of interest. We experimentally confirm these limits with a simple ghost spectroscopy demonstration.

Interaction between myelodysplasia-related gene mutations and ontogeny in acute myeloid leukemia.

Accurate classification and risk stratification are critical for clinical decision making in patients with acute myeloid leukemia (AML). In the newly proposed World Health Organization and International Consensus classifications of hematolymphoid neoplasms, the presence of myelodysplasia-related (MR) gene mutations is included as 1 of the diagnostic criteria for AML, AML-MR, based largely on the assumption that these mutations are specific for AML with an antecedent myelodysplastic syndrome. ICC also prioritizes MR gene mutations over ontogeny (as defined in the clinical history). Furthermore, European LeukemiaNet (ELN) 2022 stratifies these MR gene mutations into the adverse-risk group. By thoroughly annotating a cohort of 344 newly diagnosed patients with AML treated at the Memorial Sloan Kettering Cancer Center, we show that ontogeny assignments based on the database registry lack accuracy. MR gene mutations are frequently observed in de novo AML. Among the MR gene mutations, only EZH2 and SF3B1 were associated with an inferior outcome in the univariate analysis. In a multivariate analysis, AML ontogeny had independent prognostic values even after adjusting for age, treatment, allo-transplant and genomic classes or ELN risks. Ontogeny also helped stratify the outcome of AML with MR gene mutations. Finally, de novo AML with MR gene mutations did not show an adverse outcome. In summary, our study emphasizes the importance of accurate ontogeny designation in clinical studies, demonstrates the independent prognostic value of AML ontogeny, and questions the current classification and risk stratification of AML with MR gene mutations.

Eprenetapopt combined with venetoclax and azacitidine in TP53-mutated acute myeloid leukaemia: a phase 1, dose-finding and expansion study.

BACKGROUND: TP53-mutated acute myeloid leukaemia is associated with poor outcomes. Eprenetapopt (APR-246) is a first-in-class, small-molecule p53 reactivator. We aimed to evaluate the combination of eprenetapopt and venetoclax with or without azacitidine in patients with TP53-mutated acute myeloid leukaemia. METHODS: This phase 1, multicentre, open-label, dose-finding and cohort expansion study was done at eight academic research hospitals in the USA. Inclusion criteria were age of at least 18 years; at least one pathogenic TP53 mutation; treatment-naive acute myeloid leukaemia according to the 2016 WHO classification; an ECOG performance status of 0-2; and a life expectancy of at least 12 weeks. In dose-finding cohort 1 patients received previous therapy with hypomethylating agents for myelodysplastic syndromes. In dose-finding cohort 2, previous use of hypomethylating agents was not permitted. Treatment cycles were 28 days. Patients in cohort 1 received intravenous eprenetapopt 4·5 g/day on days 1-4 and oral venetoclax 400 mg/day on days 1-28; those in cohort 2 also received subcutaneous or intravenous azacitidine 75 mg/m2 on days 1-7. The expansion part of the study proceeded with patients enrolled as in cohort 2. Primary endpoints were safety in all cohorts (assessed in patients receiving at least one dose of assigned treatment) and complete response in the expansion cohort (assessed in patients who completed at least one treatment cycle and had at least one post-treatment clinical response assessment). The trial is registered with ClinicalTrials.gov, NCT04214860, and is complete. FINDINGS: Between Jan 3, 2020, and July 22, 2021, 49 patients were enrolled across all cohorts. Six patients were initially enrolled into each of dose-finding cohorts 1 and 2; after no dose-limiting toxicities were observed, cohort 2 was expanded to enrol an additional 37 patients. The median age was 67 years (IQR 59-73). 24 (49%) of 49 patients were female and 25 (51%) male, and 40 (82%) were White. At data cutoff (Oct 1, 2021), the median length of follow-up was 9·5 months (IQR 6·1-11·5). No dose-limiting toxicities were recorded and the recommended phase 2 dose for eprenetapopt combinations was 4·5 g/day on days 1-4. Across all patients, adverse events of grade 3 or worse occurring in at least 20% of patients were febrile neutropenia (23 [47%] of 49 patients), thrombocytopenia (18 [37%] patients), leukopenia (12 [25%] patients), and anaemia (11 [22%] patients). Treatment-related serious adverse events occurred in 13 (27%) of 49 patients and there was one (2%) treatment-related death (sepsis). 25 (64%, 95% CI 47-79) of 39 patients had an overall response with eprenetapopt and venetoclax with azacytidine; 15 (38%, 23-55) had a complete response. INTERPRETATION: Eprenetapopt and venetoclax with azacitidine had an acceptable safety profile and encouraging activity, supporting further frontline evaluation of this combination in the treatment of TP53-mutated acute myeloid leukaemia. FUNDING: Aprea Therapeutics.

Survival of TP53-mutated acute myeloid leukemia patients receiving allogeneic stem cell transplantation after first induction or salvage therapy: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND).

We conducted a multi-center study to analyze factors predicting survival among patients with TP53-mutated (m) AML receiving allogeneic hematopoietic stem cell transplant (allo-HSCT) in the recent era. Out of 370 TP53m AML patients, 68 (18%) patients were bridged to allo-HSCT. The median age of the patients was 63 years (range, 33-75), 82% of patients had complex cytogenetics and 66% of patients had multi-hit TP53m. Forty three percent received myeloablative conditioning and 57% received reduced intensity conditioning. The incidence of acute graft versus host disease (GVHD) was 37% and chronic GVHD was 44%. The median event-free survival (EFS) from the time of allo-HSCT was 12.4 months (95% CI: 6.24-18.55) and median overall survival (OS) was 24.5 months (95% CI: 21.80-27.25). In multivariate analysis utilizing variables that showed significance in univariate analysis, complete remission at day 100 post allo-HSCT retained significance for EFS (HR: 0.24, 95% CI: 0.10-0.57, p = 0.001) and OS (HR: 0.22, 95% CI: 0.10-0.50, p ≤ 0.001). Similarly, occurrence of chronic GVHD retained significance for EFS (HR: 0.21, 95% CI: 0.09-0.46, p ≤ 0.001) and OS (HR: 0.34, 95% CI: 0.15-0.75, p = 0.007). Our report suggests that allo-HSCT offers the best opportunity to improve long-term outcome among patients with TP53m AML.

Molecular predictors of immunophenotypic measurable residual disease clearance in acute myeloid leukemia.

Measurable residual disease (MRD) is a powerful prognostic factor in acute myeloid leukemia (AML). However, pre-treatment molecular predictors of immunophenotypic MRD clearance remain unclear. We analyzed a dataset of 211 patients with pre-treatment next-generation sequencing who received induction chemotherapy and had MRD assessed by serial immunophenotypic monitoring after induction, subsequent therapy, and allogeneic stem cell transplant (allo-SCT). Induction chemotherapy led to MRD- remission, MRD+ remission, and persistent disease in 35%, 27%, and 38% of patients, respectively. With subsequent therapy, 34% of patients with MRD+ and 26% of patients with persistent disease converted to MRD-. Mutations in CEBPA, NRAS, KRAS, and NPM1 predicted high rates of MRD- remission, while mutations in TP53, SF3B1, ASXL1, and RUNX1 and karyotypic abnormalities including inv (3), monosomy 5 or 7 predicted low rates of MRD- remission. Patients with fewer individual clones were more likely to achieve MRD- remission. Among 132 patients who underwent allo-SCT, outcomes were favorable whether patients achieved early MRD- after induction or later MRD- after subsequent therapy prior to allo-SCT. As MRD conversion with chemotherapy prior to allo-SCT is rarely achieved in patients with specific baseline mutational patterns and high clone numbers, upfront inclusion of these patients into clinical trials should be considered.

Disparities in receiving disease-directed therapy, allogeneic stem cell transplantation in non-Hispanic Black patients with TP53-mutated acute myeloid leukemia.

BACKGROUND: Although the clinical outcomes of patients with TP53-mutated acute myeloid leukemia (AML) are dismal, subsets of patients eligible for curative-intent therapies may fare better. Because racial disparities are known to affect outcome in hematologic malignancies, the authors sought to explore disparities among patients with TP53-mutated AML. METHODS: A multicenter, retrospective study was conducted in a cohort of 340 patients who had TP53-mutated AML (275 non-Hispanic White [NHW] and 65 non-Hispanic Black [NHB]) to analyze differences in treatment and outcome among NHW and NHB patients. RESULTS: The median patient age was comparable between NHW and NHB patients (p = .76). A higher proportion of NHB patients had therapy-related AML (31% vs. 20%; p = .08) and had co-mutations (74% vs. 61%; p = .06). A higher proportion of NHW patients received intensive chemotherapy compared with NHB patients (47% vs. 31%; p = .02). Conversely, a higher proportion of NHB patients received low-intensity chemotherapy (9% vs. 5.5%; p = .02) or best supportive care (22% vs. 7%; p < .001). The complete response rate (including complete responses with or without complete count recovery) was 31% versus 24.5% (p = .39) in NHW and NHB patients, respectively. Only 5% of NHB patients received allogeneic stem cell transplantation compared with 15.5% of NHW patients (p = .02). The proportion of patients who were event-free (18.5% vs. 8.5%; p = .49) or who remained alive (24.9% vs. 8.3%; p = .13) at 18 months was numerically higher in NHW versus NHB patients, respectively, but was not statistically significant. CONCLUSIONS: The current study highlights disparities between NHW and NHB patients with TP53-mutated AML. Efforts are warranted to eliminate treatment disparities in minority populations.

Depression in Women With Inflammatory Bowel Disease: A Multifaceted Approach for a Multidimensional Problem.

The prevalence of depression is higher in patients with inflammatory bowel disease (IBD) than in the general population. Women are more significantly affected by depression among those with IBD and in the general population. This review presents evidence on sex-based differences in depression pathogenesis and the effect of depression on various factors associated with IBD that affect women's lives, including sexual dysfunction, body image dissatisfaction, fertility, and overall quality of life. We also discuss sex-specific effects on IBD treatment, disease activity, and health care costs. Interestingly, women with IBD tend to seek and are more receptive to depression-related information. Given the underdiagnosis and undertreated nature of depression in individuals with IBD, effective screening and an optimal integrative treatment approach with relevant sex-specific needs are discussed. Evidence regarding the efficacy of psychotherapy, antidepressant pharmacotherapy, and IBD-specific therapy for depression is discussed. This review summarizes evidence of the effect of depression on both personal and professional aspects of the daily lives of women with IBD, which extends beyond negative moods. It applies this information to screening and integrative treatment, resulting in a holistic approach to this multidimensional problem. We also discuss how depression affects males with IBD differently from females. Finally, we discuss the need for gender-based studies on depression in individuals with IBD.

Depression, an important comorbidity of IBD, occurs more frequently in females and impairs quality of life. Depression screening in IBD patients is crucial, as it is widely underdiagnosed. A multifaceted treatment approach, accounting for sex- and gender-based differences, is optimal.

Venetoclax-based salvage therapy in patients with relapsed/refractory acute myeloid leukemia previously treated with FLT3 or IDH1/2 inhibitors.

FLT3, IDH1 and IDH2 inhibitors as well as venetoclax in combination with hypomethylating agents or low-dose cytarabine have expanded treatment options for patients with acute myeloid leukemia (AML). However, little data exist on the efficacy of venetoclax-based therapies in AML patients previously treated with FLT3 or IDH1/2 inhibitors. In this multicenter, retrospective cohort study, we included 44 patients who received venetoclax-based therapy after FLT3, IDH1 or IDH2 inhibitors. The overall response rate (ORR; composite of complete remission [CR]/CR with incomplete count recovery, partial remission, and morphologic leukemia free state) was 56.8% (18.2% CR) and a median overall survival of 9.2 months. While 6 out of 7 patients with IDH1 mutations who had previously been treated with ivosidenib responded to venetoclax-based therapy, FLT3-ITD mutations were associated with a lower response rate. Our data suggest that venetoclax can be an effective salvage therapy in patients previously treated with IDH1/2 or FLT3 inhibitors.

Efficacy of FLT3 and IDH1/2 inhibitors in patients with acute myeloid leukemia previously treated with venetoclax.

Small molecule inhibitors targeting mutant FLT3, IDH1, and IDH2 as well as venetoclax-based combination therapies have expanded treatment options for patients with acute myeloid leukemia (AML). As the landmark trials leading to the approval of FLT3, IDH1, and IDH2 inhibitors in R/R-AML were conducted prior to the widespread use of venetoclax, it is unclear how these results apply in the current era of venetoclax based therapy frequently being used in the frontline treatment of AML. In this multicenter, retrospective cohort study, we included 53 patients who received FLT3, IDH1 or IDH2 inhibitors after disease progression on venetoclax-based therapy. Among patients treated with targeted agents after venetoclax, the overall response rate (ORR; composite of complete remission [CR]/CR with incomplete count recovery, partial remission, and morphologic leukemia free state) was 17.7 % (n = 9 patients) and median OS of 4.2 months. Eight of 9 patients responding to targeted agents after venetoclax received gilteritinib. None of the patients with RAS pathway mutations responded to targeted agents after venetoclax. Additionally, mutations in TP53 and KRAS were associated with shorter OS among patients treated targeted agents. Our data suggest that response rates to targeted therapies after venetoclax are low and novel therapeutic strategies are warranted.