HyperCVAD versus pegaspargase-containing regimens for Hispanic adults with newly diagnosed B-cell acute lymphoblastic leukemia.

OBJECTIVE: There are significant disparities in outcomes among Hispanic patients with acute lymphoblastic leukemia (ALL). Recent studies have demonstrated favorable outcomes of pegaspargase-containing ALL regimens (PEG-CAR) in young adults however, outcomes in Hispanic ethnicity continue to be underreported. METHODS: We evaluated outcomes of newly diagnosed, adult B-cell ALL Hispanic and non-Hispanic patients consecutively treated with a PEG-CAR or HyperCVAD between January 2011 and November 2022. The primary endpoint was event-free survival (EFS) while secondary endpoints included cumulative incidence of relapse and overall survival (OS). RESULTS: Among 105 included patients, 48 (45.7%) were treated with a PEG-CAR and 57 (54.3%) with HyperCVAD. Median age was 38 years (range, 18-75 years), 61% were Hispanic, and 35.2% had poor-genetic risk. Hispanic patients demonstrated significantly worse 5-year EFS with a PEG-CAR compared to that seen with HyperCVAD (HR, 2.58; 95% CI, 1.32-5.04; p = .006) whereas non-Hispanic patients had better outcomes with PIR (52.4% vs. 42.0%). Hispanic ethnicity (p = .015) and male sex (p = .019) were independent predictors for poor OS. CONCLUSIONS: Hispanic patients with B-cell ALL had worse EFS with a PEG-CAR as compared with HyperCVAD. Future studies will aim to confirm these findings and establish a tailored treatment approach for this high-risk population.

A Phase I study of Milademetan (DS3032b) in combination with low dose cytarabine with or without venetoclax in acute myeloid leukemia: Clinical safety, efficacy, and correlative analysis.

In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. MDM2 inhibitor (MDM2i) monotherapy in AML has shown modest responses in clinical trials but combining options of MDM2i with other potent AML-directed agents like cytarabine and venetoclax could improve its efficacy. We conducted a phase I clinical trial (NCT03634228) to study the safety and efficacy of milademetan (an MDM2i) with low-dose cytarabine (LDAC)±venetoclax in adult patients with relapsed refractory (R/R) or newly diagnosed (ND; unfit) TP53 wild-type AML and performed comprehensive CyTOF analyses to interrogate multiple signaling pathways, the p53-MDM2 axis and the interplay between pro/anti-apoptotic molecules to identify factors that determine response and resistance to therapy. Sixteen patients (14 R/R, 2 N/D treated secondary AML) at a median age of 70 years (range, 23-80 years) were treated in this trial. Two patients (13%) achieved an overall response (complete remission with incomplete hematological recovery). Median cycles on trial were 1 (range 1-7) and at a median follow-up of 11 months, no patients remained on active therapy. Gastrointestinal toxicity was significant and dose-limiting (50% of patients ≥ grade 3). Single-cell proteomic analysis of the leukemia compartment revealed therapy-induced proteomic alterations and potential mechanisms of adaptive response to the MDM2i combination. The response was associated with immune cell abundance and induced the proteomic profiles of leukemia cells to disrupt survival pathways and significantly reduced MCL1 and YTHDF2 to potentiate leukemic cell death. The combination of milademetan, LDAC±venetoclax led to only modest responses with recognizable gastrointestinal toxicity. Treatment-induced reduction of MCL1 and YTHDF2 in an immune-rich milieu correlate with treatment response.

Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: Clinical efficacy and correlative analyses.

Malignancies can become reliant on glutamine as an alternative energy source and as a facilitator of aberrant DNA methylation, thus implicating glutaminase (GLS) as a potential therapeutic target. We demonstrate preclinical synergy of telaglenastat (CB-839), a selective GLS inhibitor, when combined with azacytidine (AZA), in vitro and in vivo, followed by a phase Ib/II study of the combination in patients with advanced MDS. Treatment with telaglenastat/AZA led to an ORR of 70% with CR/mCRs in 53% patients and a median overall survival of 11.6 months. scRNAseq and flow cytometry demonstrated a myeloid differentiation program at the stem cell level in clinical responders. Expression of non-canonical glutamine transporter, SLC38A1, was found to be overexpressed in MDS stem cells; was associated with clinical responses to telaglenastat/AZA and predictive of worse prognosis in a large MDS cohort. These data demonstrate the safety and efficacy of a combined metabolic and epigenetic approach in MDS.

Early Real-World First-Line Treatment With Venetoclax Plus HMAs Versus HMA Monotherapy Among Patients With AML in a Predominately US Community Setting.

BACKGROUND: Venetoclax in combination with hypomethylating agents (HMAs) is standard-of-care in patients with newly diagnosed acute myeloid leukemia (AML) who are ≥ 75 years old or unfit for intensive chemotherapy. We examined early real-world treatment experience among patients with AML receiving venetoclax+HMAs or HMA monotherapy. PATIENTS AND METHODS: This retrospective cohort study used an electronic health record-derived, deidentified, United States nationwide database comprised of patient-level structured and unstructured data, curated via technology-enabled abstraction. Patients with an AML diagnosis on or after January 1, 2014, who had ≥ 2 clinic visits, and initiated treatment with venetoclax+HMAs from June 1, 2018 to March 31, 2021, or HMA monotherapy from January 1, 2016 to May 31, 2018, were included. Kaplan-Meier analysis was used to estimate time to last administration (TTLA) and overall survival (OS). RESULTS: Overall, 619 patients treated with venetoclax+HMAs and 480 treated with HMA monotherapy were selected from the database. Median age at diagnosis was 76 and 78 years, respectively, most patients were treated in community practice (83.4% and 89.4%, respectively), and almost half had secondary AML (47.2% and 47.3%, respectively). Adjusted analyses showed both significantly longer TTLA (3.6 months vs. 2.3 months; hazard ratio [HR] = 0.69 [95% confidence interval (CI), 0.60-0.80], P< .0001) and OS (9.3 months vs. 5.9 months; HR = 0.71 [95% CI, 0.61-0.82], P < .0001) in patients treated with venetoclax+HMAs versus HMA monotherapy, respectively. CONCLUSION: This study shows benefit in real-world outcomes of venetoclax+HMAs relative to HMA monotherapy in patients with newly diagnosed AML, using a predominantly community-based database.

A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes.

Patients with relapsed/refractory (R/R) higher-risk myelodysplastic syndromes (MDS) have a dismal median overall survival (OS) after failing hypomethylating agent (HMA) treatment. There is no standard of care for patients after HMA therapy failure; hence, there is a critical need for effective therapeutic strategies. Herein, we present the safety and efficacy of venetoclax + azacitidine in patients with R/R MDS. This phase 1b, open-label, multicenter study enrolled patients ≥18 years. Patients were treated with escalating doses of oral venetoclax: 100, 200, or 400 mg daily for 14 days every 28-day cycle. Azacitidine was administered on Days 1-7 every cycle at 75 mg/m2 /day intravenously/subcutaneously. Responses were assessed per modified 2006 International Working Group (IWG) criteria. Forty-four patients (male 86%, median age 74 years) received venetoclax + azacitidine treatment. Median follow-up was 21.2 months. Hematological adverse events of Grade ≥ 3 included febrile neutropenia (34%), thrombocytopenia (32%), neutropenia (27%), and anemia (18%). Pneumonia (23%) was the most common Grade ≥ 3 infection. Marrow responses were seen including complete remission (CR, n = 3, 7%) and marrow CR (mCR, n = 14, 32%); 36% (16/44) achieved transfusion independence (TI) for RBCs and/or platelets, and 43% (6/14) with mCR achieved hematological improvement (HI). The median time to CR/mCR was 1.2 months, and the median duration of response for CR + mCR was 8.6 months. Median OS was 12.6 months. Venetoclax + azacitidine shows activity in patients with R/R MDS following prior HMA therapy failure and provides clinically meaningful benefits, including HI and TI, and encouraging OS.

Decreasing delirium through music listening (DDM) in critically ill, mechanically ventilated older adults in the intensive care unit: a two-arm, parallel-group, randomized clinical trial.

BACKGROUND: Delirium is a highly prevalent and morbid syndrome in mechanically ventilated intensive care unit (ICU) patients. Music is a promising non-pharmacological intervention with beneficial effects on anxiety and stress, while its effects on delirium duration and severity are not well understood. METHODS/DESIGN: Our study is a two-arm, randomized parallel-group, clinical trial to evaluate the efficacy of music intervention compared to a silence-track attention control on delirium/coma duration in mechanically ventilated critically ill older adults. One hundred sixty mechanically ventilated adults 50 years of age or older will be randomized to one of two arms within 72 h of ICU admission: (1) 1-h music listening sessions twice daily through noise-canceling headphones, or (2) 1-h sessions of a silence track twice daily through noise-canceling headphones. Our primary aim is to compare delirium/coma-free days after randomization during the 7-day study intervention phase using the Confusion Assessment Method for the ICU (CAM ICU) and the Richmond Agitation Sedation Scale (RASS) for delirium and coma. Secondary outcomes include pain and anxiety evaluated twice daily during the intervention phase and throughout the duration of ICU stay using the Critical Care Pain Observation Tool (CPOT) and visual analog scale-anxiety (VAS-A). Enrolled participants will be followed after hospital discharge to further measure cognition as well as screening for depression and anxiety using the following telephone-based instruments: Indiana University Telephone-Based Assessment of Neuropsychological Status (IU TBANS), Patient Health Questionnaire-9 (PHQ-9), and Generalized Anxiety Disorder-7 (GAD-7). DISCUSSION: This randomized clinical trial will measure the efficacy of a music listening intervention for delirium and coma duration early in the intensive care unit among older adults. TRIAL REGISTRATION: ClinicalTrials.gov. NCT04182334 .

Venetoclax Plus Gilteritinib for FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia.

PURPOSE: The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory FLT3-mutated (FLT3mut) acute myeloid leukemia (AML) but seldom reduces FLT3mut burden or induces sustained efficacy. Gilteritinib combines synergistically with the BCL-2 inhibitor venetoclax in preclinical models of FLT3mut AML. METHODS: This phase Ib open-label, dose-escalation/dose-expansion study (ClinicalTrials.gov identifier: NCT03625505) enrolled patients with FLT3 wild-type and FLT3mut (escalation) or FLT3mut (expansion) relapsed/refractory AML. Patients received 400 mg oral venetoclax once daily and 80 mg or 120 mg oral gilteritinib once daily. The primary objectives were safety, identification of the recommended phase II dose, and the modified composite complete response (mCRc) rate (complete response [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery + morphologic leukemia-free state) using ADMIRAL phase III-defined response criteria. RESULTS: Sixty-one patients were enrolled (n = 56 FLT3mut); 64% (n = 36 of 56) of FLT3mut patients had received prior FLT3 inhibitor therapy. The recommended phase II dose was 400 mg venetoclax once daily and 120 mg gilteritinib once daily. The most common grade 3/4 adverse events were cytopenias (n = 49; 80%). Adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively. The mCRc rate for FLT3mut patients was 75% (CR, 18%; CR with incomplete blood count recovery, 4%; CR with incomplete platelet recovery, 18%; and morphologic leukemia-free state, 36%) and was similar among patients with or without prior FLT3 inhibitor therapy (80% v 67%, respectively). The median follow-up was 17.5 months. The median time to response was 0.9 months, and the median remission duration was 4.9 months (95% CI, 3.4 to 6.6). FLT3 molecular response (< 10-2) was achieved in 60% of evaluable mCRc patients (n = 15 of 25). The median overall survival for FLT3mut patients was 10.0 months. CONCLUSION: The combination of venetoclax and gilteritinib was associated with high mCRc and FLT3 molecular response rates regardless of prior FLT3 inhibitor exposure. Dose interruptions were needed to mitigate myelosuppression.

Treatment outcomes for patients with myelodysplastic syndrome/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis.

Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is characterized by anemia, ring sideroblast erythroid precursors, and persistent thrombocytosis. Case reports suggest lenalidomide may be effective in treating MDS/MPN-RS-T. We evaluated a large series of patients with MDS/MPN-RS-T to compare hematological improvement (HI) response rates among different drug therapies including lenalidomide. We identified 167 patients with MDS/MPN-RS-T. Among the patients tested, 84% had SF3B1 mutations and 43% had JAK2 V617F mutations. The median OS for the cohort was 81 months. Overall, 76 patients (46%) received erythropoiesis-stimulating agents (ESAs), 47 patients (28%) received lenalidomide, and 45 patients (27%) received hypomethylating agents (HMAs). The HI rates were 58%, 53%, and 24%, respectively. The median duration of treatment was 11 months for lenalidomide compared to 6 months for HMAs. Rates of HI improvement were higher in patients with MDS/MPN-RS-T treated with ESAs or lenalidomide, in comparison to those treated with HMAs.

Serum Biomarkers in Postoperative Delirium After Esophagectomy.

BACKGROUND: Esophagectomy is associated with postoperative delirium, but its pathophysiology is not well defined. We conducted this study to measure the relationship among serum biomarkers of inflammation and neuronal injury and delirium incidence and severity in a cohort of esophagectomy patients. METHODS: Blood samples were obtained from patients preoperatively and on postoperative days 1 and 3 and were analyzed for S100 calcium-binding protein B, C-reactive protein (CRP), interleukin (IL) 8 and IL-10, tumor necrosis factor-α, and insulin-like growth factor 1. Delirium was assessed twice daily using the Richmond Agitation Sedation Scale and Confusion Assessment Method for Intensive Care Unit. Delirium severity was assessed once daily with the Delirium Rating Scale-Revised-98. RESULTS: Samples from 71 patients were included. Preoperative biomarker concentrations were not associated with postoperative delirium. Significant differences in change in concentrations from preoperatively to postoperative day 1 were seen in IL-8 (delirium, 38.6; interquartile range [IQR], 29.3-69.8; no delirium, 24.8; IQR, 16.0-41.7, P = .022), and IL-10 (delirium, 26.1; IQR, 13.9-36.7; no delirium, 12.4; IQR, 7.7-25.7; P = .025). Greater postoperative increase in S100 calcium-binding protein B (Spearman r = 0.289, P = .020) and lower levels of insulin-like growth factor 1 were correlated with greater delirium severity (Spearman r = -0.27, P = .040). Greater CRP change quartiles were associated with higher delirium incidence adjusting for severity of illness (odds ratio, 1.68; 95% confidence interval, 1.03-2.75; P = .037) or comorbidities (odds ratio, 1.70; 95% confidence interval, 1.05-2.76, P = .030). CONCLUSIONS: Differences in change in serum CRP, IL-8, and IL-10 concentrations were associated with postoperative delirium, suggesting biomarker measurement early in the postoperative course is associated with delirium.

Phase II study of azacitidine with pembrolizumab in patients with intermediate-1 or higher-risk myelodysplastic syndrome.

Programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) expression is upregulated in cluster of differentiation 34 (CD34)+ bone marrow cells from patients with myelodysplastic syndromes (MDS). Hypomethylating agent (HMA) treatment results in further increased expression of these immune checkpoints. We hypothesised that combining an anti-PD-1 antibody with HMAs may have efficacy in patients with MDS. To test this concept, we designed a phase II trial of the combination of azacitidine and pembrolizumab with two cohorts. In the 17 previously untreated patients, the overall response rate (ORR) was 76%, with a complete response (CR) rate of 18% and median overall survival (mOS) not reached after a median follow-up of 12·8 months. For the HMA-failure cohort (n = 20), the ORR was 25% and CR rate was 5%; with a median follow-up of 6·0 months, the mOS was 5·8 months. The most observed toxicities were pneumonia (32%), arthralgias (24%) and constipation (24%). Immune-related adverse events requiring corticosteroids were required in 43%. Overall, this phase II trial suggests that azacitidine and pembrolizumab is safe with manageable toxicities in patients with higher-risk MDS. This combined therapy may have anti-tumour activity in a subset of patients and merits further studies in the front-line setting.

Clinicopathologic correlates and natural history of atypical chronic myeloid leukemia.

BACKGROUND: There are limited data on the clonal mechanisms underlying leukemogenesis, prognostic factors, and optimal therapy for atypical chronic myeloid leukemia (aCML). METHODS: The authors evaluated the clinicopathologic features, outcomes, and responses to therapy of 65 patients with aCML. The median age was 67 years (range, 46-89 years). RESULTS: The most frequently mutated genes included ASXL1 (83%), SRSF2 (68%), and SETBP1 (58%). Mutations in SETBP1, SRSF2, TET2, and GATA2 appeared at variant allele frequencies (VAFs) greater than 40%, whereas other RAS pathway mutations were more likely to appear at low VAFs. The acquisition of new, previously undetectable mutations at transformation was observed in 63% of the evaluable patients, with the most common involving signaling pathway mutations. Hypomethylating agents (HMAs) were associated with the highest response rates but with a short duration of response (median, 2.7 months). Therapy with ruxolitinib was not associated with clinically significant responses as a single agent or in combination with an HMA. Allogeneic stem cell transplantation was the only therapy associated with improved outcomes (hazard ratio, 0.144; 95% CI, 0.035-0.593; P = .007). Age, platelet counts, bone marrow blast percentages, and serum lactate dehydrogenase (LDH) levels were independent predictors of survival and were integrated in a multivariable model that allowed the prediction of 1- and 3-year survival. CONCLUSIONS: aCML is characterized by high frequencies of ASXL1, SRSF2, and SETBP1 mutations and is associated with a high risk of acute myeloid leukemia transformation. Response and survival outcomes with current therapies remain poor. The incorporation of age, platelet counts, bone marrow blast percentages, and LDH levels can allow survival prediction, and allogeneic stem cell transplantation should be considered for all eligible patients.

Phase 2 study of lenalidomide maintenance for patients with high-risk acute myeloid leukemia in remission.

BACKGROUND: New drug combinations have led to significant improvements in remission rates for patients with acute myeloid leukemia (AML). However, many patients with high-risk AML who respond to their initial treatment and are not candidates for allogeneic stem cell transplantation (ASCT) will eventually relapse with poor outcomes. METHODS: In this phase 2 trial, the efficacy of lenalidomide maintenance was evaluated in patients with high-risk AML who had achieved their first or second remission after induction chemotherapy and at least 1 consolidation cycle and who were not candidates for immediate ASCT. Lenalidomide was given orally at 10 to 20 mg daily on days 1 to 28 of a 28-day cycle for up to 24 cycles. RESULTS: A total of 28 patients were enrolled in this study with a median age of 61 years (range, 24-87 years). The median number of cycles was 8 (range, 1-24 cycles). Ten patients (36%) completed 24 months of maintenance treatment. With a median follow-up of 22.5 months (range, 2.6-55 months), 12 patients (43%) relapsed after a median of 3 months (range, 0.7-23 months). The median duration of remission for all patients was 18.7 months (range, 0.7-55.1 months). The 2-year overall survival and relapse-free survival rates from the time of enrollment were 63% and 50%, respectively. Overall, lenalidomide was well tolerated; serious adverse events of grade 3 or 4, including rash (n = 5), thrombocytopenia (n = 4), neutropenia (n = 4), and fatigue (n = 2), were observed in 13 patients (46%). CONCLUSIONS: Lenalidomide is a safe and feasible maintenance strategy in patients with high-risk AML who are not candidates for ASCT, and it has beneficial effects for patients with negative measurable residual disease.

Type I interferon upregulation and deregulation of genes involved in monopoiesis in chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is characterized by myelomonocytic bias and monocytic proliferation. Whether cell-intrinsic innate immune or inflammatory upregulation mediate disease pathogenesis and phenotype or whether the degree of aberrant monocytic differentiation influences outcomes remains unclear. We compared the transcriptomic features of bone marrow CD34+ cells from 19 patients with CMML and compared to healthy individuals. A total of 1495 genes had significantly differential expression in CMML (q<0.05, fold change>2), including 1271 genes that were significantly upregulated and 224 that were significantly downregulated in CMML. Top upregulated genes were associated with interferon (IFN) alpha and beta signaling, chemokine receptors, IFN gamma, G protein-coupled receptor ligand signaling, and genes involved in immunomodulatory interactions between lymphoid and non-lymphoid cells. Additionally, 6 gene sets were differentially upregulated and 139 were significantly downregulated in patients with myeloproliferative compared to myelodysplastic CMML. A total of 23 genes involved in regulation of monopoiesis were upregulated in CMML compared to healthy controls. We developed a prediction model using Cox regression including 3 of these genes, which differentiated patients into two prognostic subsets with distinct survival outcomes. This data warrants further evaluation of the roles and therapeutic potential of type I IFN signaling and monopoiesis in CMML.

The effect of eltrombopag in managing thrombocytopenia associated with tyrosine kinase therapy in patients with chronic myeloid leukemia and myelofibrosis.

Approximately 20-50% patients with chronic phase chronic myeloid leukemia (CML-CP) treated with tyrosine kinase inhibitors (TKIs) or with myelofibrosis (MF) treated with ruxolitinib develop grade ≥3 thrombocytopenia needing treatment interruptions and dose reductions. We conducted a non-randomized, phase II, single-arm study to determine the efficacy of eltrombopag for patients with CML or MF with persistent thrombocytopenia while on TKI or ruxolitinib. Eltrombopag was initiated at 50 mg/day, with dose escalation up to 300 mg daily allowed every 2 weeks. Twenty-one patients were enrolled (CML=15, MF=6); median age 60 years (range, 31-97 years). The median platelet count was 44x109/L (range, 3-49x109/L) in CML and 62x109/L (range, 21-75x109/L) in MF. After a median of 18 months (range, 5-77 months), 12/15 patients with CML achieved complete platelet response. The median peak platelet count among responders was 154x109/L (range, 74-893x109/L). Among CML patients 5 could re-escalate the TKI dose and 9 improved their response. None of the 6 patients with MF had a sustained response. Therapy was generally well tolerated. One patient discontinued therapy due to toxicity (elevated transaminases). One patient with CML developed significant thrombocytosis (>1000x109/L). Another CML patient developed non occlusive deep venous thrombosis in the right upper extremity without thrombocytosis, and one MF patient had myocardial infarction. Eltrombopag may help improve platelet counts in CML patients receiving TKI with recurrent thrombocytopenia. Further studies are warranted.

Isavuconazole as Primary Antifungal Prophylaxis in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome: An Open-label, Prospective, Phase 2 Study.

BACKGROUND: Mold-active primary antifungal prophylaxis (PAP) is routinely recommended in neutropenic patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) undergoing remission-induction chemotherapy (RIC). Isavuconazole (ISAV) is an extended spectrum mold-active triazole and has superior tolerability and fewer significant drug-drug interactions compared with other triazoles. METHODS: In our investigator-initiated, phase 2 trial, treatment-naive adult patients with AML or MDS starting RIC received ISAV per the dosing recommendations in the US label until neutrophil recovery (absolute neutrophil count [ANC] ≥ 0.5 × 109/L) and attainment of complete remission, occurrence of invasive fungal infection (IFI), or for a maximum of 12 weeks. The primary endpoint was the incidence of proven/probable IFI during ISAV PAP and up to 30 days after the last dose. RESULTS: Sixty-five of 75 enrolled patients received ISAV PAP (median age, 67 years, median ANC at enrollment, 0.72 × 109/L). Thirty-two patients (49%) received oral targeted leukemia treatments (venetoclax, FTL3 inhibitors). Including the 30-day follow-up period, probable/proven and possible IFIs were encountered in 4 (6%) and 8 patients (12%), respectively. ISAV trough serum concentrations were consistently > 1 µg/mL, showed low intraindividual variation, and were not significantly influenced by chemotherapy regimen. Tolerability of ISAV was excellent, with only 3 cases (5%) of mild to moderate elevations of liver function tests and no QTc prolongations. CONCLUSIONS: ISAV is a safe and effective alternative for PAP in patients with newly diagnosed AML/MDS undergoing RIC in the era of recently approved or emerging small-molecule antileukemia therapies. CLINICAL TRIALS REGISTRATION: NCT03019939.

Venetoclax with decitabine vs intensive chemotherapy in acute myeloid leukemia: A propensity score matched analysis stratified by risk of treatment-related mortality.

Hypomethylating agents (HMA) with venetoclax is a new standard for older/unfit patients with acute myeloid leukemia (AML). However, it is unknown how HMA with venetoclax compare to intensive chemotherapy (IC) in patients who are "fit" or "unfit" for IC. We compared outcomes of older patients with newly diagnosed AML receiving 10-day decitabine with venetoclax (DEC10-VEN) vs IC. DEC10-VEN consisted of daily venetoclax with decitabine 20 mg/m2 for 10 days for induction and decitabine for 5 days as consolidation. The IC cohort received regimens containing cytarabine ≥1 g/m2 /d. A validated treatment-related mortality score (TRMS) was used to classify patients at high-risk or low-risk for TRM with IC. Propensity scores were used to match patients to minimize bias. Median age of the DEC10-VEN cohort (n = 85) was 72 years (range 63-89) and 28% patients were at high-risk of TRM with IC. The comparator IC group (n = 85) matched closely in terms of baseline characteristics. DEC10-VEN was associated with significantly higher CR/CRi compared to IC (81% vs 52%, P < .001), and lower rate of relapse (34% vs 56%, P = .01), 30-day mortality (1% vs 24%, P < .01), and longer overall survival (OS; 12.4 vs 4.5 months, HR = 0.48, 95%CI 0.29-0.79, P < .01). In patients at both at high-risk and low-risk of TRM, DEC10-VEN showed significantly higher CR/CRi, lower 30-day mortality, and longer OS compared to IC. Patients at both high-risk and low-risk of TRM had comparable outcomes with DEC10-VEN. In conclusion, DEC10-VEN offers better outcomes compared to intensive chemotherapy in older patients with newly diagnosed AML, particularly in those at high-risk of TRM.

The LEukemia Artificial Intelligence Program (LEAP) in chronic myeloid leukemia in chronic phase: A model to improve patient outcomes.

Extreme gradient boosting methods outperform conventional machine-learning models. Here, we have developed the LEukemia Artificial intelligence Program (LEAP) with the extreme gradient boosting decision tree method for the optimal treatment recommendation of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia in chronic phase (CML-CP). A cohort of CML-CP patients was randomly divided into training/validation (N = 504) and test cohorts (N = 126). The training/validation cohort was used for 3-fold cross validation to develop the LEAP CML-CP model using 101 variables at diagnosis. The test cohort was then applied to the LEAP CML-CP model and an optimum TKI treatment was suggested for each patient. The area under the curve in the test cohort was 0.81899.Backward multivariate analysis identified age at diagnosis, the degree of comorbidities, and TKI recommended therapy by the LEAP CML-CP model as independent prognostic factors for overall survival. The bootstrapping method internally validated the association of the LEAP CML-CP recommendation with overall survival as an independent prognostic for overall survival. Selecting treatment according to the LEAP CML-CP personalized recommendations, in this model, is associated with better survival probability compared to treatment with a LEAP CML-CP non-recommended therapy. This approach may pave a way of new era of personalized treatment recommendations for patients with cancer.