Showing papers by "Elias Jabbour published in 2022"

Chronic myeloid leukemia: 2022 update on diagnosis, therapy, and monitoring

Abstract: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1–2 cases per 100 000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults.

Hypomethylating agent and venetoclax with FLT3 inhibitor “triplet” therapy in older/unfit patients with FLT3 mutated AML

Abstract: In older/unfit newly diagnosed patients with FLT3 mutated acute myeloid leukemia (AML), lower intensity chemotherapy (LIC) in combination with either a FLT3 inhibitor or with venetoclax results in poor overall survival (median 8 to 12.5 months). We performed a retrospective analysis of 87 newly diagnosed FLT3 mutated AML patients treated on triplet (LIC + FLT3 inhibitor + Venetoclax, [N = 27]) and doublet (LIC + FLT3 inhibitor, [N = 60]) regimens at our institution. Data were collected from prospective clinical trials in 75% (N = 65) and 25% (N = 22) who received the same treatment regimens outside of a clinical trial. Triplet therapy was associated with significantly higher rates of complete remission (CR) (67% versus 32%, P = 0.002), CR/CRi (93% versus 70%, P = 0.02), FLT3-PCR negativity (96% versus 54%, P < 0.01), and flow-cytometry negativity (83% versus 38%, P < 0.01) than doublets. At the end of the first cycle, the median time to ANC > 0.5 (40 versus 21 days, P = 0.15) and platelet > 50 K (29 versus 25 days, P = 0.6) among responders was numerically longer with triplets, but 60-day mortality was similar (7% v 10%). With a median follow-up of 24 months (median 12 months for triplet arm, and 63 months for doublet arm), patients receiving a triplet regimen had a longer median overall survival (not reached versus 9.5 months, P < 0.01). LIC combined with FLT3 inhibitor and venetoclax (triplet) may be an effective frontline regimen for older/unfit FLT3 mutated AML that should be further validated prospectively.

Treatment of Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia-From Intensive Chemotherapy Combinations to Chemotherapy-Free Regimens: A Review.

Abstract: Importance With the advent of potent BCR::ABL1 tyrosine kinase inhibitors (TKIs), Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) is now a relatively favorable-risk acute leukemia. In this review, we discuss the current evidence for frontline therapies of Ph-positive ALL, the major principles that guide therapy, and the progress with chemotherapy-free regimens. Observations Incorporating TKIs into the chemotherapy regimens of patients with newly diagnosed Ph-positive ALL has led to improved remission rates, higher probability of reaching allogeneic stem cell transplantation (SCT), and longer survival compared with chemotherapy alone. Early achievement of a complete molecular remission (CMR) is an important end point in Ph-positive ALL and identifies patients who have excellent long-term survival and may not need allogeneic SCT. Second-generation TKIs combined with intensive or low-intensity chemotherapy resulted in higher CMR rates compared with imatinib-based regimens. This translated into better outcomes, with less reliance on allogeneic SCT. To further improve the outcomes, the potent third-generation TKI ponatinib was added to chemotherapy. The combination of hyper-CVAD and ponatinib resulted in an overall CMR rate of 84% and a 5-year survival rate of 73% and 86% among patients who did and did not undergo allogeneic SCT, respectively, suggesting that allogeneic SCT may not be needed with this regimen. The recent chemotherapy-free combination of dasatinib and blinatumomab was safe and effective in patients with newly diagnosed Ph-positive ALL and resulted in an estimated 3-year OS rate of 80%; 50% of patients underwent allogeneic SCT. The chemotherapy-free regimen of ponatinib and blinatumomab resulted in a CMR rate of 86% and a 2-year survival rate of 93%, with no relapses or leukemia-related deaths, and with only 1 patient proceeding to allogeneic SCT. Conclusions and Relevance The promising results obtained with the chemotherapy-free regimens of blinatumomab plus TKIs question the role of allogeneic SCT in first remission. Patients with Ph-positive ALL who achieve early and deep molecular responses have excellent long-term outcomes and may not benefit from allogeneic SCT.

Treatment‐free remission in patients with chronic myeloid leukemia following the discontinuation of tyrosine kinase inhibitors

Abstract: Tyrosine kinase inhibitors (TKIs) discontinuation in patients with Philadelphia‐chromosome‐positive chronic myeloid leukemia (Ph‐positive CML) is increasingly considered. We aim to evaluate the outcome of patients with CML who discontinued TKIs, and determine the factors associated with differences in the success rates of treatment‐free remission (TFR). Patients with Ph‐positive CML treated between October 1999 and February 2017 who discontinued therapy were analyzed. A major molecular response (MMR) was defined as BCR‐ABL1/ABL1 ratio on the International Scale ≤0.1%. TFR failure was defined as the loss of MMR on any single test. We analyzed TFR rates according to duration and depth of response, and conducted a multivariate analysis for factors associated with loss of MMR. Two‐hundred and eighty‐four patients were analyzed; 199 patients (70%) electively discontinued TKIs. At a median follow‐up of 36 months (95% confidence interval, 32–40) after TKI discontinuation, 53 patients (19%) lost MMR. The estimated 5‐year TFR rate was 79%. All but one patient regained MMR after resuming therapy. The estimated 5‐year TFR rates were higher with MR4 and MR4.5 ≥5 years, compared with MR4 <5 years (87% vs. 92% vs. 64%; p < .0001). By multivariate analysis, only the duration of MR4 or MR4.5 ≥5 years before stopping treatment was associated with a lower risk of loss of MMR. In summary, TFR is safe and feasible in patients with Ph‐positive CML on TKI therapy. Achieving MR4 or MR4.5 for at least 5 years is correlated with a better outcome.

AML-348 A Phase Ib/II Study of Ivosidenib With Venetoclax +/- Azacitidine in IDH1-Mutated Hematologic Malignancies.

Abstract: CONTEXT IDH1-mutated (IDH1+) myeloid malignancies depend on the anti-apoptotic protein BCL-2 for survival. Combining the IDH1 inhibitor ivosidenib (IVO) with the BCL-2 inhibitor venetoclax (VEN) may improve outcomes. We report the completed P1b portion of a P1b/II study investigating IVO (500 mg PO daily D15-continuous) with VEN (D1-14), with or without azacitidine (AZA; 75 mg/m2 D1-7) every 28 days. OBJECTIVES Primary P1b objectives included safety, tolerability, and IWG-defined overall response (ORR: CR+CRi+CRh+PR+MLFS). DESIGN A dose-escalation/-de-escalation study evaluating cohorts of 6 patients enrolled within 4 dose levels: DL1 (IVO+VEN 400 mg), DL2 (IVO+VEN 800 mg), DL3 (IVO+VEN 400 mg+AZA), DL4 (IVO+VEN 800 mg+AZA). PARTICIPANTS Eligible patients were ≥ age 18 with IDH1+ MDS, newly diagnosed (ND) or relapsed/refractory (R/R) AML. RESULTS Thirty-one patients enrolled with a median follow-up of 26 months. The median age was 67 years (range: 44-84), 71% had AML (ND: N=14, R/R: N=8), and 29% had MDS. ELN risk was intermediate or adverse in 19% and 55%, respectively (N=17). The ORR was 94% (DL1: 67%, DL2-DL4: 100%); composite CR (CRc: CR+CRi+CRh) was 87% (DL1: 67%, DL2: 100%, DL3: 85%, DL4: 100%). Of the AML patients, 60% attained measurable residual disease-negative CRc by multiparameter flow cytometry. IDH1+ mutation clearance by digital droplet PCR (sensitivity: 0.1%-0.25%) occurred in 64% of patients following cycle 5. Grade 3-5 adverse events (AEs) in ≥ 10% of patients included febrile neutropenia (29%) and pneumonia (23%). AEs of special interest (AESI) included grade 3 tumor lysis syndrome in 2 (dose-limiting toxicity in 1), and differentiation syndrome in 4 (G2: N=2, G3: N=2) patients. All AESIs were transient and reversible. Median EFS and OS were 36 and 42 months, respectively, and 24-month OS was 71% (95% CI: 55-91; ND-AML: 67%, R/R-AML: 50%, MDS: 100%). MRD-negative CRc improved OS (median NR vs. 8 months, P: 0.002) in ND- and R/R-AML. Based on efficacy and toxicity, DL3 (IVO+VEN400+AZA) was the recommended phase 2 dose. CONCLUSIONS IVO+VEN±AZA is an effective treatment for IDH1+ myeloid malignancies with an expected toxicity profile and notable activity across disease groups. Single-cell sequencing and CyTOF correlatives will also be presented.

Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia

Abstract: T-cell acute lymphoblastic leukemia (T-ALL) is commonly driven by activating mutations in NOTCH1 that facilitate glutamine oxidation. Here we identify oxidative phosphorylation (OxPhos) as a critical pathway for leukemia cell survival and demonstrate a direct relationship between NOTCH1, elevated OxPhos gene expression, and acquired chemoresistance in pre-leukemic and leukemic models. Disrupting OxPhos with IACS-010759, an inhibitor of mitochondrial complex I, causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in NOTCH1-mutated and less so in NOTCH1-wt T-ALL cells. Mechanistically, inhibition of OxPhos induces a metabolic reprogramming into glutaminolysis. We show that pharmacological blockade of OxPhos combined with inducible knock-down of glutaminase, the key glutamine enzyme, confers synthetic lethality in mice harboring NOTCH1-mutated T-ALL. We leverage on this synthetic lethal interaction to demonstrate that IACS-010759 in combination with chemotherapy containing L-asparaginase, an enzyme that uncovers the glutamine dependency of leukemic cells, causes reduced glutaminolysis and profound tumor reduction in pre-clinical models of human T-ALL. In summary, this metabolic dependency of T-ALL on OxPhos provides a rational therapeutic target.

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia

Abstract: PURPOSE The combination of venetoclax and 5-azacitidine (5-AZA) for older or unfit patients with acute myeloid leukemia (AML) improves remission rates and survival compared with 5-AZA alone. We hypothesized that the addition of venetoclax to cladribine (CLAD)/low-dose araC (low-dose cytarabine [LDAC]) alternating with 5-AZA backbone may further improve outcomes for older patients with newly diagnosed AML. METHODS This is a phase II study investigating the combination of venetoclax and CLAD/LDAC alternating with venetoclax and 5-AZA in older (≥ 60 years) or unfit patients with newly diagnosed AML. The primary objective was composite complete response (CR) rate (CR plus CR with incomplete blood count recovery); secondary end points were overall survival, disease-free survival (DFS), overall response rate, and toxicity. RESULTS A total of 60 patients were treated; median age was 68 years (range, 57-84 years). By European LeukemiaNet, 23%, 33%, and 43% were favorable, intermediate, and adverse risk, respectively. Fifty-six of 60 evaluable patients responded (composite CR: 93%) and 84% were negative for measurable residual disease. There was one death (2%) within 4 weeks. With a median follow-up of 22.1 months, the median overall survival and DFS have not yet been reached. The most frequent grade 3/4 nonhematologic adverse events were febrile neutropenia (n = 33) and pneumonia (n = 14). One patient developed grade 4 tumor lysis syndrome. CONCLUSION Venetoclax and CLAD/LDAC alternating with venetoclax and 5-AZA is an effective regimen among older or unfit patients with newly diagnosed AML. The rates of overall survival and DFS are encouraging. Further study of this non–anthracycline-containing backbone in younger patients, unfit for intensive chemotherapy, as well as comparisons to standard frontline therapies is warranted.

Impact of frontline treatment approach on outcomes in patients with secondary AML with prior hypomethylating agent exposure

Abstract: Treated secondary acute myeloid leukemia (ts-AML)-i.e., AML arising from a previously treated antecedent hematologic disorder-is associated with very poor outcomes. The optimal frontline treatment regimen for these patients is uncertain.We retrospectively analyzed 562 patients who developed AML from preceding myelodysplastic syndrome or chronic myelomonocytic leukemia for which they had received a hypomethylating agent (HMA). Patients with ts-AML were stratified by frontline AML treatment with intensive chemotherapy (IC, n = 271), low-intensity therapy (LIT) without venetoclax (n = 237), or HMA plus venetoclax (n = 54).Compared with IC or LIT without venetoclax, HMA plus venetoclax resulted in higher CR/CRi rates (39% and 25%, respectively; P = 0.02) and superior OS (1-year OS 34% and 17%, respectively; P = 0.05). The benefit of HMA plus venetoclax was restricted to patients with non-adverse risk karyotype, where HMA plus venetoclax resulted in a median OS of 13.7 months and 1-year OS rate of 54%; in contrast, for patients with adverse risk karyotype, OS was similarly dismal regardless of treatment approach (median OS 3-5 months). A propensity score analysis accounting for relevant clinical variables confirmed the significant OS benefit of HMA plus venetoclax, as compared with other frontline treatment approaches. In a landmark analysis, patients with ts-AML who underwent subsequent hematopoietic stem cell transplantation (HSCT) had superior 3-year OS compared to non-transplanted patients (33% vs. 8%, respectively; P = 0.003).The outcomes of ts-AML are poor but may be improved with use of an HMA plus venetoclax-based regimen, followed by HSCT, particularly in those with a non-adverse risk karyotype.

Improved outcomes among newly diagnosed patients with FMS‐like tyrosine kinase 3 internal tandem duplication mutated acute myeloid leukemia treated with contemporary therapy: Revisiting the European LeukemiaNet adverse risk classification

Abstract: Mutations in fms‐like tyrosine kinase 3 (FLT3) gene are common genomic alterations in acute myeloid leukemia (AML). FLT3 internal tandem duplication mutations (FLT3‐ITD) have consistently been shown to be adversely prognostic, particularly those with high allelic ratio (AR). Current AML treatment strategies, including high dose cytarabine, purine analogs, FLT3 inhibitors (FLT3i), and with or without allogeneic stem cell transplant (SCT) have been shown to improve the outcomes in patients with FLT3 mutations. We analyzed a consecutive cohort of newly diagnosed patients with AML treated at a large academic medical center from January 2012 to January 2020. A total of 1576 patients with a new diagnosis of AML were reviewed. Among these, 1438 (91%) had molecular testing for FLT3 mutations and 21% (304/1438) had an FLT3 mutation, including 17% with an FLT3‐ITD mutation. We show that FLT3‐ITD high AR with NPM1 wild‐type have significantly improved survival compared with other European LeukemiaNet (ELN) adverse risk disease. In multivariable cox proportional hazards model of patients receiving intensive or low‐intensity induction regimens, FLT3 mutations did not have prognostic significance. The use of allogeneic SCT in CR1 for patients with FLT3 mutations appears to improve survival, particularly in those with ELN adverse risk disease. Overall, this data highlights the changing prognostic impact of FLT3 mutations in a contemporary era with appropriate use of induction therapy combined with targeted agents and allogenic SCT.

Improved Outcomes Among Newly Diagnosed Patients with FLT3-ITD Mutated AML Treated with Contemporary Therapy: Revisiting the ELN Adverse Risk Classification.

Abstract: Mutations in in fms-like tyrosine kinase 3 (FLT3) gene are common genomic alterations in acute myeloid leukemia (AML). FLT3 internal tandem duplication mutations (FLT3-ITD) have consistently been shown to be adversely prognostic, particularly those with high allelic ratio. Current AML treatment strategies including high dose cytarabine, purine analogs, FLT3 inhibitors (FLT3i), and with or without allogeneic stem cell transplant (SCT) have been shown to improve the outcomes in patients with FLT3 mutations. We analyzed a consecutive cohort of newly diagnosed patients with AML treated at a large academic medical center from January 2012 through January 2020. A total of 1576 patients with a new diagnosis of AML were reviewed. Among these, 1438 (91%) had molecular testing for FLT3 mutations and 21% (304/1438) had a FLT3 mutation, including 17% with a FLT3-ITD mutation. We show that FLT3-ITD high allelic ratio with NPM1 wild-type have significantly improved survival compared with other European LeukemiaNet (ELN) adverse risk disease. In multivariable cox proportional hazards model of patients receiving intensive or low intensity induction regimens, FLT3 mutations did not have prognostic significance. The use of allogeneic stem cell transplant in CR1 for patients with FLT3 mutations appears to improve survival, particularly in those with ELN adverse risk disease. Overall, this data highlights the changing prognostic impact of FLT3 mutations in a contemporary era with appropriate use of induction therapy combined with targeted agents and allogenic stem cell transplant. This article is protected by copyright. All rights reserved.

Prediction of survival with intensive chemotherapy in acute myeloid leukemia

Abstract: Progress with intensive chemotherapy and supportive care measures has improved survival in newly diagnosed acute myeloid leukemia (AML). Predicting outcome helps in treatment decision making. We analyzed survival as the treatment endpoint in 3728 patients with newly diagnosed AML treated with intensive chemotherapy from 1980 to 2021. We divided the total study group (3:1 basis) into a training (n = 2790) and a validation group (n = 938). The associations between survival and 27 characteristics were investigated. In the training cohort, the multivariate analysis identified 12 consistent adverse prognostic variables independently associated with worse survival: older age, therapy‐related myeloid neoplasm, worse performance status, cardiac comorbidity, leukocytosis, anemia, thrombocytopenia, elevated creatinine and lactate dehydrogenase, cytogenetic abnormalities, and the presence of infection at diagnosis except fever of unknown origin. We categorized patients into four prognostic groups, favorable (7%), intermediate (43%), poor (39%), and very poor (11%) with estimated 5‐year survival rates of 69%, 36%, 13%, and 3% respectively (p < .001). The predictive model was validated in an independent cohort. In a subset of patients with molecular mutation profiles, adding the mutation profiles after accounting for the effects of previous factors identified NPM1 (favorable), PTPN11, and TP53 (both unfavorable) mutations as molecular prognostic factors. The new proposed predictive model for survival with intensive chemotherapy in patients with AML is robust and can be used to advise patients regarding their prognosis, to modify therapy in remission (e.g., proposing allogeneic stem cell transplantation in first remission), and to compare outcome and benefits on future investigational therapies.

Low-Dose Decitabine versus Low-Dose Azacitidine in Lower-Risk MDS

Abstract: BackgroundThe hypomethylating agents are part of the standard of care in the treatment of myelodysplastic syndromes (MDS), but their role in patients with lower-risk disease is unclear.MethodsWe randomly assigned patients with previously untreated MDS with low/intermediate-1 risk by the International Prognostic Scoring System with a Bayesian response-adaptive design to receive either 20 mg/m2 decitabine daily or 75 mg/m2 azacitidine daily on days 1 to 3 every 28-day cycle.ResultsA total of 113 patients were treated: 73 (65%) with decitabine and 40 (35%) with azacitidine. The overall response rate was 67% and 48% in the decitabine and azacitidine groups, respectively (P=0.042); among 59 patients with baseline transfusion dependency, 19 (32%) reached transfusion independence (decitabine, 16 of 39 [41%]; azacitidine, 3 of 20 [15%]; P=0.039). Of the 19 patients who reached transfusion independence, the median duration of transfusion independency was 22 months. Among 54 patients who were transfusion independent at baseline, 5 patients (9%) became transfusion dependent after therapy. No early death was observed. With a median follow-up of 68 months, the median overall event-free survival and overall survival were 17 months and 33 months, respectively.ConclusionsAttenuated dose treatment of hypomethylating agents in patients with lower-risk MDS can improve outcomes without dose-limiting side effects in a high-risk cohort as defined by the Lower-Risk Prognostic Scoring System. (Funded in part by The University of Texas MD Anderson Cancer Center and others; ClinicalTrials.gov number, NCT01720225.)

Intrathecal prophylaxis with 12 versus 8 administrations reduces the incidence of central nervous system relapse in patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia

Abstract: The incidence of central nervous system (CNS) disease in adults with acute lymphoblastic leukemia (ALL) is 5% – 15% at diagnosis and 5% at relapse with intrathecal chemotherapy (ITC). 1,2 CNS is a known sanc-tuary site of ALL, and leukemic infiltration into the CNS can lead to significant morbidity and mortality. Disease features such as hyper-leukocytosis at presentation, 3 common in Philadelphia chromosome-positive ALL (Ph + ALL), increase the risk of CNS relapse. The addition of BCR::ABL1 tyrosine kinase inhibitors (TKIs) to the back-bone of ALL therapies, including ITC, has significantly improved survival. However, with survival prolongation, CNS relapses occurred in 8% – 17% of Ph + ALL patients. 2,4,5 To reduce this incidence and prevent CNS relapses, treatment protocols with hyper-fractionated cyclophosphamide, dexamethasone, vincristine, and doxorubicin alternating with high-dose methotrexate and cytarabine (HCVAD) plus a BCR::ABL1 TKI for adults with Ph + ALL were amended in 2012 to increase the number of prophylactic ITCs empirically from 8 to 12. This study assessed the rate of CNS relapses in adults with Ph + ALL treated with 8 versus 12 ITC. We evaluated 150 consecutive patients ≥ 18 years of age (median: 51 years, range: 19 – 84), with newly diagnosed Ph + ALL treated with HCVAD ± rituximab plus imatinib, dasatinib, or ponatinib between July 2001 and January 2019. Patients with CNS disease at diagnosis were excluded. The ITC consisted mainly of methotrexate 12 mg alternating with cytarabine 100 mg given via lumbar puncture during

Ponatinib after failure of second‐generation tyrosine kinase inhibitor in resistant chronic‐phase chronic myeloid leukemia

Abstract: Ponatinib, the only third‐generation pan‐BCR::ABL1 inhibitor with activity against all known BCR::ABL1 mutations including T315I, has demonstrated deep and durable responses in patients with chronic‐phase chronic myeloid leukemia (CP‐CML) resistant to prior second‐generation (2G) TKI treatment. We present efficacy and safety outcomes from the Ponatinib Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) and CML Evaluation (PACE) and Optimizing Ponatinib Treatment in CP‐CML (OPTIC) trials for this patient population. PACE (NCT01207440) evaluated ponatinib 45 mg/day in CML patients with resistance to prior TKI or T315I. In OPTIC (NCT02467270), patients with CP‐CML and resistance to ≥2 prior TKIs or T315I receiving 45 or 30 mg/day reduced their doses to 15 mg/day upon achieving ≤1% BCR::ABL1IS or received 15 mg/day continuously. Efficacy and safety outcomes from patients with CP‐CML treated with ≥1 2G TKI (PACE, n = 257) and OPTIC (n = 93), 45‐mg starting dose cohort, were analyzed for BCR::ABL1IS response rates, overall survival (OS), progression‐free survival (PFS), and safety. By 24 months, the percentages of patients with ≤1% BCR::ABL1IS response, PFS, and OS were 46%, 68%, and 85%, respectively, in PACE and 57%, 80%, and 91%, respectively, in OPTIC. Serious treatment‐emergent adverse events and serious treatment‐emergent arterial occlusive event rates were 63% and 18% in PACE and 34% and 4% in OPTIC. Ponatinib shows high response rates and robust survival outcomes in patients whose disease failed prior to 2G TKIs, including patients with T315I mutation. The response‐based dosing in OPTIC led to improved safety and similar efficacy outcomes compared with PACE.

A clinician perspective on the treatment of chronic myeloid leukemia in the chronic phase

Abstract: Abstract Tyrosine kinase inhibitors (TKIs) have vastly improved long-term outcomes for patients with chronic myeloid leukemia (CML). After imatinib (a first-generation TKI), second- and third-generation TKIs were developed. With five TKIs (imatinib, dasatinib, bosutinib, nilotinib, and ponatinib) targeting BCR :: ABL approved in most countries, and with the recent approval of asciminib in the USA, treatment decisions are complex and require assessment of patient-specific factors. Optimal treatment strategies for CML continue to evolve, with an increased focus on achieving deep molecular responses. Using clinically relevant case studies developed by the authors of this review, we discuss three major scenarios from the perspective of international experts. Firstly, this review explores patient-specific characteristics that affect decision-making between first- and second-generation TKIs upon initial diagnosis of CML, including patient comorbidities. Secondly, a thorough assessment of therapeutic options in the event of first-line treatment failure (as defined by National Comprehensive Cancer Network and European LeukemiaNet guidelines) is discussed along with real-world considerations for monitoring optimal responses to TKI therapy. Thirdly, this review illustrates the considerations and importance of achieving treatment-free remission as a treatment goal. Due to the timing of the writing, this review addresses global challenges commonly faced by hematologists treating patients with CML during the COVID-19 pandemic. Lastly, as new treatment approaches continue to be explored in CML, this review also discusses the advent of newer therapies such as asciminib. This article may be a useful reference for physicians treating patients with CML with second-generation TKIs and, as it is focused on the physicians’ international and personal experiences, may give insight into alternative approaches not previously considered.

Contemporary outcomes in IDH‐mutated acute myeloid leukemia: The impact of co‐occurring NPM1 mutations and venetoclax‐based treatment

Abstract: Isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) mutations occur frequently in newly diagnosed (ND) acute myeloid leukemia (AML) often with co‐occurring NPM1 mutations, which may influence treatment outcomes. Detailed analysis of IDH‐mutated AML treated with venetoclax and influence of co‐occurring NPM1 mutations remains unclear. This retrospective single‐center cohort study evaluated clinical and molecular demographics,response and survival, and impact of co‐occurring NPM1 mutations in patients with IDH1 or IDH2‐mutated AML. 556 patients with IDH1, IDH2, and/or NPM1 mutated AML were included. Patients with IDH1mut AML (N = 119) were more likely to have older age, sAML, ELN‐adverse risk disease, and adverse‐risk cytogenetics compared to those with IDH2mut (N = 229) or IDHwt/NPM1mut AML (N = 208). In multivariate analysis, patients with IDH2mut (HR 0.61 [95%CI: 0.43–0.88], p value: .007) or IDHwt/NPM1mut (HR 0.65 [95% CI: 0.45–0.94], p value: .024) AML had a decreased risk of death versus IDH1mut AML. Venetoclax‐based lower‐intensity regimens partially abrogated the detrimental effect of IDH1mut with similar OS observed between IDH1mut/NPM1wt, IDH2mut/NPM1wt, and IDHwt/NPM1mut AML. With regards to the influence of IDHmut/NPM1mut cases, IC improved survival in IDH2mut/NPM1mut versus IDH2mut/NPM1wt AML (HR: 0.54 [95% CI: 0.2644–1.082], p value: .077), while venetoclax‐based therapy improved survival in IDH1mut/NPM1mut versus IDH1mut/NPM1wt AML (HR: 0.094 [95% CI: 0.01–0.74], p value: .0056). Differing outcomes were observed in IDH1mut versus IDH2mut or NPM1mut AML which were influenced by co‐occurring NPM1 mutations and partially abrogated with venetoclax‐based therapy. Given the differing biology and survival in IDH1mut AML, investigations incorporating molecularly targeted therapies such as IDH inhibitors remain warranted in this subgroup.