Ponatinib vs Imatinib in Frontline Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.

Importance: In newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is common. Ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I. Objective: To compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL. Design, Setting, and Participants: Global registrational, phase 3, open-label trial in adults aged 18 years or older with newly diagnosed Ph+ ALL. From January 2019 to May 2022, eligible patients at 77 sites were randomized 2:1 to ponatinib (30 mg/d) or imatinib (600 mg/d) with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after the cycle 20 phase of the trial. The last date of follow-up for this analysis was August 12, 2022. Intervention: Patients received ponatinib, 30 mg/d, or imatinib, 600 mg/d, with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. The ponatinib dose was reduced to 15 mg on achievement of minimal residual disease-(MRD) negative complete remission. Main Outcomes and Measures: The primary end point of this interim analysis was MRD-negative complete remission (≤0.01% BCR::ABL1 [MR4] centrally assessed by reverse transcriptase-quantitative polymerase chain reaction), with complete remission maintained for at least 4 weeks at the end of cycle 3. The key secondary end point was event-free survival. Results: Of 245 patients randomized (median age, 54 years; 133 [54.3%] female), 232 (ponatinib, n = 154; imatinib, n = 78) who had p190 or p210 dominant isoforms verified by the central laboratory were analyzed for the primary end point. The MRD-negative complete remission rate (primary end point) was significantly higher with ponatinib (34.4% [53/154]) vs imatinib (16.7% [13/78]) (risk difference, 0.18 [95% CI, 0.06-0.29]; P = .002). At the data cutoff, event-free survival had not met the prespecified number of events. Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group. The most common adverse events were similar between treatment groups. Arterial occlusive events were infrequent and comparable between groups (ponatinib, 2.5%; imatinib, 1.2%). Conclusions and Relevance: Ponatinib demonstrated a superior rate of MRD-negative complete remission at the end of induction vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. The safety profile of ponatinib was comparable with imatinib. Trial Registration: ClinicalTrials.gov Identifier: NCT03589326.

Ponatinib-review of historical development, current status, and future research.

Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with high potency against Philadelphia chromosome (Ph)-positive leukemias, including T315I-mutated disease, which is resistant to first- and second-generation TKIs. Ponatinib was approved for T315I-mutated chronic myeloid leukemia (CML), CML resistant/intolerant to ≥2 prior TKIs, advanced phase CML and Ph-positive acute lymphoblastic leukemia (ALL) where no other TKIs are indicated, and T315I-mutated CML and Ph-positive ALL. The response-based dosing of ponatinib in chronic phase CML (CP-CML) improved treatment tolerance and reduced the risk of toxicities, including cardiovascular risks. Ponatinib-based therapy also resulted in significantly better outcomes in frontline Ph-positive ALL compared with prior TKIs and is becoming a new standard of care in this setting. As the clinical development of third-generation TKIs and their rational combinations progresses, we envision further transformative changes in the treatment of CML and Ph-positive ALL.

Association of leukemic molecular profile with efficacy of inotuzumab ozogamicin in adults with relapsed/refractory ALL.

The phase 3 INO-VATE trial demonstrated higher rates of remission, measurable residual disease negativity, and improved overall survival for patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (InO) vs standard of care chemotherapy (SC). Here we examined associations between genomic alterations and the efficacy of InO. Of 326 randomized patients, 91 (InO, n=43; SC, n=48) had samples evaluable for genomic analysis. The spectrum of gene fusions and other genomic alterations observed was comparable with prior studies of adult ALL. Responses to InO were observed in all leukemic subtypes, genomic alterations, and risk groups. Significantly higher rates of complete remission (CR)/CR with incomplete count recovery rates were observed with InO vs SC in patients with BCR::ABL1-like ALL (85.7% [6/7] vs 0% [0/5] P=0.0076), with TP53 alterations (100% [5/5] vs 12.5% [1/8], P=0.0047), and in the high-risk BCR::ABL1- (BCR::ABL1-like, low hypodiploid, KMT2A-rearranged) group (83.3% [10/12] vs 10.5% [2/19]; P<0.0001). This retrospective, exploratory analysis of the INO-VATE trial demonstrated potential for benefit with InO for patients with R/R ALL across leukemic subtypes, including BCR::ABL1-like ALL, and for those bearing diverse genomic alterations. Further confirmation of the efficacy of InO in patients with R/R ALL exhibiting the BCR::ABL1-like subtype or harboring TP53 alterations is warranted. This trial was registered at www.clinicaltrials.gov as no. NCT01564784.

Therapy-related chronic myelomonocytic leukemia does not have the high-risk features of a therapy-related neoplasm.

Therapy-related myeloid neoplasms (t-MNs) arise after exposure to cytotoxic therapies and are associated with high-risk genetic features and poor outcomes. We analyzed a cohort of patients with therapy-related chronic myelomonocytic leukemia (tCMML; n = 71) and compared its features to that of de novo CMML (dnCMML; n = 461). Median time from cytotoxic therapy to tCMML diagnosis was 6.5 years. Compared with dnCMML, chromosome 7 abnormalities (4% vs. 13%; P = .005), but not complex karyotype (3% vs. 7%; P = .15), were more frequent in tCMML. tCMML was characterized by higher TP53 mutation frequency (4% vs. 12%; P = .04) and lower NRAS (6% vs 22%, P =0.007) and CBL (4% vs 12%, P =0.04) mutation frequency. Prior therapy with antimetabolites (OR, 1.22 [95% CI, 1.05-1.42]; P = .01) and mitotic inhibitors (OR, 1.24 [95% CI, 1.06-1.44]; P = .009) was associated with NF1 and SETBP1 mutations while prior mitotic inhibitor therapy was associated with lower TET2 mutation frequency (OR, 0.71 [95% CI, 0.55-0.92]; P = .01). Although no differences in median overall survival (OS) were observed among tCMML and dnCMML (34.7 months vs 35.9 months, P = .26), multivariate analysis for OS revealed that prior chemotherapy was associated with increased risk of death (HR 1.76 [95% CI, 1.07-2.89]; P = .026). Compared to a cohort of therapy-related myelodysplastic syndrome, tCMML had lower TP53 mutation frequency (12% vs 44.4%, P <.001) and less unfavorable outcomes. In summary, tCMML does not exhibit the high-risk features and poor outcomes of t-MNs.

Cancer patients with clonal hematopoiesis die from primary malignancy or comorbidities despite higher rates of transformation to myeloid neoplasms.

BACKGROUND: The occurrence of somatic mutations in patients with no evidence of hematological disorders is called clonal hematopoiesis (CH). CH, whose subtypes include CH of indeterminate potential and clonal cytopenia of undetermined significance, has been associated with both hematologic cancers and systemic comorbidities. However, CH's effect on patients, especially those with concomitant malignancies, is not fully understood. METHODS: We performed a retrospective evaluation of all patients with CH at a tertiary cancer center. Patient characteristics, mutational data, and outcomes were collected and analyzed. RESULTS: Of 78 individuals included, 59 (76%) had a history of cancer and 60 (77%) had moderate to severe comorbidity burdens. DNMT3A, TET2, TP53, and ASXL1 were the most common mutations. For the entire cohort, the 2-year overall survival rate was 79% (95% CI: 70, 90), while the median survival was not reached. Of 20 observed deaths, most were related to primary malignancies (n = 7, 35%), comorbidities (n = 4, 20%), or myeloid neoplasms (n = 4, 20%). Twelve patients (15%) experienced transformation to a myeloid neoplasm. According to the clonal hematopoiesis risk score, the 3-year transformation rate was 0% in low-risk, 15% in intermediate-risk (p = 0.098), and 28% in high-risk (p = 0.05) patients. By multivariate analysis, transformation was associated with variant allele frequency ≥0.2 and hemoglobin <10 g/dL. CONCLUSIONS: In a population including mostly cancer patients, CH was associated with comorbidities and myeloid transformation in patients with higher mutational burdens and anemia. Nevertheless, such patients were less likely to die of their myeloid neoplasm than of primary malignancy or comorbidities.

SOHO State of the Art Updates and Next Questions | Novel Agents and the Diminishing Role of Allogeneic Stem Cell Transplant in B-Acute Lymphoblastic Leukemia.

Outcomes of patients with B-acute lymphoblastic leukemia (B-ALL) have improved remarkably in the past decade. This has largely been due to the development and introduction of novel immunotherapies such as blinatumomab, inotuzumab ozogamicin, chimeric antigen receptor T (CAR-T) cells, highly potent tyrosine kinase inhibitors, and improved risk stratification, including better understanding of high risk genomic subgroups and better methods of measurable residual disease (MRD) detection. Historically, allogeneic stem cell transplant (allo-SCT) has been the consolidative treatment of choice in first complete remission for fit adults with B-ALL. However, allo-SCT is associated with significant treatment-related mortality and morbidity. Current research is directed at the incorporation of novel immunotherapies into frontline regimens to improve depth and durability of responses and ultimately increase cure rates. In this review, we will discuss the emerging role of novel immune-based treated strategies in both the frontline and relapsed/refractory settings. We present our approach to newly diagnosed patients with B-ALL and illustrate how the incorporation of novel agents and use of high-sensitivity MRD assays can abrogate the need for allo-SCT in most patients with B-ALL.

Genomic determinants of response and resistance to inotuzumab ozogamicin in B-cell ALL.

Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO-treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of response and resistance to InO. Pre- and post-InO patient samples were analyzed by whole genome, exome, and/or transcriptome sequencing. Acquired CD22 mutations were observed in 11% (3/27) of post-InO relapsed tumor samples, but not in refractory samples (0/16). There were multiple CD22 mutations per sample and the mechanisms of CD22 escape included epitope loss (protein truncation, protein destabilization) and epitope alteration. Two CD22 mutant cases were post-InO hypermutators resulting from error-prone DNA damage repair (non-homologous/alternative end joining, mismatch repair deficiency), suggesting hypermutation drove escape from CD22-directed therapy. CD22-mutant relapses occurred after InO and subsequent hematopoietic stem cell transplantation (HSCT), suggesting InO eliminated predominant clones, leaving subclones with acquired CD22 mutations that conferred resistance to InO and subsequently expanded. Acquired loss-of-function mutations in TP53, ATM and CDKN2A were observed, consistent with compromise of the G1/S DNA damage checkpoint as a mechanism of evading InO-induced apoptosis. Genome wide CRISPR/Cas9 screening in cell lines identified DNTT (TdT) loss as a marker of InO resistance. In conclusion, genetic alterations modulating CD22 expression and DNA damage response influence InO efficacy. Our findings highlight the importance of defining the basis of CD22 escape, and eradication of residual disease prior to HSCT. The identified mechanisms of escape from CD22-targeted therapy extend beyond antigen loss, and provide opportunities to improve therapeutic approaches and overcome resistance.

Ivosidenib significantly reduces triazole levels in patients with acute myeloid leukemia and myelodysplastic syndrome.

BACKGROUND: Ivosidenib is primarily metabolized by CYP3A4; however, it induces CYP450 isozymes, including CYP3A4 and CYP2C9, whereas it inhibits drug transporters, including P-glycoprotein. Patients with acute myeloid leukemia are at risk of invasive fungal infections, and therefore posaconazole and voriconazole are commonly used in this population. Voriconazole is a substrate of CYP2C9, CYP2C19, and CYP3A4; therefore, concomitant ivosidenib may result in decreased serum concentrations. Although posaconazole is a substrate of P-glycoprotein, it is metabolized primarily via UDP glucuronidation; thus, the impact of ivosidenib on posaconazole exposure is unknown. METHODS: Patients treated with ivosidenib and concomitant triazole with at least one serum trough level were included. Subtherapeutic levels were defined as posaconazole <700 ng/mL and voriconazole <1.0 µg/mL. The incidences of breakthrough invasive fungal infections and QTc prolongation were identified at least 5 days after initiation of ivosidenib with concomitant triazole. RESULTS: Seventy-eight serum triazole levels from 31 patients receiving ivosidenib-containing therapy and concomitant triazole were evaluated. Of the 78 concomitant levels, 47 (60%) were subtherapeutic (posaconazole: n = 20 of 43 [47%]; voriconazole: n = 27 of 35 [77%]). Compared to levels drawn while patients were off ivosidenib, median triazole serum levels during concomitant ivosidenib were significantly reduced. There was no apparent increase in incidence of grade 3 QTc prolongation with concomitant azole antifungal and ivosidenib 500 mg daily. CONCLUSIONS: This study demonstrated that concomitant ivosidenib significantly reduced posaconazole and voriconazole levels. Voriconazole should be avoided, empiric high-dose posaconazole (>300 mg/day) may be considered, and therapeutic drug monitoring is recommended in all patients receiving concomitant ivosidenib.

Targetable genetic abnormalities in patients with acute myeloblastic leukemia across age groups.

Incidence of potential targetable genetic abnormalities by age in AML.

Pivekimab sunirine (IMGN632), a novel CD123-targeting antibody-drug conjugate, in relapsed or refractory acute myeloid leukaemia: a phase 1/2 study.

BACKGROUND: Pivekimab sunirine (IMGN632) is a first-in-class antibody-drug conjugate comprising a high-affinity CD123 antibody, cleavable linker, and novel indolinobenzodiazepine pseudodimer payload. CD123 is overexpressed in several haematological malignancies, including acute myeloid leukaemia. We present clinical data on pivekimab sunirine in relapsed or refractory acute myeloid leukaemia. METHODS: This first-in-human, phase 1/2 dose-escalation and dose-expansion study enrolled participants aged 18 years or older at nine hospitals in France, Italy, Spain, and the USA with CD123+ haematological malignancies (Eastern Cooperative Oncology Group performance status of 0-1); participants reported here were in a cohort of participants with acute myeloid leukaemia who were refractory to or had relapsed on one or more previous treatments for acute myeloid leukaemia. The 3 + 3 dose-escalation phase evaluated two dosing schedules: schedule A (once every 3 weeks, on day 1 of a 3-week cycle) and fractionated schedule B (days 1, 4, and 8 of a 3-week cycle). The dose-expansion phase evaluated two cohorts: one cohort given 0·045 mg/kg of bodyweight (schedule A) and one cohort given 0·090 mg/kg of bodyweight (schedule A). The primary endpoints were the maximum tolerated dose and the recommended phase 2 dose. Antileukaemia activity (overall response and a composite complete remission assessment) was a secondary endpoint. The study is ongoing and registered with ClinicalTrials.gov, NCT03386513. FINDINGS: Between Dec 29, 2017, and May 27, 2020, 91 participants were enrolled (schedule A, n=68; schedule B, n=23). 30 (44%) of schedule A participants were female and 38 (56%) were male; 60 (88%) were White, six (9%) were Black or African American, and two (3%) were other races. Pivekimab sunirine at doses of 0·015 mg/kg to 0·450 mg/kg in schedule A was administered in six escalating doses with no maximum tolerated dose defined; three dose-limiting toxicities were observed (reversible veno-occlusive disease; 0·180 mg/kg, n=1 and 0·450 mg/kg, n=1; and neutropenia; 0·300 mg/kg, n=1). Schedule B was not pursued further on the basis of comparative safety and antileukaemia findings with schedule A. The recommended phase 2 dose was selected as 0·045 mg/kg once every 3 weeks. At the recommended phase 2 dose (n=29), the most common grade 3 or worse treatment-related adverse events were febrile neutropenia (three [10%]), infusion-related reactions (two [7%]), and anaemia (two [7%]). Treatment-related serious adverse events occurring in 5% or more of participants treated at the recommended phase 2 dose were febrile neutropenia (two [7%]) and infusion-related reactions (two [7%]). Among 68 participants who received schedule A, one death (1%) was considered to be treatment-related (cause unknown; 0·300 mg/kg cohort). At the recommended phase 2 dose, the overall response rate was 21% (95% CI 8-40; six of 29) and the composite complete remission rate was 17% (95% CI 6-36; five of 29). INTERPRETATION: Pivekimab sunirine showed single-agent activity across multiple doses, with a recommended phase 2 dose of 0·045 mg/kg once every 3 weeks. These findings led to a phase 1b/2 study of pivekimab sunirine plus azacitidine and venetoclax in patients with CD123-positive acute myeloid leukaemia. FUNDING: ImmunoGen.

A Review of the Therapeutic Role of Bosutinib in Chronic Myeloid Leukemia.

The development of the BCR::ABL1 tyrosine kinase inhibitors (TKIs) has transformed Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) from a fatal disease to an often-indolent illness that, when managed effectively, can restore a life expectancy close to that of the normal population. Bosutinib is a second-generation TKI approved for adults with Ph-positive CML in chronic phase, accelerated phase, or blast phase that is resistant or intolerant to prior therapy, and for newly diagnosed Ph-positive chronic phase CML. This review details the efficacy of bosutinib for the treatment of CML in the first- and second-line settings, as well as in third- and later-line settings for high-risk patients resistant or intolerant to at least 2 TKIs. It also outlines bosutinib studies that provide evidence for dose-optimization strategies that can be used to improve efficacy and effectively manage adverse events. The studies that provide evidence for specific patient populations benefiting particularly from bosutinib dose-optimization strategies are also discussed. The well-established, long-term side-effect profile and the potential to make dose adjustments with bosutinib make it an appropriate treatment option for patients with CML. Bosutinib has demonstrated a positive impact on health-related quality of life and an important role in the long-term treatment of patients with CML.

Acute kidney injury in acute promyelocytic leukemia: a possible adverse effect of high dose arsenic trioxide in obese patients.

Arsenic trioxide (ATO)-based regimens are standard in acute promyelocytic leukemia (APL). ATO-related nephrotoxicity has not been reported. We reviewed APL patients treated with ATO to identify cases of acute kidney injury (AKI). Clinically significant cases were characterized. Multivariate analysis was performed to identify predictors of idiopathic, clinically significant AKI. One hundred and eight patients were included. ATO dose was 0.15 mg/kg/day using actual body weight with no dose cap. Thirty-one (28.7%) AKI cases were identified, 10 (32.3%) clinically significant. Six were idiopathic; five required dialysis. The proportion with significant, idiopathic AKI was 15.8% in patients receiving >15mg ATO versus 0% in those receiving ≤15mg (p = 0.001). On multivariate analysis, only ATO dose was a significant predictor of clinically significant AKI (odds ratio of 1.91, 95%CI, 1.19-3.07, p = 0.007). High-dose ATO may be associated with significant nephrotoxicity. We recommend that ATO dose be capped at 15 mg to minimize toxicity for this curable disease.

Prognostic risk signature in patients with acute myeloid leukemia treated with hypomethylating agents and venetoclax.

ABSTRACT: Hypomethylating agents (HMAs) and venetoclax (Ven) represent the standard of care for patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. However, the European LeukemiaNet (ELN) risk classifications have been validated for patients treated with intensive therapy. In this study, we validate a recently proposed new molecular prognostic risk signature (mPRS) for patients with AML treated with HMAs and Ven. This classification allocated patients to favorable, intermediate (N/KRAS or FLT3-internal tandem duplication mutations), and lower (TP53 mutations) benefit groups. We retrospectively analyzed 159 patients treated with HMA and Ven. The mPRS classification allocated 74 (47%), 31 (19%), and 54 (34%) patients to the higher, intermediate, and lower-benefit groups, respectively. The overall response rate was 71% (86%, 54%, and 59% in the higher, intermediate, and lower-benefit groups, respectively). The median overall survival (OS) and event-free survival (EFS) times were 30 and 19 months, respectively, in the higher-benefit group; 12 and 8 months in the intermediate-benefit group; and 5 and 4 months in the lower-benefit group (P < .001). The C-index for OS and EFS was higher when stratifying patients according to mPRS classification than with the ELN 2022 classification. The 2-year cumulative incidence of relapse was 35%, 70%, and 60% in the higher, intermediate, and lower-benefit groups, respectively (P = .005). The mPRS classification accurately segregated groups of patients with AML treated with HMA plus Ven. In these patients, N/KRAS and TP53 mutations appear to negatively affect outcomes; therefore, new treatment approaches are warranted.

Genomic determinants of response and resistance to inotuzumab ozogamicin in B-cell ALL.

Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of response to InO. Acquired CD22 mutations were observed in 11% (3/27) of post-InO relapsed tumor samples. There were multiple CD22 mutations per sample and the mechanisms of CD22 escape included protein truncation, protein destabilization, and epitope alteration. Hypermutation by error-prone DNA damage repair (alternative end-joining, mismatch repair deficiency) drove CD22 escape. Acquired loss-of-function mutations in TP53 , ATM and CDKN2A were observed, suggesting compromise of the G1/S DNA damage checkpoint as a mechanism of evading InO-induced apoptosis. In conclusion, genetic alterations modulating CD22 expression and DNA damage response influence InO efficacy. The escape strategies within and beyond antigen loss to CD22-targeted therapy elucidated in this study provide insights into improving therapeutic approaches and overcoming resistance. KEY POINTS: We identified multiple mechanisms of CD22 antigen escape from inotuzumab ozogamicin, including protein truncation, protein destabilization, and epitope alteration.Hypermutation caused by error-prone DNA damage repair was a driver of CD22 mutation and escape.

Survival outcomes in patients with relapsed/refractory or MRD-positive B-cell acute lymphoblastic leukemia treated with blinatumomab.

Blinatumomab has demonstrated significant efficacy in adult and pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-cell ALL) and patients with measurable residual disease (MRD). This review aimed to compare median relapse-free survival (RFS) and median overall survival (OS) in adult and pediatric patients with R/R or MRD-positive B-cell ALL from pivotal studies [MT-103-211 and TOWER for adults with Philadelphia chromosome (Ph)-negative R/R B-cell ALL, ALCANTARA for adults with Ph-positive R/R B-cell ALL, MT-103-203 for adults with MRD-positive B-cell ALL, and MT-103-205 for pediatric patients with R/R B-cell ALL], with the median RFS and OS from retrospective analyses, country or ethnicity-specific studies, and studies based on real-world evidence (RWE) identified from a literature search. Adults with Ph-negative R/R B-cell ALL who received blinatumomab as first salvage demonstrated a numerically longer median OS compared with that in patients from pivotal studies (MT-103-211 and TOWER) without additional safety concerns. In pediatric patients with R/R B-cell ALL treated with blinatumomab, the median RFS and OS from retrospective analyses and country/ethnicity-specific studies were comparable with the median RFS and OS from the pivotal study MT-103-205. The median RFS and OS from RWE studies in adults with R/R B-cell ALL were numerically longer than the median RFS and OS from pivotal studies (MT-103-211, TOWER, and ALCANTARA); however, this trend was not observed in pediatric patients with R/R B-cell ALL. In conclusion, this analysis identified first salvage adults with Ph-negative R/R B-cell ALL as particularly well-suited for treatment with blinatumomab since survival outcomes from retrospective analyses reported in this patient subgroup were numerically better compared with those from pivotal studies without additional safety signals.

Characteristics and clinical outcomes of patients with myeloid malignancies and DDX41 variants.

DDX41 is the most frequently mutated gene in myeloid neoplasms associated with germline predisposition including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We analyzed 3795 patients with myeloid neoplasms and identified 151 (4%) with DDX41 variants and a diagnosis of AML (n = 96), MDS (n = 52), and chronic myelomonocytic leukemia (n = 3). The most frequent DDX41 variants were the somatic variant p.R525H, followed by the germline variants p.M1I and p.D140fs. Most neoplasms had a normal karyotype (59%) and the most frequent co-mutations were TP53 (16%) and ASXL1 (15%). 30% of patients had no concomitant mutations besides DDX41 mutation. Patients with myeloid malignancies and DDX41 variants responded well to therapy, with an overall response rate for patients with treatment naïve AML and MDS of 87% and 84%, respectively. The median overall survival (mOS) of patients with treatment-naïve AML or MDS was 49 and 71 months, respectively. Patients with AML treated with low-intensity regimens including venetoclax had an improved survival (2-year OS 91% vs. 60%, p = .02) and lower cumulative incidence of relapse compared to those treated without venetoclax (10% vs. 56%, p = .03). In the 33% of patients receiving hematopoietic stem cell transplantation, the 2-year OS was 80% and 85% for AML and MDS, respectively.