Venetoclax abrogates the prognostic impact of splicing factor gene mutations in newly diagnosed acute myeloid leukemia.

Mutations in splicing factor (SF) genes SRSF2, U2AF1, SF3B1, and ZRSR2 are now considered adverse risk in the European LeukemiaNet 2022 acute myeloid leukemia (AML) risk stratification. The prognostic impact of SF mutations in AML has been predominantly derived from younger patients treated with intensive (INT) therapy. We evaluated 994 patients with newly diagnosed AML, including 266 (27%) with a SFmut. Median age was 67 years overall, with patients with SFmut being older at 72 years. SRSF2 (n = 140, 53%) was the most common SFmut. In patients treated with INT, median relapse-free survival (RFS) (9.6 vs 21.4 months, P = .04) and overall survival (OS) (15.9 vs 26.7 months, P = .06) were shorter for patients with SFmut than without SFwt, however this significance abrogated when evaluating patients who received venetoclax with INT therapy (RFS 15.4 vs 20.3 months, P = .36; OS 19.6 vs 30.7 months, P = .98). In patients treated with LI, median RFS (9.3 vs 7.7 months, P = .35) and OS (12.3 vs 8.5 months, P = .14) were similar for patients with and without SFmut , and outcomes improved in all groups with venetoclax. On multivariate analysis, SFmut did not affect hazards of relapse and death for INT arm but reduced both these hazards in LI arm. In a large AML data set with >60% of patients receiving venetoclax with LI/INT therapy, SFmut had no independent negative prognostic impact. Newer prognostic models that consider LI therapy and use of venetoclax among other factors are warranted.

NPM1-mutated myeloid neoplasms are a unique entity not defined by bone marrow blast percentage.

INTRODUCTION: NPM1-mutated (NPM1mut) myeloid neoplasms (MNs) with <20% bone marrow (BM) blasts (NPM1mut MNs<20) are uncommon, and their classification remains inconsistent. METHODS: The clinicopathologic features of 54 patients with NPM1mut MNs <20 were evaluated and compared with wild-type NPM1 MNs <20 and NPM1mut MNs≥20, respectively. RESULTS: NPM1mut MNs had similar features regardless of blast percentage, except for higher IDH2 (29% vs 7%, p = .023) and FLT3 (70% vs 11%, p < .001) frequency in patients with ≥20% BM blasts. Thirty-three (61%) patients with NPM1mut MNs <20 received low-intensity chemotherapy (LIC) and 12 (22%) received intensive chemotherapy (IC). Higher complete remission rates (75% vs 27%, p = .006) and median overall survival (mOS) (not reached vs 30.4 months, p = .06) were observed with IC compared to LIC. Young patients (age <60 years) did not reach mOS either when treated with LIC or IC. Stem cell transplant was associated with increased survival only in patients treated with LIC (HR, 0.24; p = .025). No differences in mOS were observed by BM blast strata (32.2 months, not reached and 46.9 months for <10%, 10%-19%, and ≥20% blasts, p = .700) regardless of treatment modality (LIC: p = .900; IC: p = .360). Twenty-three patients (43%) with NPM1mut MNs <20 had marrow blast progression to ≥20%. CONCLUSIONS: Overall, NPM1mut MNs define a unique entity independent of BM blast percentage.

Phase 1/2 study of CPX-351 for patients with Int-2 or high risk International Prognostic Scoring System myelodysplastic syndromes and chronic myelomonocytic leukaemia after failure to hypomethylating agents.

Failure after hypomethylating agents (HMAs) is associated with dismal outcomes in higher risk myelodysplastic syndromes (HR-MDS) or chronic myelomonocytic leukaemia (CMML). We aimed to evaluate the safety and preliminary activity of lower doses of CPX-351, a liposomal encapsulation of cytarabine and daunorubicin, in a single-centre, phase 1/2 study for patients with HR-MDS or CMML after HMA failure. Four doses of CPX-351 (10, 25, 50 and 75 units/m2 ) administered on Days 1, 3 and 5 of induction and Days 1 and 3 of consolidation were evaluated. Between June 2019 and June 2023, 25 patients were enrolled (phase 1: n = 15; phase 2: n = 10) including 19 (76%) with HR-MDS and 6 (24%) with CMML. Most common grade 3-4 non-haematological treatment-emergent adverse events were febrile neutropenia (n = 12, 48%) and lung infection (n = 5, 20%). Three patients (age >75) experienced cardiac toxicity at the 75 units/m2 dose. Further enrolment continued at 50 units/m2 . Four- and 8-week mortality were 0% and 8% respectively. The overall response rate was 56% with median relapse-free and overall survivals of 9.2 (95% CI 3.2-15.1 months) and 8.7 months (95% CI 1.8-15.6 months) respectively. These data suggest that lower doses of CPX-351 are safe. Further studies are needed to evaluate its activity.

A phase 2 trial of mini-hyper-CVD, blinatumomab, and ponatinib in Philadelphia positive acute lymphoblastic leukemia.

Twenty adults with newly diagnosed (ND) or relapsed/refractory (RR) Ph-positive acute lymphoblastic leukemia (ALL), or chronic myeloid leukemia in lymphoid blast phase (CML-LBP), were treated with mini-hyperCVD, ponatinib, and blinatumomab. Complete molecular response was achieved in 78% of ND patients, while CR/CRi was achieved in 100% of RR and CML-LBP. The 3-year overall survival rate was 76% (95% CI, 47%-90%).

Effect of Digital Health Coaching on Self-Efficacy and Patient-Reported Outcomes in Individuals with Acute Myeloid and Chronic Lymphocytic Leukemia: A Pilot Randomized Controlled Trial.

INTRODUCTION: Promotion of self-efficacy can enhance engagement with health care and treatment adherence in patients with cancer. We report the outcomes of a pilot trial of a digital health coach intervention in patients with leukemia with the aim of improving self-efficacy. METHODS: Adult patients with newly diagnosed acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) were randomized 1:1 to a digital health coach intervention or standard of care. The primary outcome of self-efficacy was measured by the Cancer Behavior Inventory (CBI) score. RESULTS: A total of 147 patients (37 AML, 110 CLL) were enrolled from July 2020 to December 2022. In the AML cohort, there was a mean increase in CBI score of 7.03 in the digital health coaching arm compared to a mean decrease of -3.57 in the control arm at 30 days (p = 0.219). There were no significant associations between the intervention and other patient-reported outcomes for patients with CLL. CONCLUSION: There were numerical, but not statistically significant increases in self-efficacy metrics in AML patients who received digital health coaching. Although this trial was underpowered due to enrollment limitations during a pandemic, digital health coaching may provide benefit to patients with hematologic malignancy and warrants further investigation.

Clonal hematopoiesis: malignant implications, extrahematologic manifestations, and management.

As individuals age, their hematopoietic stem cells can sporadically acquire genetic mutations, known as clonal hematopoiesis. Although most of these genomic aberrations are of little consequence, particular changes in certain contexts can lead to the development of hematologic malignancies, such as myelodysplastic syndromes and acute myeloid leukemia. Owing to its pervasive extrahematologic interactions, clonal hematopoiesis is a recognized risk factor for and is causally implicated in the development of several chronic diseases of aging and/or inflammation, such as atherosclerotic cardiovascular disease. Here, we provide a review of the diagnosis and clinical implications of clonal hematopoiesis, as well as evolving management strategies in the absence of formal consensus guidelines.

A retrospective study of cladribine and low-dose cytarabine-based regimens for the treatment of chronic myelomonocytic leukemia and secondary acute myeloid leukemia.

BACKGROUND: Patients with higher risk chronic myelomonocytic leukemia (CMML) have limited therapeutic options beyond hydroxyurea and hypomethylating agents (HMAs). Regimens based on a backbone of cladribine (CLAD), low-dose cytarabine (LDAC), and an HMA are effective low-intensity therapies for acute myeloid leukemia (AML). METHODS: The authors conducted a retrospective chart review to evaluate the efficacy of CLAD/LDAC/HMA in CMML and secondary acute myeloid leukemia (sAML) arising from CMML. Responses were evaluated according to the 2006 International Working Group criteria for CMML and the 2017 European LeukemiaNet criteria for AML. The overall survival (OS), leukemia-free survival (LFS), and duration of response were evaluated with the Kaplan-Meier method. Patients were stratified on the basis of prior HMA exposure. RESULTS: The authors identified 21 patients with CMML (eight with HMA-naive CMML and 13 with HMA-failure CMML) and 33 patients with sAML (11 with HMA-naive sAML and 22 with HMA-failure sAML) treated with CLAD/LDAC/HMA-based regimens. The CMML cohort was enriched for high-risk features (proliferative type, elevated blasts, and RAS/MAPK mutations). The overall response rate was 33% in CMML (50% in HMA-naive CMML and 23% in HMA-failure CMML) and 48% in sAML (82% in HMA-naive sAML and 32% in HMA-failure sAML). The median OS was 14.4, 8.8, 42.9, and 2.9 months for HMA-naive CMML, HMA-failure CMML, HMA-naive sAML, and HMA-failure sAML, respectively. The median LFS was 14.4 and 3.9 months for HMA-naive CMML and HMA-failure CMML, respectively. CONCLUSIONS: CLAD/LDAC/HMA-based regimens are effective in a subset of patients with higher risk CMML and sAML arising from CMML who have not previously experienced HMA failure. These findings must be confirmed in prospective studies.

Phenotypic subtypes of leukaemic transformation in chronic myelomonocytic leukaemia.

Chronic myelomonocytic leukaemia (CMML) is a haematological disorder with high risk of transformation to acute myeloid leukaemia (AML). To characterize the phenotypic and genomic patterns of CMML progression, we evaluated a cohort of 189 patients with AML evolving from CMML. We found that transformation occurs through distinct trajectories characterized by genomic profiles and clonal evolution: monocytic (Mo-AML, 53%), immature myeloid (My-AML, 43%) or erythroid (Ery-AML, 2%). Mo-AML, characterized by expansion of monoblasts and promonocytes (low CD34, CD117 expression; high CD14, CD33, CD56 and CD64 expression), were defined by SRSF2, TET2 and RAS pathway mutation co-dominance and were more likely to evolve from SRSF2-TET2 co-mutant CMML through emergence/expansion of RAS pathway mutant clones. Conversely, My-AML, characterized by expansion of immature myeloid blasts (high frequency of CD34, CD38, CD117; low frequency of CD14, CD64 and CD56 expression) were less likely to exhibit SRSF2-TET2 co-mutations or RAS pathway mutations and had higher frequency of CEBPA mutations. Ery-AML was defined by complex karyotypes and TP53 mutations. A trend towards improved OS and EFS with hypomethylating agent-venetoclax combination was observed in My-AML, but not Mo-AML. These findings define distinct progression of CMML and set the basis for future studies evaluating the role of phenotype-specific therapeutics.

Performance of IPSS-M in patients with myelodysplastic syndrome after hypomethylating agent failure.

Evaluation of IPSS-M and exploratory prognostic model for MDS at the time of HMA failure.

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.

Invasive mucorales sinusitis in a young patient with Emberger syndrome and newly diagnosed AML: A case report and literature review of invasive fungal infections in GATA2 deficiency.

Germline pathogenic variants (PVs) in the gene encoding the GATA2 transcription factor can result in profound reductions of monocytes, dendritic cells, natural killer cells and B cells. GATA2 PVs are associated with an increased risk of myeloid malignancies and a predisposition to nontuberculous mycobacterial and human papillomavirus infections. Additionally, invasive fungal infections (IFIs) have been reported in individuals with GATA2 PVs, even in the absence of myeloid malignancies. In this report, we present the case of a 40-year-old man with Emberger syndrome (GATA2 mutation, recently diagnosed acute myeloid leukaemia [AML] and history of lymphedema with hearing loss) who developed Mucorales sinusitis while receiving his first course of remission induction chemotherapy. Additionally, we review the literature on all published cases of proven IFIs in patients with GATA2 PVs. Clinicians should be aware that patients with GATA2 PVs could be vulnerable to opportunistic IFIs, even in the absence of AML and antineoplastic therapy. Furthermore, the distinctly unusual occurrence of mucormycosis during the first course of induction chemotherapy for AML in our patient indicates that patients with germline GATA2 PVs receiving induction chemotherapy for AML might be at high risk for early onset of IFIs due to aggressive, opportunistic moulds.

Differential prognostic impact of RUNX1 mutations according to frontline therapy in patients with acute myeloid leukemia.

RUNX1-mutated (mRUNX1) acute myeloid leukemia (AML) has historically been associated with poor outcomes in the setting of conventional chemotherapy. The prognostic impact of mRUNX1 AML is not well-established in the current era of lower-intensity treatment regimens incorporating venetoclax. We retrospectively analyzed 907 patients with newly diagnosed AML, including 137 patients with mRUNX1 AML, who underwent first-line therapy with intensive chemotherapy (IC), low-intensity therapy without venetoclax (LIT without VEN), or LIT with VEN. When stratified by RUNX1 status, there was no statistically significant difference in outcomes between mRUNX1 and wild-type (wtRUNX1) AML, regardless of therapy received. However, among patients who received LIT with VEN, there was a trend towards superior overall survival (OS) in those with mRUNX1 AML (median OS for mRUNX1 vs. wtRUNX1: 25.1 vs. 11.3 months; 2-year OS 54% vs. 33%; p = 0.12). In patients without another adverse-risk cyto-molecular feature, the presence of mRUNX1 conferred inferior OS in patients who received IC (p = 0.02) or LIT without VEN (p = 0.003) but not in those who received LIT with VEN (mRUNX1 vs. wtRUNX1: 25.1 vs. 30.0 months; 2-year OS 59% vs. 54%; p = 0.86). A multivariate analysis showed possible interaction between RUNX1 mutation status and treatment, suggesting a differential prognostic impact of RUNX1 mutations when patients received IC versus LIT with VEN. In summary, the prognostic impact of mRUNX1 AML may be treatment-dependent, and the presence of RUNX1 mutations may not impact clinical outcomes when venetoclax-based regimens are used.

A Phase II Study of Azacitidine, Venetoclax, and Trametinib in Relapsed or Refractory Acute Myeloid Leukemia Harboring RAS Pathway-Activating Mutations.

INTRODUCTION: RAS pathway mutations are common mechanisms of resistance to acute myeloid leukemia (AML) therapies. Trametinib, an oral MEK inhibitor, has been shown to have single-agent activity in relapsed/refractory AML and preclinical synergy with venetoclax. METHODS: We conducted a single-center, open-label, phase 2 trial of the combination of azacitidine, venetoclax, and trametinib in patients with relapsed or refractory AML harboring a RAS pathway-activating mutation. RESULTS: Sixteen patients were treated. The patients were heavily pretreated with a median number of 4 prior therapies; 13 (81%) had received a prior hypomethylating agent (HMA) with venetoclax, and 8 (50%) had undergone prior stem cell transplant. Four patients (25%) responded (CR, n = 1; CRi, n = 1; MLFS, n = 2). Two of the 3 patients (67%) who had not previously received HMA plus venetoclax responded; in contrast, only 2 of the 13 patients (15%) who had previously received HMA plus venetoclax responded. The median OS was 2.4 months, and the 6-month OS rate was 31%. Related grade 3-4 adverse events occurred in 50% of patients, and 50% of patients required a dose adjustment of trametinib. CONCLUSIONS: The combination of azacitidine, venetoclax, and trametinib had only modest activity in patients with relapsed/refractory AML, with a response rate that was similar to previous reports of trametinib monotherapy. Substantial toxicity was observed with this combination. Given the established role of RAS pathway mutations in mediating resistance to AML therapies, future studies of better tolerated, more active inhibitors of this pathway are still needed.

Only SF3B1 mutation involving K700E independently predicts overall survival in myelodysplastic syndromes.

BACKGROUND: SF3B1 mutations (SF3B1mut ) in myelodysplastic syndromes (MDS) frequently involve codon K700E and have a favorable prognosis. The prognostic effect of non-K700E SF3B1mut is uncertain. METHODS: The authors analyzed the clinicopathological features and outcomes of a single-institution series of 94 treatment-naive SF3B1mut MDS patients (18%) and 415 treatment-naive SF3B1wt MDS patients and explored the differences between K700E and non-K700E SF3B1mut MDS. RESULTS: Fifty-five patients (59%) carried K700E. Recurrent non-K700E mutations (39 [41%]) included R625, H662, and K666. Compared with SF3B1mut K700E patients, non-K700E patients had a lower median absolute neutrophil count (1.8 vs 2.4; P = .005) and were frequently "high" according to the Revised International Prognostic Scoring System (19% vs 4%; P = .031). Non-K700E MDS was associated frequently with RUNX1 (26% vs 7%; P = .012) and exclusively with BCOR, IDH2, and SRSF2 mutations. A splicing analysis showed the differential distribution of alternatively spliced events and gene expression profiles between K700 and non-K700E MDS patients. The majority (at least 80%) of SF3B1mut K700E, SF3B1mut non-K700E, and SF3B1wt patients were treated with hypomethylating agents. Over a median follow-up of 16 months, SF3B1mut had superior overall survival (OS) in comparison with SF3B1wt in all MDS patients (not reached vs 25.2 months; P = .0003), in patients with low-grade MDS, and in patients with myelodysplastic syndromes with ring sideroblasts (MDS-RS). Compared with SF3B1wt , SF3B1mut K700E had superior outcomes in all MDS (median OS, 25 months vs not reached; P = .0001), in low-grade MDS (median OS, 41.3 months vs not reached; P = .0015), and in MDS-RS (median OS, 22.3 months vs not reached; P = .0001), but no significant difference was seen between non-K700E and SF3B1wt MDS. By multivariable analysis, the absence of SF3B1mut K700E mutations was independently associated with the prognosis. CONCLUSIONS: This study highlights the importance of the SF3B1 mutation subtype in MDS risk assessment. LAY SUMMARY: Myelodysplastic syndromes (MDS) with SF3B1 mutations are regarded as having a favorable prognosis by both the World Health Organization and the International Working Group for the Prognosis of Myelodysplastic Syndromes. However, this article shows that only MDS patients with SF3B1 K700E mutations have a favorable prognosis (and not MDS patients with SF3B1 mutations involving other codons). This has important implications for refining future MDS subclassification and risk assessment criteria.

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.

Myelodysplastic syndromes: 2021 update on diagnosis, risk stratification and management.

DISEASE OVERVIEW: The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). Myelodysplastic syndromes occur more frequently in older males and in individuals with prior exposure to cytotoxic therapy. DIAGNOSIS: Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry and molecular genetics is usually complementary and may help refine diagnosis. RISK-STRATIFICATION: Prognosis of patients with MDS can be calculated using a number of scoring systems. In general, all these scoring systems include analysis of peripheral cytopenias, percentage of blasts in the bone marrow and cytogenetic characteristics. The most commonly accepted system is the Revised International Prognostic Scoring System (IPSS-R). Somatic mutations can help define prognosis and therapy. RISK-ADAPTED THERAPY: Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts, cytogenetic and mutational profiles, comorbidities, potential for allogeneic stem cell transplantation (alloSCT) and prior exposure to hypomethylating agents (HMA). Goals of therapy are different in lower-risk patients than in higher-risk individuals and in those with HMA failure. In lower-risk MDS, the goal is to decrease transfusion needs and transformation to higher risk disease or AML, as well as to improve survival. In higher-risk disease, the goal is to prolong survival. In 2020, we witnessed an explosion of new agents and investigational approaches. Current available therapies include growth factor support, lenalidomide, HMAs, intensive chemotherapy and alloSCT. Novel therapeutics approved in 2020 are luspatercept and the oral HMA ASTX727. At the present time, there are no approved interventions for patients with progressive or refractory disease particularly after HMA-based therapy. Options include participation in a clinical trial, cytarabine-based therapy or alloSCT.

Safety and tolerability of lurbinectedin (PM01183) in patients with acute myeloid leukemia and myelodysplastic syndrome.

Trabectedin is an FDA-approved DNA minor groove binder that has activity against translocation-associated sarcomas. Lurbinectedin is a next-generation minor groove binder with preclinical activity against myeloid leukemia cells. A dose-finding phase 1 clinical trial was performed in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of safety and tolerability. Forty-two patients with relapsed/refractory AML/MDS received lurbinectedin administered as a 1-hour intravenous infusion in a 3 + 3 study design. Two dosing schedules were used: 3.5, 5, 7, or 6 mg on days 1 and 8 or 2, 3, 1, or 1.5 mg for 3 consecutive days on days 1 to 3. Three patients experienced dose-limiting toxicities of rhabdomyolysis (grade 4), hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the day 1 and 8 schedule. Otherwise, adverse events mainly consisted of gastrointestinal manifestations (n = 11), febrile neutropenia/infections (n = 4), pulmonary toxicity (n = 2), and renal failure (n = 2). The most common laboratory abnormalities observed were an increase in creatinine (93%) and anemia, neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had reduction in blasts in peripheral blood or bone marrow. One patient achieved a partial response and 2 patients a morphologic leukemia-free state. Most (n = 30, 71%) were discontinued due to progressive disease. Early deaths occurred from disease-related causes that were not attributable to lurbinectedin. Four patients with a chromosome 11q21-23 abnormality had significantly greater bone marrow blast reduction than those without such abnormality, with decrease of 31 ± 14% (n = 4) vs 8 ± 8% (n = 16), respectively (P = .04). Overall, lurbinectedin was safe and tolerated using the schedules and dose levels tested. While no sustained remissions were observed, single-agent lurbinectedin was transiently leukemia suppressive for some patients.