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.

Outcomes and genetic dynamics of acute myeloid leukemia at first relapse.

Patients with relapsed acute myeloid leukemia (AML) experience dismal outcomes. We performed a comprehensive analysis of patients with relapsed AML to determine the genetic dynamics and factors predicting survival. We analyzed 875 patients with newly diagnosed AML who received intensive treatment or low-intensity treatment. Of these patients, 197 subsequently relapsed. Data were available for 164 of these patients, with a median time from complete remission/complete remission with incomplete blood count recovery to relapse of 6.5 months. Thirty-five of the 164 patients (21%) experienced relapse after allogeneic hematopoietic stem cell transplantation. At relapse, mutations in genes involved in pathway signaling tended to disappear, whereas clonal hematopoiesis-related mutations or TP53 tended to persist. Patients with normal karyotypes tended to acquire cytogenetic abnormalities at relapse. Patients treated intensively had a higher rate of emergence of TP53 mutations (16%), compared to patients given low-intensity treatment (1%, P=0.009). The overall response rates were 38% and 35% for patients treated with salvage intensive treatment or low-intensity treatment, respectively. Seventeen patients (10%) underwent allogeneic stem cell transplantation after salvage therapy. The median overall survival duration after relapse was 5.3 months, with a 1-year overall survival rate of 17.6%. Complex karyotype (hazard ratio [HR]=2.14, P<0.001), a KMT2A rearrangement (HR=3.52, P=0.011), time in remission <12 months (HR=1.71, P=0.011), and an elevated white blood cell count at relapse (HR=2.38, P=0.005) were independent risk factors for overall survival duration. More effective frontline and maintenance therapies are warranted to prevent relapsed AML.

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

Incidence of potential targetable genetic abnormalities by age in AML.

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.

Prediction of survival with lower intensity therapy among older patients with acute myeloid leukemia.

BACKGROUND: The aim of this study was to develop a prognostic model for survival in older/unfit patients with newly diagnosed acute myeloid leukemia (AML) who were treated with lower-intensity chemotherapy regimens. METHODS: The authors reviewed all older/unfit patients with newly diagnosed AML who received lower-intensity chemotherapy from 2000 until 2020 at their institution. A total of 1462 patients were included. They were divided (3:1 basis) into a training (n = 1088) and a validation group (n = 374). RESULTS: In the training cohort of 1088 patients (median age, 72 years), the multivariate analysis identified 11 consistent independent adverse factors associated with survival: older age, therapy-related myeloid neoplasm, existence of previous myelodysplastic syndrome or myeloproliferative neoplasms, poor performance status, pulmonary comorbidity, anemia, thrombocytopenia, elevated lactate dehydrogenase, cytogenetic abnormalities, and the presence of infection at diagnosis, and therapy not containing venetoclax. The 3-year survival rates were 52%, 24%, 10%, and 1% in favorable, intermediate, poor, and very poor risk, respectively. This survival model was validated in an independent cohort. In a subset of patients in whom molecular mutation profiles were performed in more recent times, adding the mutation profiles after accounting for the effects of previous factors identified IDH2 (favorable), NPM1 (favorable), and TP53 (unfavorable) mutations as molecular prognostic factors. CONCLUSION: The proposed survival model with lower-intensity chemotherapy in older/unfit patients with newly diagnosed AML may help to advise patients on their expected outcome, to propose different strategies in first complete remission, and to compare the results of different existing or future investigational therapies. PLAIN LANGUAGE SUMMARY: Lower intensity therapy can be considered for older patients to avoid severe toxicities and adverse events. However, survival prediction in AML was commonly developed in patients who received intensive chemotherapy. In this study, we have proposed a survival model to guide therapeutic approach in older patients who received lower-intensity therapy.

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.

Comparison of Mold Active Triazoles as Primary Antifungal Prophylaxis in Patients With Newly Diagnosed Acute Myeloid Leukemia in the Era of Molecularly Targeted Therapies.

BACKGROUND: Multiple factors influence the choice of primary antifungal prophylaxis (PAP) in patients with acute myeloid leukemia (AML) undergoing remission induction chemotherapy (RIC) given the recent incorporation of targeted leukemia therapies into these regimens. METHODS: We evaluated the incidence and characteristics of breakthrough invasive fungal infections (bIFI) in 277 adult patients with newly diagnosed AML undergoing RIC with high-intensity, or low-intensity venetoclax-containing therapy. Patients receiving posaconazole (PCZ), voriconazole (VCZ), or isavuconazole (ISA) for > 5 days as PAP during RIC were included. Echinocandin use prior to, but not concomitantly with, the PAP azole was allowed. IFI (modified EORTC/MSG criteria) occurring after > 5 days of continuous azole exposure or within 14 days of discontinuation were considered bIFI. RESULTS: Proven or probable bIFI were observed in 11 patients (4%). The incidence of bIFI was 2.9% for PCZ, 4.8% for VCZ, and 5.7% for ISA (P = .55). In total, 161 patients (58%) received echinocandin prophylaxis prior to azole initiation. Neither echinocandin exposure nor chemotherapy intensity impacted bIFI rate. Patients with bIFI had a lower rate of absolute neutrophil count recovery > 1000 cells/µL (64% vs 90%, P = .021) or complete remission (CR; 18% vs 66%, P = .002) after RIC. Thirty-eight patients (14%) discontinued PAP due to toxicity, most often hepatotoxicity. Discontinuation due to hepatotoxicity was similar among azoles (PCZ: 13%; VCZ: 15%; ISA: 13%). CONCLUSIONS: The rate of bIFI is low during RIC in patients with newly diagnosed AML receiving any of the mold-active triazoles as PAP. Neutrophil recovery and achievement of CR are important for bIFI risk.

Immunohistochemical loss of enhancer of Zeste Homolog 2 (EZH2) protein expression correlates with EZH2 alterations and portends a worse outcome in myelodysplastic syndromes.

EZH2 coding mutation (EZH2MUT), resulting in loss-of-function, is an independent predictor of overall survival in MDS. EZH2 function can be altered by other mechanisms including copy number changes, and mutations in other genes and non-coding regions of EZH2. Assessment of EZH2 protein can identify alterations of EZH2 function missed by mutation assessment alone. Precise evaluation of EZH2 function and gene-protein correlation in clinical MDS cohorts is important in the context of upcoming targeted therapies aimed to restore EZH2 function. In this study, we evaluated the clinicopathologic characteristics of newly diagnosed MDS patients with EZH2MUT and correlated the findings with protein expression using immunohistochemistry. There were 40 (~6%) EZH2MUT MDS [33 men, seven women; median age 74 years (range, 55-90)]. EZH2 mutations spanned the entire coding region. Majority had dominant EZH2 clone [median VAF, 30% (1-92)], frequently co-occurring with co-dominant TET2 (38%) and sub-clonal ASXL1 (55%) and RUNX1 (43%) mutations. EZH2MUT MDS showed frequent loss-of-expression compared to EZH2WT (69% vs. 27%, p = 0.001). Interestingly, NINE (23%) EZH2WT MDS also showed loss-of-expression. EZH2MUT and loss-of-expression significantly associated with male predominance and chr(7) loss. Further, only EZH2 loss-of-expression patients showed significantly lower platelet counts, a trend for higher BM blast% and R-IPSS scores. Over a 14-month median follow-up, both EZH2MUT (p = 0.027) and loss-of-expression (p = 0.0063) correlated with poor survival, independent of R-IPSS, age and gender. When analyzed together, loss-of-expression showed a stronger correlation than mutation (p = 0.061 vs. p = 0.43). In conclusion, immunohistochemical assessment of EZH2 protein, alongside mutation, is important for prognostic workup of MDS.

The ABNL-MARRO 001 study: a phase 1-2 study of randomly allocated active myeloid target compound combinations in MDS/MPN overlap syndromes.

BACKGROUND: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malignancies with shared concomitant dysplastic and proliferative clinicopathologic features of bone marrow failure and propensity of acute leukemic transformation, and have significant impact on patient quality of life. The only approved disease-modifying therapies for any of the MDS/MPN are DNA methyltransferase inhibitors (DNMTi) for patients with dysplastic CMML, and still, outcomes are generally poor, making this an important area of unmet clinical need. Due to both the rarity and the heterogeneous nature of MDS/MPN, they have been challenging to study in dedicated prospective studies. Thus, refining first-line treatment strategies has been difficult, and optimal salvage treatments following DNMTi failure have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides the framework for collaborative studies to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response. METHODS: ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning with the novel targeted agent itacitinib, a selective JAK1 inhibitor, combined with ASTX727, a fixed dose oral combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine bioavailability. DISCUSSION: Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will (i) Establish the ABNL MARRO infrastructure for future prospective studies, (ii) Forge innovative scientific research that will improve our understanding of pathogenetic mechanisms of disease, and (iii) Inform the clinical application of diagnostic criteria, risk stratification and prognostication tools, as well as response assessments in this heterogeneous patient population. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov on August 19, 2019 (Registration No. NCT04061421).

Implications of RAS mutational status in subsets of patients with newly diagnosed acute myeloid leukemia across therapy subtypes.

Activating mutations in RAS have been reported in about 10-15% of patients with AML; previous studies have not identified a prognostic significance. However, RAS mutations have emerged as a potential resistance mechanism to treatment with inhibitors of FLT3, IDH, and BCL2. We aimed to determine the characteristics and outcomes of patients with RAS-mutated (RAS-mut) AML across therapy subsets of 1410 patients newly diagnosed (ND AML). RAS-mut was observed in 273 (20%) patients. Overall, patients with RAS-mut AML had an estimated 3-year survival rate of 38% vs. 28% in those with RAS wild type (RAS-wt), p = .01. Among patients with RAS-mut, favorable karyotype and concomitant NPM1 mutations were associated with a higher CR/CRi rate, OR 23.2 (95% CI: 2.7-192.7; p < .001) and OR 2.8 (95% CI: 1.1-6.9; p = .02), respectively, while secondary and treated secondary (ts)-AML were associated with low response rates, OR 0.34 (95% CI: 0.1-0.9; p = .04) and OR 0.22 (95% CI: 0.09-0.5; p = .001), respectively. Intensive chemotherapy was associated with high response rates OR 5.9 (95% CI: 2.9-12.2; p < .001). Better median OS was observed among those with favorable karyotype, HR 0.28 (95% CI: 0.1-0.6; p = .002), and those treated with intensive chemotherapy, HR 0.42 (95% CI: 0.2-0.6 p < .001). Conversely, ts- AML and co-occurrence of mutations in TP53 were associated with poor median OS; HR 2.3 (95% CI: 1.4-3.9; p = .001) and HR 1.7 (95% CI: 0.9-3.1; p = .06), respectively. The addition of venetoclax was associated with a non-significant improvement in CR/CRi and OS.

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.

Prediction of survival with intensive chemotherapy in acute myeloid leukemia.

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.

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.

Outcome of patients with chronic myeloid leukemia in lymphoid blastic phase and Philadelphia chromosome-positive acute lymphoblastic leukemia treated with hyper-CVAD and dasatinib.

BACKGROUND: Dasatinib monotherapy has demonstrated modest clinical activity in chronic myeloid leukemia in lymphoid blastic phase (CML-LBP). The outcome of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) has dramatically improved with hyperfractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD) in combination with tyrosine kinase inhibitors (TKIs). METHODS: The authors reviewed 85 patients (23 with CML-LBP and 62 with newly diagnosed Ph-positive ALL) who received hyper-CVAD plus dasatinib. RESULTS: In the CML-LBP cohort, 19 had prior chronic myeloid leukemia as chronic phase (n = 17; 74%), accelerated phase (n = 1; 4%), or myeloid blastic phase (n = 1; 4%); 4 (17%) presented with de novo CML-LBP. The BCR-ABL1 transcript was p210 in 22 patients (96%) and p190 in 1 patient (4%). In the Ph-positive ALL cohort, p210 and p190 transcripts were detected in 13 patients (21%) and 48 patients (77%), respectively. Patients with CML-LBP were less likely to achieve deep molecular remission than patients with Ph-positive ALL: the major molecular response (MMR) rates were 70% and 95%, respectively (P = .007), and the complete molecular response (CMR) rates were 55% and 74%, respectively (P = .16). Survival outcomes were similar for CML-LBP and Ph-positive ALL: the 5-year overall survival (OS) rates were 59% and 48%, respectively (P = .97). Allogeneic stem cell transplantation was associated with a better outcome in CML-LBP (5-year OS rate, 88% vs 57%; P = .04). In Ph-positive ALL, the outcome was driven by deeper molecular remission: the 5-year OS rates were 63% and 25% with CMR and MMR, respectively (P = .002). CONCLUSIONS: The outcome of CML-LBP has improved with hyper-CVAD plus dasatinib therapy with survival comparable to that of Ph-positive ALL. Further improvement may be achieved with the use of novel TKIs and targeted agents.

Outcomes in patients with newly diagnosed TP53-mutated acute myeloid leukemia with or without venetoclax-based therapy.

BACKGROUND: Venetoclax (VEN) in combination with a hypomethylating agent (HMA) has become the standard of care for patients aged >75 years and for those not eligible for intensive chemotherapy who have newly diagnosed acute myeloid leukemia (AML). The benefit of VEN-based therapy in patients who have newly diagnosed AML with mutations in the TP53 gene (TP53mut ) over standard therapy is undefined. METHODS: In this single-institutional, retrospective analysis, the authors assessed the clinical outcomes of 238 patients with newly diagnosed TP53mut AML and compared the clinical characteristics, response to different therapies, and outcomes of those who received VEN-based (n = 58) and non-VEN-based (n = 180) regimens. RESULTS: Patients who received VEN-based regimens were older (aged >65 years: 81% vs 65%; P = .02) and had higher response rates (complete remission, 43% vs 32%; P = .06) than those who received non-VEN-based regimens. Compared with patients who received non-VEN-based regimens, no difference in overall survival (median, 6.6 vs 5.7 months; P = .4) or relapse-free survival (median, 4.7 vs 3.5 months; P = .43) was observed in those who received VEN-based regimens, regardless of age or intensity of treatment. CONCLUSIONS: The addition of VEN to standard treatment regimens did not improve outcomes in younger or older patients who had TP53mut AML. These data highlight the need for novel therapies beyond VEN to improve the outcome of patients with TP53mut AML.

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.

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.