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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. NPM1 mutations define a unique leukemia entity regardless of bone marrow blast percentage. Patients with NPM1‐mutated myeloid neoplasms benefit from intensive chemotherapy approaches even in the setting of low bone marrow blast percentage. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

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. The proposed survival model with lower‐intensity chemotherapy in older/unfit patients with newly diagnosed acute myeloid leukemia 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. [ABSTRACT FROM AUTHOR]

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. Cladribine and low‐dose cytarabine–based regimens are a therapeutic option for a subset of high‐risk patients with chronic myelomonocytic leukemia. These regimens are also effective after transformation to secondary acute myeloid leukemia in patients who have not previously experienced hypomethylating agent failure. [ABSTRACT FROM AUTHOR]

Background: The impact of the allelic burden of ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations on survival remains unclear in patients with newly diagnosed acute myeloid leukemia (AML).Methods: The authors assessed bone marrow aspirates from 421 patients with newly diagnosed AML using next-generation sequencing for ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations, defined as the presence of mutations in ASXL1, DNMT3A, JAK2, TET2, or TP53 with a minimum variant allele frequency (VAF) of 5%.Results: A total of 71 patients (17%) had ASXL1 mutations, 104 patients (25%) had DNMT3A mutations, 16 patients (4%) had JAK2 mutations, 82 patients (20%) had TET2 mutations, and 86 patients (20%) had TP53 mutations. Among patients with each mutation, the median VAF of ASXL1 was 34.31% (range, 1.17%-58.62%), the median VAF of DNMT3A was 41.76% (range, 1.02%-91.66%), the median VAF of JAK2 was 46.70% (range, 10.4%-71.7%), the median VAF of TET2 was 42.78% (range, 2.26%-95.32%), and the median VAF of TP53 was 45.47% (range, 1.15%-93.74%). The composite complete response rate was 60%, and was 77% in patients with AML with and without ASXL1, DNMT3A, JAK2, TET2, or TP53 mutations, respectively (P = .006); the median overall survival was 11 months and 27 months, respectively (P < .001). Multivariate analysis identified age; an antecedent history of dysplasia; white blood cell count; adverse cytogenetic risk; previous treatment with an FLT3 inhibitor; and the VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations by next-generation sequencing as prognostic factors for overall survival.Conclusions: The VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations is associated with worse prognosis in patients with newly diagnosed AML. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

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. Myelodysplastic syndromes (MDS) with K700E and non‐K700E SF3B1 mutations show distinct clinicopathological and genomic characteristics, with only SF3B1 K700E mutated MDS showing significantly better overall survival compared to wild‐type MDS. The SF3B1 mutation type is important for MDS risk assessment. [ABSTRACT FROM AUTHOR]

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. The benefit of venetoclax‐based therapy over standard approaches in patients with newly diagnosed, TP53‐mutated acute myeloid leukemia (AML) needs to be better defined. Although the addition of venetoclax to standard therapy is associated with numerically higher response rates, there is no improvement in overall or relapse‐free survival compared with standard therapy in patients with newly diagnosed, TP53‐mutated AML. [ABSTRACT FROM AUTHOR]

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. Atypical chronic myeloid leukemia is characterized by specific mutational clonal dominance with a high frequency of codominant SRSF2 and SETBP1 mutations and other RAS pathway mutations present in minor clones at the time of diagnosis but associated with acute myeloid leukemia transformation. The incorporation of age, platelet counts, bone marrow blast percentages, and lactate dehydrogenase levels can allow survival prediction, and allogeneic stem cell transplantation should be considered for all eligible patients. [ABSTRACT FROM AUTHOR]

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. The outcome of chronic myeloid leukemia in lymphoid blastic phase (CML‐LBP) treated with hyperfractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone plus dasatinib is similar to the outcome of Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL). Allogeneic stem cell transplantation offers better survival for patients with CML‐LBP, whereas for patients with Ph‐positive ALL, the outcome is driven by deeper molecular remission. [ABSTRACT FROM AUTHOR]

Background: Clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations increase the risk of atherosclerotic heart disease. Comorbidities significantly impact the prognosis of patients with myelodysplastic syndromes (MDS). The objective of this study was to determine the association and impact of CHIP mutations with comorbidities in patients with MDS.Methods: This retrospective analysis of 566 consecutive patients with MDS was conducted at The University of Texas MD Anderson Cancer Center from August 2013 to December 2016. The 27-item Adult Comorbidity Evaluation (ACE-27) scale was used to assess the severity of comorbid conditions. Next-generation sequencing was used to detect the presence of CHIP mutations in bone marrow aspirates. Spearman correlations and logistic regression analyses were used to determine the association between mutations and comorbidities.Results: Mutations in the genes tet methylcytosine dioxygenase 2 (TET2), ASXL transcriptional regulator 1 (ASXL1), DNA methyltransferase 3α (DNMT3A), Janus kinase 2 (JAK2), and tumor protein 53 (TP53) were noted in 20%, 18%, 9%, 2%, and 21% of patients, respectively. Patients with DNMT3A and JAK2 mutations had higher likelihoods of a prior history of myocardial infarction (odds ratio, 2.62; P = .03) and veno-occlusive disease (odds ratio, 6.48; P = .02), respectively. TP53 mutation was associated with a prior history of malignancy. Patients with TET2 mutation had no association with any comorbidity. A prognostic model including the revised International Prognostic Scoring System classification, the ACE-27 score, and TP53 mutation status (the I-RAT model) predicted median overall survival.Conclusions: In patients with MDS, the presence of CHIP-associated mutations is associated with comorbidities. DNMT3A and JAK2 mutations were associated with higher likelihoods of prior myocardial infarction and thrombotic events. There was no association between comorbidity and TET2 mutation. Incorporating the revised International Prognostic Scoring System classification with the ACE-27 and TP53 mutation status improved outcome prediction in patients with MDS. [ABSTRACT FROM AUTHOR]

Background: The outcome of patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. The combination of inotuzumab with low-intensity mini-hyper-CVD (mini-hyper-CVD; cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 × 4 doses) chemotherapy has shown encouraging results. The sequential addition of blinatumomab might improve outcome in patients with R/R ALL.Methods: We used lower intensity chemotherapy, mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses) compared to conventional hyper-CVAD.Results: Ninety-six patients with a median age of 37 years (range, 18-87 years) were treated. Overall, 77 patients (80%) responded, 55 (57%) of whom achieved complete response. The overall measurable residual disease negativity rate among responders was 83%. Forty-four (46%) patients underwent later allogeneic stem cell transplantation. Veno-occlusive disease of any grade occurred in 10 (10%) patients. The rates were 13% with the original schedule and 3% with the use of lower-dose inotuzumab and sequential blinatumomab. With a median follow-up of 36 months, the median overall survival (OS) was 13.4 months, with 3-year OS rates of 33%. The 3-year OS rate for patients with CD22 expression ≥70% and without adverse cytogenetics (KMT2A rearrangements, low hypodiploidy/near triploidy) was 55%.Conclusion: The combination of inotuzumab and low-intensity mini-hyper-CVD chemotherapy with or without blinatumomab shows sustained efficacy in patients with R/R ALL. [ABSTRACT FROM AUTHOR]

Background: Tumor protein 53 (TP53) mutations are uncommon in adult patients with acute lymphoblastic leukemia (ALL) and predict a poor outcome.Methods: TP53 mutation analysis was performed in 164 newly diagnosed adult patients with ALL using a combination of targeted amplicon-based next-generation sequencing and Sanger sequencing.Results: TP53 mutations were detected in 25 patients (15%), with a median allelic frequency of 42.2% (range, 5.6%-93.8%). The majority of mutations were single-nucleotide variants of missense type and involved the DNA-binding domain. TP53-mutated (TP53mut ) ALL was found to be significantly associated with older age, lower median white blood cell and platelet counts, lower frequency of Philadelphia chromosome and a higher frequency of low hypodiploid karyotype compared with ALL with wild-type TP53 (TP53wt ). To evaluate the prognostic effect of TP53 mutations, the authors selected 146 patients with B-cell immunophenotype ALL (24 with TP53mut and 122 with TP53wt ) who were uniformly treated with frontline hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD)-based regimens; >90% of these individuals also received a monoclonal antibody. Over a median follow-up duration of 15 months, there was no significant difference in the median overall survival, event-free survival, and duration of complete remission noted between patients with TP53mut ALL and those with TP53wt ALL.Conclusions: Hyper-CVAD-based regimens appear to negate the poor prognostic impact of TP53 mutations in patients with adult B-cell immunophenotype ALL. Cancer 2017;123:3717-24. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: The prognosis of patients with higher-risk myelodysplastic syndromes (MDS) remains poor despite available therapies. Histone deacetylase inhibitors have demonstrated activity in patients with MDS and in vitro synergy with azacitidine.Methods: A phase 2 randomized, placebo-controlled clinical trial of azacitidine and pracinostat was conducted in patients who had International Prognostic Scoring System intermediate-2-risk or high-risk MDS. The primary endpoint was the complete response (CR) rate by cycle 6 of therapy.Results: Of 102 randomized patients, there were 51 in the pracinostat group and 51 in the placebo group. The median age was 69 years. The CR rate by cycle 6 of therapy was 18% and 33% (P = .07) in the pracinostat and placebo groups, respectively. No significant differences in overall survival (median, 16 vs 19 months, respectively; hazard ratio, 1.21; 95% confidence interval, 0.66-2.23) or progression-free survival (11 vs 9 months, respectively; hazard ratio, 0.82; 95% confidence interval, 0.546-1.46) were observed between groups. Grade ≥3 adverse events occurred more frequently in the pracinostat group (98% vs 74%), leading to more treatment discontinuations (20% vs 10%).Conclusions: The combination of azacitidine with pracinostat did not improve outcomes in patients with higher-risk MDS. Higher rates of treatment discontinuation may partially explain these results, suggesting alternative dosing and schedules to improve tolerability may be required to determine the potential of the combination. Cancer 2017;123:994-1002. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]