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PR1, an HLA-A2-restricted peptide derived from both proteinase 3 and neutrophil elastase, is recognized on myeloid leukemia cells by cytotoxic T lymphocytes (CTLs) that preferentially kill leukemia and contribute to cytogenetic remission. To evaluate safety, immunogenicity and clinical activity of PR1 vaccination, a phase I/II trial was conducted. Sixty-six HLA-A2+ patients with acute myeloid leukemia (AML: 42), chronic myeloid leukemia (CML: 13) or myelodysplastic syndrome (MDS: 11) received three to six PR1 peptide vaccinations, administered subcutaneously every 3 weeks at dose levels of 0.25, 0.5 or 1.0 mg. Patients were randomized to the three dose levels after establishing the safety of the highest dose level. Primary end points were safety and immune response, assessed by doubling of PR1/HLA-A2 tetramer-specific CTL, and the secondary end point was clinical response. Immune responses were noted in 35 of 66 (53%) patients. Of the 53 evaluable patients with active disease, 12 (24%) had objective clinical responses (complete: 8; partial: 1 and hematological improvement: 3). PR1-specific immune response was seen in 9 of 25 clinical responders versus 3 of 28 clinical non-responders (P=0.03). In conclusion, PR1 peptide vaccine induces specific immunity that correlates with clinical responses, including molecular remission, in AML, CML and MDS patients.

Progress in the management of patients with myelodysplastic syndromes (MDS) has been hampered by the inability to detect cytogenetic abnormalities in 40-60% of cases. We prospectively analyzed matched pairs of bone marrow and buccal cell (normal) DNA samples from 51 MDS patients by single nucleotide polymorphism (SNP) arrays, and identified somatically acquired clonal genomic abnormalities in 21 patients (41%). Among the 33 patients with normal bone marrow cell karyotypes, 5 (15%) had clonal, somatically acquired aberrations by SNP array analysis, including 4 with segmental uniparental disomies (UPD) and 1 with three separate microdeletions. Each abnormality was detected more readily in CD34+ cells than in unselected bone marrow cells. Paired analysis of bone marrow and buccal cell DNA from each patient was necessary to distinguish true clonal genomic abnormalities from inherited copy number variations and regions with apparent loss of heterozygosity. UPDs affecting chromosome 7q were identified in two patients who had a rapidly deteriorating clinical course despite a low-risk International Prognostic Scoring System score. Further studies of larger numbers of patients will be needed to determine whether 7q UPD detected by SNP array analysis will identify higher risk MDS patients at diagnosis, analogous to those with 7q cytogenetic abnormalities.

Outcomes for adults with relapsed/refractory (R/R) high-grade myeloid neoplasms remain poor, with allogeneic hematopoietic cell transplantation (HCT) the sole therapy likely to result in cure. We conducted the present study to determine the feasibility of early HCT-within 60 days of beginning reinduction chemotherapy-to see whether getting patients to HCT in an expeditious manner would expand the number of patients being offered this curative option. In this proof-of-principle feasibility study, we included adults age 18 to 75 years with R/R myeloid malignancies with ≥10% blood/marrow blasts at diagnosis who were eligible for a reduced-intensity HCT. Subjects received reinduction chemotherapy with cladribine, cytarabine, mitoxantrone, and filgrastim (CLAG-M) and proceeded to HCT with reduced-intensity conditioning (fludarabine/ melphalan). We enrolled 30 subjects, all of whom received CLAG-M reinduction, although only 9 underwent HCT within 60 days (<15, the predetermined threshold for feasibility "success"), with a median time to HCT of 48 days (range, 42 to 60 days). Eleven additional subjects received HCT beyond the target 60 days (off-study), with a median time to transplantation of 83 days (range, 53 to 367 days). Barriers to early HCT included infection, physician preference, lack of an HLA-matched donor, logistical delays, and disease progression, all of which may limit the real-world uptake of such early-to-transplantation protocols., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Objectives: We recently performed a single-arm phase II trial of DA-EPOCH in adults with acute lymphoblastic leukemia (ALL). We sought to compare these results to those with standard Hyper-CVAD., Methods: We created a retrospective matched cohort of patients who received Hyper-CVAD (n = 69) at our center and otherwise met eligibility criteria for the DA-EPOCH trial (n = 53)., Results: Our outcomes support the use of Hyper-CVAD over DA-EPOCH in Ph- disease for both overall survival (OS; HR 0.18, p = .004) and event-free survival (EFS; HR 0.51, p = .06). In contrast, outcomes were similar in Ph+ disease (OS HR 0.97, p = .96; EFS HR 0.65, p = .21). Rates of morphologic remission and measurable residual-disease negativity were similar between the regimens. Hyper-CVAD was associated with significantly more febrile neutropenia (OR 1.9, p = .03) and a greater incidence of Grade 4 or 5 adverse events (20% vs. 6%). Average transfusions per cycle of both red blood cells (p < .001) and platelets (p < .001) were five-fold higher with Hyper-CVAD., Conclusions: Our findings support continued use of Hyper-CVAD for Ph- ALL but suggest that DA-EPOCH may be a reasonable alternative for Ph+ ALL. These data also highlight a potential role for DA-EPOCH in resource-limited settings or when more intense therapy is not feasible., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The multikinase inhibitor sorafenib improves event-free survival (EFS) when used with 7 + 3 in adults with newly-diagnosed acute myeloid leukemia (AML), irrespective of the FLT3-mutation status. Here, we evaluated adding sorafenib to cladribine, high-dose cytarabine, granulocyte colony-stimulating factor, and mitoxantrone (CLAG-M) in a phase 1/2 trial of 81 adults aged ≤60 years with newly diagnosed AML. Forty-six patients were treated in phase 1 with escalating doses of sorafenib and mitoxantrone. No maximum tolerated dose was reached, and a regimen including mitoxantrone 18 mg/m2 per day and sorafenib 400 mg twice daily was declared the recommended phase 2 dose (RP2D). Among 41 patients treated at RP2D, a measurable residual disease-negative complete remission (MRD- CR) rate of 83% was obtained. Four-week mortality was 2%. One-year overall survival (OS) and EFS were 80% and 76%, without differences in MRD- CR rates, OS, or EFS between patients with or without FLT3-mutated disease. Comparing outcomes using CLAG-M/sorafenib with those of a matched cohort of 76 patients treated with CLAG-M alone, multivariable-adjusted survival estimates were improved for 41 patients receiving CLAG-M/sorafenib at RP2D (OS: hazard ratio,0.24 [95% confidence interval, 0.07-0.82]; P = .023; EFS: hazard ratio, 0.16 [95% confidence interval, 0.05-0.53]; P = .003). Benefit was limited to patients with intermediate-risk disease (univariate analysis: P = .01 for OS; P = .02 for EFS). These data suggest that CLAG-M/sorafenib is safe and improves OS and EFS relative to CLAG-M alone, with benefits primarily in patients with intermediate-risk disease. The trial was registered at www.clinicaltrials.gov as #NCT02728050., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Treatments for adults with newly-diagnosed acute lymphoblastic leukemia (ALL) may be prohibitively toxic and/or resource-intense. To address this, we performed a phase II study of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH). Imatinib or dasatinib was added for Ph + disease; rituximab was added when CD20+. Fifty-three patients were evaluable: 28 with Ph + disease, and 25 with Ph-. All patients had ≥1 high-risk clinical feature. Measurable residual disease-negativity by multiparameter flow cytometry within 4 cycles was achieved in 71% in patients with Ph + ALL and 64% in Ph - ALL. Median overall survival (OS) was 49 months, with a 2-year OS of 71%. Median relapse-free survival (RFS) in the 47 patients that attained morphologic remission was 24 months, with a 2-year RFS of 57%. Early mortality was 2%. In summary, DA-EPOCH yields deep and durable remissions in adults with ALL comparable to some resource-intense strategies but with a low rate of treatment-related death.

Patients with acute myeloid leukemia (AML) who have failed hypomethylating agents (HMA) have a poor prognosis. We examined whether high intensity induction chemotherapy could abrogate negative outcomes in 270 patients with AML or other high-grade myeloid neoplasms. Prior HMA therapy was significantly associated with a lower overall survival (OS) as compared to a reference group of patients with secondary disease without prior HMA therapy (median 7.2 vs 13.1 months). In patients with prior HMA therapy, high intensity induction was associated with a non-significant trend toward longer OS (median 8.2 vs 4.8 months) and decreased rates of treatment failure (39% vs 64%). These results redemonstrate poor outcomes in patients with prior HMA and suggest possible benefit of high intensity induction that should be evaluated in future studies.

We designed a prospective, observational study enrolling patients presenting for treatment of acute myeloid leukemia (AML) at 13 institutions to analyze associations between hematopoietic cell transplantation (HCT) and survival, quality of life (QOL), and function in: the entire cohort, those aged ≥65 years, those with high comorbidity burden, intermediate cytogenetic risk, adverse cytogenetic risk, and first complete remission with or without measurable residual disease. Patient were assessed 8 times over 2 years. Time-dependent regression models were used. Among 692 patients that were evaluable, 46% received HCT with a 2-year survival of 58%. In unadjusted models, HCT was associated with reduced risks of mortality most of the subgroups. However, after accounting for covariates associated with increased mortality (age, comorbidity burden, disease risks, frailty, impaired QOL, depression, and impaired function), the associations between HCT and longer survival disappeared in most subgroups. Although function, social life, performance status, and depressive symptoms were better for those selected for HCT, these health advantages were lost after receiving HCT. Recipients and nonrecipients of HCT similarly ranked and expected cure as main goal of therapy, whereas physicians had greater expectations for cure than the former. Accounting for health impairments negates survival benefits from HCT for AML, suggesting that the unadjusted observed benefit is mostly owing to selection of the healthier candidates. Considering patients' overall expectations of cure but also the QOL burdens of HCT motivate the need for randomized trials to identify the best candidates for HCT. This trial was registered at www.clinicaltrials.gov as #NCT01929408., (© 2023 by The American Society of Hematology.)

We have previously shown that complete response (CR) rates and overall survival of patients with acute myeloid leukemia have improved since the 1980s. However, we have not previously evaluated how the length of first CR (CR1) has changed over this time period. To address this, we analyzed 1,247 patients aged 65 or younger randomized to "7+3" arms from five SWOG studies: S8600 (n=530), S9031 (n=98), S9333 (n=57), S0106 (n=301), and S1203 (n=261). We evaluated length of CR1 and survival after relapse from CR1 over the four decades that these studies represent. Both length of CR1 and survival after relapse from CR1 have improved over the last four decades. The relative benefit associated with CR1 and the relative detriment associated with relapse have decreased over this period; while achieving CR1 and relapse from CR1 still have strong prognostic associations with outcomes, the magnitude of the association has decreased over time. Possible explanations for these patterns include higher CR rates with salvage therapies after relapse, more frequent use of hematopoietic cell transplant, and better supportive care.

The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.

Gemtuzumab ozogamicin (GO) improves outcomes when added to intensive AML chemotherapy. A meta-analysis suggested the greatest benefit when combining fractionated doses of GO (GO3) with 7 + 3. To test whether GO3 can be safely used with high intensity chemotherapy, we conducted a phase 1/2 study of cladribine, high-dose cytarabine, G-CSF, and dose-escalated mitoxantrone (CLAG-M) in adults with newly diagnosed AML or other high-grade myeloid neoplasm (NCT03531918). Sixty-six patients with a median age of 65 (range: 19-80) years were enrolled. Cohorts of six and twelve patients were treated in phase 1 with one dose of GO or three doses of GO (GO3) at 3 mg/m 2 per dose. Since a maximum-tolerated dose was not reached, the recommended phase 2 dose (RP2D) was declared to be GO3. At RP2D, 52/60 (87%) patients achieved a complete remission (CR)/CR with incomplete hematologic recovery (CRi), 45/52 (87%) without flow cytometric measurable residual disease (MRD). Eight-week mortality was 0%. Six- and twelve-month event-free survival (EFS) were 73% and 58%; among favorable-risk patients, these estimates were 100% and 95%. Compared to 186 medically matched adults treated with CLAG-M alone, CLAG-M/GO3 was associated with better survival in patients with favorable-risk disease (EFS: p = 0.007; OS: p = 0.030). These data indicate that CLAG-M/GO3 is safe and leads to superior outcomes than CLAG-M alone in favorable-risk AML/high-grade myeloid neoplasm.

Abnormal nuclear morphology is a hallmark of malignant cells widely used in cancer diagnosis. Pelger-Huët anomaly (PHA) is a common abnormality of neutrophil nuclear morphology of unknown molecular etiology in myeloid neoplasms (MNs). We show that loss of nuclear lamin B1 (LMNB1) encoded on chromosome 5q, which is frequently deleted in MNs, induces defects in nuclear morphology and human hematopoietic stem cell (HSC) function associated with malignancy. LMNB1 deficiency alters genome organization inducing in vitro and in vivo expansion of HSCs, myeloid-biased differentiation with impaired lymphoid commitment, and genome instability due to defective DNA damage repair. Nuclear dysmorphology of neutrophils in patients with MNs is associated with 5q deletions spanning the LMNB1 locus, and lamin B1 loss is both necessary and sufficient to cause PHA in normal and 5q-deleted neutrophils. LMNB1 loss thus causes acquired PHA and links abnormal nuclear morphology with HSCs and progenitor cell fate determination via genome organization., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Potential involvement of the central nervous system (CNS) by acute lymphoblastic leukemia is typically evaluated by a conventional cytospin (CC) of cerebrospinal fluid (CSF). Multiparameter flow cytometry (MFC) is generally more sensitive and specific than morphology, but data to guide its use versus CC are limited., Methods: This study identified 92 patients who had MFC performed on their initial CSF specimen and received at least 4 cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine (hyperCVAD) as their initial treatment., Results: Eighteen (20%) were CSF+ by MFC at the baseline, and only 6 of these patients were positive by CC. In contrast, 0 of 51 patients who were negative by MFC and had CC available were positive by CC. Despite the receipt of significantly more intra-CSF chemotherapy (P < .001), the cumulative incidence of CNS relapse by MFC was 22% among CSF+ patients versus 5% among those who were CSF- (P = .044). No such association was observed between CNS relapse and CC results (P = .42). None of the 74 CSF- patients became CSF+ during their initial treatment despite being tested a median of 5 times (range, 2-10). CSF positivity by MFC was the factor most strongly associated with CNS relapse in a series of univariate Cox models (hazard ratio, 3.7; P = .067). The initial CSF status by MFC had no significant impact on overall or event-free survival., Conclusions: MFC of CSF is superior to CC of CSF in identifying adults at high risk for CNS relapse after treatment with hyperCVAD. Surveillance of CSF by MFC has limited utility., (© 2021 American Cancer Society.)

Mutations characterize diverse human cancers; there is a positive correlation between elevated mutation frequency and tumor progression. One exception is acute myeloid leukemia (AML), which has few clonal single nucleotide mutations. We used highly sensitive and accurate Duplex Sequencing (DS) to show now that AML, in addition, has an extensive repertoire of variants with low allele frequencies, < 1%, which is below the accurate detection limit of most other sequencing methodologies. The subclonal variants are unique to each individual and change in composition, frequency, and sequence context from diagnosis to relapse. Their functional significance is apparent by the observation that many are known variants and cluster within functionally important protein domains. Subclones provide a reservoir of variants that could expand and contribute to the development of drug resistance and relapse. In accord, we accurately identified subclonal variants in AML driver genes NRAS and RUNX1 at allele frequencies between 0.1% and 0.3% at diagnosis, which expanded to comprise a major fraction (14-53%) of the blast population at relapse. Early and accurate detection of subclonal variants with low allele frequency thus offers the opportunity for early intervention, prior to detection of clinical relapse, to improve disease outcome and enhance patient survival., (Copyright © 2022. Published by Elsevier Ltd.)