Evolution from an antecedent chronic myeloid malignancy does not impact survival outcomes in NPM1-mutated AML.

Nucleophosmin-1 (NPM1)-mutated AML is a molecularly defined subtype typically associated with favorable treatment response and prognosis; however, its prognostic significance in AML evolving from an antecedent chronic myeloid malignancy is unknown. This study's primary objective was to determine the impact of mutated NPM1 on the prognosis of AML evolving from an antecedent chronic myeloid malignancy. We conducted a retrospective chart review including patients with NPM1-mutated de novo and sAML. sAML was defined as those with a preceding chronic-phase myeloid malignancy before diagnosis of AML. Of 575 NPM1-mutated patients eligible for inclusion in our study, 51 (8.9%) patients were considered to have sAML. The median time from diagnosis of NPM1-mutated chronic myeloid malignancy to sAML evolution was 3.6 months (0.5-79.3 months). No significant differences in leukemia-free (2-year LKFS 52.0% vs. 51.2%, p = .9922) or overall survival (2-year OS 56.3% vs. 49.4%, p = .4246) were observed between patients with NPM1-mutated de novo versus sAML. Our study suggests that evolution from a preceding myeloid malignancy is not a significant predictor of poor prognosis in the setting of an NPM1 mutation. Our study demonstrated a short time to progression to sAML in most patients, which further supports the consideration of NPM1 as an AML-defining mutation.

Outcomes and adverse events in older acute lymphoblastic Leukemia patients treated with a pediatric-inspired protocol with Pegylated or native Asparaginase.

This retrospective report presents the outcomes and adverse events (AEs) observed in 73 patients aged 60 years or older diagnosed with Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia (Ph-negative ALL) treated with a pediatric-inspired protocol incorporating either Pegylated (PEG-ASP) or Native Asparaginase (EC-ASP). Notably, 61% of patients experienced AEs of Grade III-IV severity. The most prevalent AEs included thrombosis (35.6%), febrile neutropenia (38.4%), and transaminitis (34.2%). AEs did not translate into significant differences concerning overall survival, leukemia-free survival, or early mortality. Furthermore, we observed a reduction in early mortality rates (11% vs. 20%) and an increase in median overall survival (54 vs. 48 months) compared to our previous data. These findings suggest that the utilization of a pediatric-inspired chemotherapy protocol, with ASP, is an effective and well-tolerated therapeutic option for older patients with Ph-negative ALL. However, it emphasizes the importance of diligent monitoring and close follow-up throughout treatment.

Clinical Features and Long-Term Outcomes of a Pan-Canadian Cohort of Adolescents and Young Adults with Myeloproliferative Neoplasms: A Canadian MPN Group Study.

Myeloproliferative neoplasms (MPNs) are a group of chronic hematologic malignancies that lead to morbidity and early mortality due to thrombotic complications and progression to acute leukemia. Clinical and mutational risk factors have been demonstrated to predict outcomes in patients with MPNs and are used commonly to guide therapeutic decisions, including allogenic stem cell transplant, in myelofibrosis. Adolescents and young adults (AYA, age ≤45 years) comprise less than 10% of all MPN patients and have unique clinical and therapeutic considerations. The prevalence and clinical impact of somatic mutations implicated in myeloid disease has not been extensively examined in this population. We conducted a retrospective review of patients evaluated at eight Canadian centers for MPN patients diagnosed at ≤45 years of age. In total, 609 patients were included in the study, with median overall survival of 36.8 years. Diagnosis of prefibrotic or overt PMF is associated with the lowest OS and highest risk of AP/BP transformation. Thrombotic complications (24%), including splanchnic circulation thrombosis (9%), were frequent in the cohort. Mutations in addition to those in JAK2/MPL/CALR are uncommon in the initial disease phase in our AYA population (12%); but our data indicate they may be predictive of transformation to post-ET/PV myelofibrosis.

Flow cytometry-based measurable residual disease (MRD) analysis identifies AML patients who may benefit from allogeneic hematopoietic stem cell transplantation.

Measurable residual disease (MRD) monitoring independently predicts long-term outcomes in patients with acute myeloid leukemia (AML). Of the various modalities available, multiparameter flow cytometry-based MRD analysis is widely used and relevant for patients without molecular targets. In the transplant (HCT) setting, the presence of MRD pre-HCT is associated with adverse outcomes. MRD-negative remission status pre-HCT was also associated with longer overall (OS) and progression-free survival and a lower risk of relapse. We hypothesize that the combination of disease risk and MRD at the time of first complete remission (CR1) could identify patients according to the benefit gained from HCT, especially for intermediate-risk patients. We performed a retrospective analysis comparing the outcomes of HCT versus non-HCT therapies based on MRD status in AML patients who achieved CR1. Time-dependent analysis was applied considering time-to-HCT as a time-dependent covariate and compared HCT versus non-HCT outcomes according to MRD status at CR1. Among 336 patients assessed at CR1, 35.1% were MRD positive (MRDpos) post-induction. MRDpos patients benefitted from HCT with improved OS and relapse-free survival (RFS), while no benefit was observed in MRDneg patients. In adverse-risk patients, HCT improved OS (HR for OS 0.55; p = 0.05). In intermediate-risk patients, HCT benefit was not significant for OS and RFS. Intermediate-risk MRDpos patients were found to have benefit from HCT with improved OS (HR 0.45, p = 0.04), RFS (HR 0.46, p = 0.02), and CIR (HR 0.41, p = 0.02). Our data underscore the benefit of HCT in adverse risk and MRDpos intermediate-risk AML patients.

Outcomes of intensive and nonintensive blast-reduction strategies in accelerated and blast-phase MPN.

ABSTRACT: Transformation of BCR::ABL1-negative myeloproliferative neoplasms (MPN) to an accelerated or blast phase is associated with poor outcomes. The efficacy of acute myeloid leukemia (AML)-type intensive and nonintensive hypomethylating agent-based regimens is not well studied. We therefore performed a retrospective analysis of patients with MPN-AP/BP (N = 138) treated with intensive (N = 81) and nonintensive (N = 57) blast-reduction strategies. We used clinically relatable response criteria developed at the Princess Margaret Cancer Centre. The overall best response, comprising complete remission (CR), complete remission with incomplete hematologic recovery (CRi), and reversion to chronic phase MPN (cMPN), in the intensive and nonintensive groups was 77% (62 of 81) and 39% (21 of 54), respectively. Similar overall best response rates were observed in patients receiving induction with daunorubicin combined with cytarabine arabinoside (daunorubicin + ara-C) (74% [23 of 31]) or FLAG-IDA/NOVE-HiDAC (78% [39 of 50], P = .78). However, patients receiving daunorubicin + ara-C more often required second inductions (29% [9 of 31] vs 4% [2 of 50], P = .002). Most responses in the entire cohort were reversions to cMPN (55 of 83 [66%]). CR and CRi comprised 30% (25 of 83) and 4% (3 of 83) of responses, respectively. Mutations in TP53 (overall response [OR] 8.2 [95% confidence interval [CI] 2.01, 37.1], P = .004) and RAS pathway (OR 5.1 [95%CI 1.2, 23.7], P = .03) were associated with inferior treatment response for intensively treated patients, and poorer performance status (Eastern Cooperative Oncology Group) was associated with inferior treatment response in both intensively (OR 10.4 [95% CI 2.0, 78.5], P = .009) and nonintensively treated groups (OR 12 [95% CI 2.04, 230.3], P = .02). In patients with paired samples before and after therapy (N = 26), there was a significant residual mutation burden remaining irrespective of response to blast-reduction therapy.

Prevalence of frailty and its association with clinical outcomes in myeloproliferative neoplasms: a population-based study.

Clinical implications of frailty in myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are unknown. In this population-based study, all incident cases of MPN from the Ontario cancer registry between 2004 and 2019 (N = 10 336; ET = 5108; PV = 3843; MF = 1385) and their matched controls (for age, sex, residence, and income) in a 1:4 ratio were included. Baseline frailty measured using the Johns Hopkins Adjusted Clinical Groups frailty indicator and McIsaac frailty index (mFI), categorized as fit, prefrail, or frail if mFI <0.10, 0.11 to 0.20, >0.20), was significantly higher in ET, PV, and MF compared with matched controls (standardized mean difference of 0.27, 0.27, and 0.28). Over 23%, 20%, and 34% of patients with ET, PV, and MF were frail or prefrail despite a younger age (<65 years) or minimal comorbidities. In Cox proportional regression, frailty was independently associated with worse overall survival (OS) after adjusting for age, sex, and comorbidities compared with mFI-fit patients. The hazard ratios (95% confidence interval) for OS for mFI-prefrail and mFI-frail patients were: 1.6 (1.3-1.9) and 3.6 (2.9-4.4) in ET, 1.3 (1.1-1.5) and 2.7 (2.1-3.4) in PV, and 1.2 (1.0-1.5) and 2.0 (1.5-2.7) in MF. Patients with MPN have a substantially higher prevalence of frailty compared with matched controls, which is associated with reduced OS, independent of age or comorbidities.

Association of creatine kinase elevation with clinical outcomes in chronic myeloid leukemia: a retrospective cohort study.

Implications of creatine kinase (CK) elevation, a frequent complication of tyrosine kinase inhibitor (TKI) treatment for chronic myeloid leukemia (CML), on its key treatment outcomes (overall survival (OS) and event-free survival (EFS)), remain unknown. In this single center, retrospective study on 283 chronic phase CML patients on first-line TKI (median follow-up of 8.8 years), 71.7% patients had hyperCKemia with no difference in incidence between imatinib and second generation TKIs (SG-TKIs). In multivariable Cox regression analysis, hyperCKemia was associated with better OS and intermediate- and high-Sokal risk score with worse OS. In multivariable Cox regression for EFS, hyperCKemia and treatment with SG-TKI were associated with improved EFS while intermediate or high Sokal index and higher comorbidities showed worse EFS. Our study provides an evidence on the prognostic value of hyperCKemia in CML and informs clinicians not to change TKI based solely on laboratory elevations of CK.

Association of frailty with clinical outcomes in myelofibrosis: a retrospective cohort study.

There is limited understanding of the impact of frailty on clinical outcomes in patients with myelofibrosis (MF). In this retrospective cohort study on 439 chronic phase MF patients [mean age: 68·7 ± 12 years; median follow-up: 3·4 years (IQR 0·4-8·6)] from 2004 till 2018, we used a 35-variable frailty index (FI) to categorise patient's frailty status as fit (FI < 0·2, reference), prefrail (FI 0·2-0·29) or frail (FI ≥ 0·3). The association of frailty with overall survival (OS) and cumulative JAK inhibitor (JAKi) therapy failure was measured using hazard ratio (HR, 95% CI). In multivariable analysis, prefrail (HR 1·7, 1·1-2·5) and frail patients (HR 2·9, 1·6-5·5), those with higher DIPSS score (HR 2·5, 1·6-3·9) and transfusion dependency (HR 1·9, 1·3-2·9) had shorter OS. In a subset analysis of patients on JAKi treatment (n = 222), frail patients (HR 2·5, 1·1-5·7), patients with higher DIPSS score (HR 1·7, 1·0-3·1) and transfusion dependence (HR 1·7, 1·1-2·7) had higher cumulative incidence of JAKi failure. Age, comorbidities, ECOG performance status, and MPN driver mutations did not impact outcomes. Thus, higher frailty scores are associated with worse OS and increased JAKi failure in MF, and is a superior indicator of fitness in comparison to age, comorbidities, and performance status.

Association of Factors Influencing Selection of Upfront Hematopoietic Cell Transplantation versus Nontransplantation Therapies in Myelofibrosis.

Despite the curative potential of allogeneic hematopoietic cell transplantation (HCT) for myelofibrosis (MF), a significant number of patients with MF do not undergo HCT. Factors influencing treatment preferences in these patients have not been well studied. This study was conducted to identify patient-, disease-, and donor-related factors influencing the decision regarding HCT in patients with MF. A secondary objective was to compare survival between patients who elected upfront HCT and those who opted for nontransplantation therapy. We conducted a retrospective chart review amongst patients meeting criteria for transplant indication, evaluating clinical characteristics, treatment preferences, and outcomes. Of the 183 study eligible patients age <70 years, 129 (70%) developed an HCT indication. Age >60 years was significantly associated with higher rates of HLA-typing refusal (13 of 72 versus 1 of 44; P = .02). Caucasian ethnicity was significantly associated with an increased rate of identifying well-matched donors compared with non-Caucasian ethnicity (75% versus 48%; P = .02). Of the 69 patients with well-matched donors, 34 (49%) preferred to not pursue upfront HCT despite an indication for transplantation. Patient preference for nontransplantation therapies was the most common reason for declining HCT. We did not find any difference in survival between patients pursuing upfront HCT and those opting for nontransplantation therapies, although more patients in the HCT arm were in remission at the last follow-up. Patients of Caucasian ethnicity were significantly more likely than non-Caucasian patients to identify a well-matched donor. Despite availability of a well-matched donor, a significant proportion of MF patients with an indication for transplantation do not pursue HCT. Patient age, donor type, and patient preference play major roles in the selection of upfront HCT. Although a survival difference was not observed between upfront HCT versus non-transplant therapy, more patients in the HCT arm were in remission at the last follow-up.

Healthcare resource utilization in myeloproliferative neoplasms: a population-based study from Ontario, Canada.

Health resource utilization (HRU) and associated factors of high cost are not well understood in myeloproliferative neoplasms (MPNs). In this population-based, retrospective matched-cohort study, we used administrative health databases of Ontario, Canada to measure treatment costs and HRU for patients with MPN from 2004 to 2016 and compared them to matched controls. In 7130 patients with MPN [essential thrombocythemia (ET) = 3481; polycythemia vera (PV) = 2618; myelofibrosis (MF) = 1031], the mean annualized treatment costs were $16,646 for ET (controls, $7070); $16,360 for PV (controls, $7293); and $25,863 for MF (controls, $7386). Out of the total costs, the largest expenditure was on acute hospital care (ET: 57%, PV: 57%, MF: 66%). Older age (≥65), male gender, patients not seen by a specialist, and greater comorbidity burden were independent predictors of higher costs (p < 0.05). In addition, history of venous thrombosis in patients with ET and PV was associated with significantly higher treatment costs (p < 0.05).

Investigational non-JAK inhibitors for chronic phase myelofibrosis.

INTRODUCTION: Patients with myelofibrosis (MF) have no effective treatment option after the failure of approved JAK inhibitor (JAKi) therapy. Non-JAK inhibitors (non-JAKi) that target non-canonical molecular pathways are undergoing clinical evaluations to optimize efficacy and/or to reduce hematological toxicity of JAKi. AREA COVERED: This article reviews the efficacy data from completed and ongoing early phase clinical trials of non-JAKi agents for chronic phase MF. The article also illuminates some of the challenges of myelofibrosis drug development. EXPERT OPINION: Most non-JAKi agents tested so far have shown modest benefit in improving the efficacy of ruxolitinib. Several novel agents such as BET inhibitor- CPI-0610, activin receptor ligand trap- luspatercept, recombinant pentraxin-PRM-151, telomerase inhibitor- imetelstat and bcl-2 inhibitor- navitoclax, have shown promising activity; however, they require vigorous evaluation in randomized controlled trials to understand the clinical benefit. Drugs that target new molecular pathways (MDM2, p-selectin, TIM-3, TGF-ß, aurora kinase) and immune-based strategies (CALR vaccine, anti-PD-1, allogeneic cord blood regulatory T cells) are in early phase trials. Further translational studies to target leukemic stem cells, improvement in trial designs by incorporating control arm and survival endpoints, and patient-focused collaborations among all stakeholders could pave a way for future success in MF drug development.

Comparison of the Efficacy of Innovator Rituximab and its Biosimilars in Diffuse Large B Cell Lymphoma Patients: A Retrospective Analysis.

Diffuse large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma among adults, although it also affects the young and the elderly. DLBCL is treated with a chimeric monoclonal antibody against CD20, a B cell surface protein, named rituximab, in combination with a multidrug chemotherapeutic regimen. However, owing to its high cost, rituximab cannot be afforded by patients in developing or underdeveloped countries. In such cases, biosimilars of rituximab have been used instead of rituximab, with equivalent efficacy. In this single center, retrospective, observational study, we have compared patient outcomes such complete response (CR), partial response (PR), and overall response rate (ORR) in a cohort of 152 patients in an Indian hospital, who were treated either with innovator rituximab or Reditux, a biosimilar. We observed that the ORRs of both groups (88% in innnovator group and 82% in biosimilar group) were comparable. There was no statistically significant difference between the two groups in terms of CR (p = 0.353), PR (p = 0.42), ORR (p = 0.23), unfavorable responses, and stable or progressive disease (p = 0.42). The number of patients who died due to complications were few, and there was no significant difference between the two groups. The differences in the 3-year event-free survival and overall survival were not statistically significant. Biosimilar rituximab can suitably and safely replace the innovator rituximab for treatment of diffuse large B cell lymphoma.

Resource utilization and cost effectiveness of treating acute promyelocytic leukaemia using generic arsenic trioxide.

Arsenic trioxide (ATO)-based regimens are the standard of care for treating acute promyelocytic leukaemia (APL) and have replaced chemotherapy-based approaches. However, the cost of "patented" ATO is prohibitive because of patent rights. "Generic" ATO has been used in a few countries, but its implications for health resource utilization (HRU) and cost of treatment are unknown. We hypothesized that treating APL patients using generic ATO (APL-ATO) will be cost effective compared to the chemotherapy-based regimen (APL-CT). In a single-centre retrospective study, we used a bottom-up costing method to compare the direct medical cost of treatment and HRU between APL-ATO and APL-CT. These costs and the survival and relapse probabilities were imputed in a three-state Markov decision model to estimate the cost effectiveness of APL-ATO compared to APL-CT. The mean cost of treatment for APL-ATO (n = 30, $8500 ± 2078) was significantly less than for APL-CT (n = 30, $22 600 ± 5528) (P < 0·001). APL-ATO reduced hospitalization, antibiotic and antifungal usage (P < 0·001). In the Markov model, five-year treatment costs were significantly lower for APL-ATO ($11 131) than for APL-CT ($17 926) (P < 0·001). Treatment cost and health resource utilization were significantly lower for generic ATO-treated APL patients compared to the chemotherapy-based regimen.