Rita Yim

There is currently no consensus on the optimal treatment of early myelofibrosis (MF). Ropeginterferon alfa-2b (ropeg) is a next-generation monopegylated interferon alfa-2b developed specifically to treat myeloproliferative neoplasms. We conducted a phase 2 study in patients with prefibrotic primary MF (pre-PMF) and Dynamic International Prognostic Scoring System low-/intermediate-1–risk fibrotic PMF or secondary MF (SMF) who required cytoreduction. Ongoing treatment with hydroxyurea was substituted with ropeg (week 0, 250 μg; week 2, 350 μg; week 4 onward, 500 μg every 2 weeks). The primary end points were safety and clinicohematologic complete response (CHCR). Seventy-one patients (40 men and 31 women) with a median age of 60 years (range, 31-86) were enrolled and followed up for a median of 119 weeks (range, 10-131). At weeks 24, 48, and 104, CHCR was achieved in 63.8% (pre-PMF, 74%; fibrotic PMF, 20%; fibrotic SMF, 42.9%), 63.5% (pre-PMF, 69.6%; fibrotic PMF, 25%; SMF, 53.9%), and 70% of patients (pre-PMF, 78.4%; fibrotic PMF, 33.3%; SMF, 50%), respectively. Thrombo-hemorrhagic events were not observed after stopping hydroxyurea. At weeks 24, 48, and 104, reduction in JAK2V617F variant allele frequency (VAF) was observed in 53.1%, 70%, and 67.6% of patients, and reduction in CALR mutant VAF was observed in 52.6%, 42.9%, and 40% of patients, respectively. In 50 evaluable cases at week 104, 13 patients (26%) had reduced bone marrow reticulin fibrosis. There were 3 treatment discontinuations (4.2%) due to adverse events. In conclusion, ropeg was safe and induced CHCR associated with significant molecular responses in patients with early MF. This trial was registered at www.clinicaltrials.gov as NCT04988815.

The Acute Promyelocytic Leukemia (APL) Asian Consortium analyzed a contemporaneous cohort of newly diagnosed patients with APL treated with and without frontline arsenic trioxide (ATO) in 6 centers. The objectives were to define the impact of ATO on early deaths and relapses and its optimal positioning in the overall treatment strategy. In a 21.5-year period, 324 males and 323 females at a median age of 45.5 years (range, 18.1-91.8; low/intermediate risk, n = 448; high risk, n = 199) were treated. Regimens included frontline all-trans retinoic acid (ATRA)/chemotherapy and maintenance with/without ATO (n = 436), ATRA/IV-ATO/chemotherapy (ATRA/IV-ATO; n = 61), and ATRA/oral-ATO/ascorbic acid with ATO maintenance (oral-AAA; n = 150). The ATRA/chemotherapy group had significantly more frequent early deaths within 60 days (8.3% vs 3.3%; P = .05), inferior 60-day survival (91.7% vs 98.4%/96%; P < .001), inferior 5-year relapse-free survival (RFS; 76.9% vs 92.8%/97.8%; P < .001), and inferior 5-year overall survival (OS; 84.6% vs 91.4%/92.3%; P = .03) than ATO-containing groups (ATRA/IV-ATO and oral-AAA). The addition of oral-ATO maintenance partly mitigated the inferior 5-year RFS resulting from the omission of ATO during induction (ATRA/chemotherapy/non-ATO maintenance vs ATRA/chemotherapy/ATO maintenance vs ATRA/IV-ATO vs oral-AAA, 71.1% vs 87.9% vs 92.8% vs 97.8%; P < .001). The favorable survival impacts of ATO were observed in all risk groups. In conclusion, ATO decreased early deaths, improved 60-day survival, and resulted in significantly superior RFS and OS. This trial was registered at www.clinicaltrials.gov as #NCT04251754.

Clonal hematopoiesis (CH) is associated with an increased risk of developing myeloid neoplasms (MNs) such as myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML). In general, CH comprises clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS). It is an age-related phenomenon characterized by the presence of somatic mutations in hematopoietic stem cells (HSCs) and hematopoietic stem and progenitor cells (HSPCs) that acquire a fitness advantage under selection pressure. Individuals with CHIP have an absolute risk of 0.5–1.0% per year for progressing to MDS or AML. Inflammation, smoking, cytotoxic therapy, and radiation can promote the process of clonal expansion and leukemic transformation. Of note, exposure to chemotherapy or radiation for patients with solid tumors or lymphomas can increase the risk of therapy-related MN. Beyond hematological malignancies, CH also serves as an independent risk factor for heart disease, stroke, chronic obstructive pulmonary disease, and chronic kidney disease. Prognostic models such as the CH risk score and MN-prediction models can provide a framework for risk stratification and clinical management of CHIP/CCUS and identify high-risk individuals who may benefit from close surveillance. For CH or related disorders, therapeutic strategies targeting specific CH-associated mutations and specific selection pressure may have a potential role in the future.

Background: In Asia, treatment decisions in myelodysplastic neoplasms (MDS) are conventionally based on the Revised International Prognostic Scoring system (IPSS-R). A unique clinical-molecular prognostic model, the IPSS-molecular (IPSS-M), has been developed based on 2957 patients with de-novo MDS, therapy-related MDS, and MDS/myeloproliferative neoplasm (MPN) overlap syndrome. The IPSS-M comprises haematological parameters, karyotypic abnormalities and somatic mutations in a 31-gene panel. Validation of the IPSS-M in large multicentre studies in Asian has however not been performed. Hence, prognostic models taking into account the unique clinical-molecular characteristics of Asian MDS patients remain undefined. Aims: The objectives of this multicenter cohort study were: 1. to define the haematological, cytogenetic and molecular characteristics of Asian MDS patients; and 2. to develop a prognostic model based on these characteristics. Methods: Consecutive MDS patients in Hong Kong, Singapore and Taiwan diagnosed between 2004 to 2021 were studied. Data were censored on 17 September 2022. Patients with MDS/MPN overlap syndrome were excluded. A panel of 54 myeloid-related genes was sequenced in the diagnostic bone marrow by next-generation sequencing. Hematological, pathological, cytogenetic and molecular variables were evaluated for their association with overall survival (OS), leukemia-free survival (LFS), and time to progression to secondary acute myeloid leukemia (TTP-sAML). Variable selection was performed to determine the confounding variable and independent prognostic variables. The relative weights of the selected variables were estimated using a Cox multivariable model adjusted for confounders. According to the weights of each prognostic variable, individual patient-specific prognostic scores were calculated. Based on the scores of the entire cohort, six prognostic subgroups were defined. The statistical predictive power of this prognostic model was assessed by the concordance index (C-index). The prognostic model was validated with publicly available data from the IPSS-M cohort. Results: Seven hundred and seventy-eight men (63.5%) and 447 women (36.5%) at a median age of 68.4 (interquartile range, IQR: 57-77) years were studied. After a median follow-up of 2.85 (IQR: 0.97-7.06) years, there were 693 deaths (56.6%) and 284 transformations to sAML (23.2%). Three-hundred and ninety-four patients (32.2%) received hypomethylating agents (azaciticine, N=367; decitabine, N=27), and 158 patients (12.9%) underwent allogeneic haematopoietic stem cell transplantation. All patients showed at least one genetic alteration in the 54-gene panel (Figure 1A). Prognostic scoring systems (each with 6 prognostic subgroups) were established for OS (C-index: 0.72) (Figure 1A), LFS (C-index:0.71) (Figure 1B) and TTP-sAML (C-index: 0.74) (Figure 1C). Genomic factors significantly associated with inferior outcomes were monosomy 7, del(5q), and mutations in GNAS and TP53 for OS; trisomy 19, del(5q), monosomy 7, and mutations in GNAS, PTPN11 and TP53 for LFS, and i(17q), del(5q), and mutations in NPM1, NRAS, GNAS, IDH2, SF3B1, and RUNX1 for TTP-sAML. Using the IPSS-M publically available dataset as the validation cohort, our prognostic model gave C-indices of 0.70, 0.71 and 0.74 for OS, LFS and TTP-sAML respectively. Finally, this prognostic model had superior prognostic power as compared with the IPSS-R and IPSS-M for the current Asian cohort (Figure 1D). Conclusion: Combining genomic with hematological and cytogenetic parameters, the Asian clinical-molecular prognostic model improved the risk stratification of patients with MDS in Asia, potentially improving clinical decision-making.

In myelodysplastic syndrome (MDS), resistance to hypomethylating agents (HMA) portends a poor prognosis, underscoring the importance of understanding the molecular mechanisms leading to HMA-resistance. In this study, P39 and Kasumi-1 cells and their azacitidine-resistant and decitabine-resistant sublines were evaluated comparatively with transcriptomic and methylomic analyses. Expression profiling and genome-wide methylation microarray showed downregulation of PTEN associated with DNA hypermethylation in P39 cell lines resistant to azacitidine and decitabine. This pattern of PTEN dysregulation was also confirmed in a cohort of patients failing treatment with HMA. DNA hypomethylation of MDM2 was detected with downregulation of MDM2 in HMA resistant cell lines. Long-read sequencing revealed significant RNA hypomethylation of MDM2 resulting in alternative splicing and production of a truncated MDM2 transcript in azacitidine-resistant P39 cells. The expression of this MDM2 truncated transcript was also significantly increased in HMA-resistant patients compared with HMA-responsive patients. In conclusion, epigenetic and epi-transcriptomic dysregulation of PTEN and MDM2 were associated with resistance to hypomethylating agents.

Myelodysplastic syndrome (MDS) is a clonal myeloid neoplasm characterized by ineffective hematopoiesis, cytopenia, dysplasia, and clonal instability, leading to leukemic transformation. Hypomethylating agents are the mainstay of treatment in higher-risk MDS. However, treatment resistance and disease transformation into acute myeloid leukemia (AML) is observed in the majority of patients and is indicative of a dismal outcome. The residual cell clones resistant to therapy or cell clones acquiring new genetic aberrations are two of the key events responsible for drug resistance. Bulk tumor sequencing often fails to detect these rare subclones that confer resistance to therapy. In this study, we employed a single-cell DNA (sc-DNA) sequencing approach to study the clonal heterogeneity and clonal evolution in two MDS patients refractory to HMA. In both patients, different single nucleotide variations (SNVs) or insertions and deletions (INDELs) were detected with bulk tumor sequencing. Rare cell clones with mutations that are undetectable by bulk tumor sequencing were detected by sc-DNA sequencing. In addition to SNVs and short INDELs, this study also revealed the presence of a clonal copy number loss of DNMT3A, TET2, and GATA2 as standalone events or in association with the small SNVs or INDELs detected during HMA resistance and disease progression.

Myelodysplastic syndrome (MDS) is a heterogeneous, clonal hematological disorder characterized by ineffective hematopoiesis, cytopenia, morphologic dysplasia, and predisposition to acute myeloid leukemia (AML). Stem cell genomic instability, microenvironmental aberrations, and somatic mutations contribute to leukemic transformation. The hypomethylating agents (HMAs), azacitidine and decitabine are the standard of care for patients with higher-risk MDS. Although these agents induce responses in up to 40–60% of patients, primary or secondary drug resistance is relatively common. To improve the treatment outcome, combinational therapies comprising HMA with targeted therapy or immunotherapy are being evaluated and are under continuous development. This review provides a comprehensive update of the molecular pathogenesis and immune-dysregulations involved in MDS, mechanisms of resistance to HMA, and strategies to overcome HMA resistance.

Despite therapeutic advances, early death (ED) remains a major factor curtailing survival of acute promyelocytic leukemia (APL). Studies examining factors that cause early death (ED; within 30 days of admission) and the correlation of survival with the timing of administration of all-trans retinoic acid (ATRA) and hemostatic parameters are scarce. We performed a cohort analysis of nonselect patients with newly diagnosed APL who presented to the health care system in Hong Kong, where oral arsenic trioxide was used. From 1 January 2007 to 30 April 2020, 358 patients (median age, 47 [1-97] years) with newly diagnosed APL were identified. ED occurred in 56 patients (16%): 11 (3%) died in the first 2 days after admission (intracranial hemorrhage [ICH], n = 6; APL-differentiation syndrome [APL-DS], n = 4; infection, n = 1); 22 (6%) died within 3 to 7 days (ICH, n = 12; APL-DS, n = 8; infections, n = 2), and 23 (6%) died within 8 to 30 days (ICH, n = 7; APL-DS, n = 11; infection, n = 5). Factors significantly associated with ED by multivariate analysis included male sex (P = .01); presenting leukocyte count ≥10 × 109/L (P = .03); fibrinogen 24 hours after hospital admission (P < .001). After a median follow-up of 47 (0-166) months, the 5- and 10-year overall survival (OS) was 68.6% and 61.2%, respectively. Excluding EDs, the 5- and 10-year post–30-day OS improved to 81.3% and 72.5%. Early administration of ATRA (<24 hours) and vigorous correction of hemostatic abnormalities, including hypofibrinogenemia, are key to reducing ED.

Introduction: Real-world data of responses, quality-of-life (QOL) changes and adverse events in patients with myeloproliferative neoplasms (MPN) on conventional therapy (hydroxyurea ± anagrelide), pegylated interferon alpha-2A (PEG-IFNα-2A) or ruxolitinib are limited. Methods: We prospectively studied MPN patients receiving conventional therapy, PEG-IFNα-2A or ruxolitinib. Next-generation sequencing of 69 myeloid-related genes was performed. Clinicohematologic responses, adverse events, and QOL (determined by the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score, MPN-SAF TSS) were evaluated. Results: Seventy men and fifty-five women with polycythemia vera (PV) (N = 23), essential thrombocythemia (ET) (N = 56) and myelofibrosis (MF) (N = 46) were studied for a median of 36 (range: 19–42) months. In PV, responses were comparable for different modalities. CREBBP mutations were associated with inferior responses. In ET, PEG-IFNα-2A resulted in superior clinicohematologic complete responses (CHCR) (P = 0.045). In MF, superior overall response rates (ORR) were associated with ruxolintib (P = 0.018) and JAK2V617F mutation (P = 0.04). For the whole cohort, ruxolitinib led to rapid and sustained reduction in spleen size within the first 6 months, and significant improvement of QOL as reflected by reduction in MPN-SAF TSS (P < 0.001). Adverse events of grades 1–2 were observed in 44%, 62% and 20% of patients receiving conventional therapy, PEG-IFNα-2A and ruxolitinib respectively; and of grade 3–4 in 7% and 9% of patients receiving PEG-IFNα-2A and ruxolitinib. Conclusions: Conventional therapy, PEG-IFNα-2A and ruxolitinib induced responses in all MPN subtypes. PEG-IFNα-2A led to superior CHCR in ET; whereas ruxolitinib resulted in superior ORR in MF, and significant reduction in spleen size and improvement in QOL.

OBJECTIVES: To review the evidence for clinical efficacy and cost‐effectiveness of proven medications in the treatment and prevention of myocardial infarction (MI) in older patients; to summarize Canadian data on treatment patterns and clinical outcomes for younger and older patients with coronary heart disease; to explore the reasons for gaps between best care, based on the evidence of efficacy from trials, and usual care, based on the population effectiveness audits; and to explore potential approaches to closing the care gaps. DESIGN: Review of the recent clinical trial literature on the management of MI, highlighting results in older patients. Review of medication utilization and outcomes data from a series of large, consecutively enrolled patient cohorts with acute MI (N = 7070) in a variety of cardiac care settings (10 centers in five Canadian provinces, including university‐ based teaching hospitals, community hospitals, cardiologist and family physician out‐patient clinics) from 1987 to 1996. RESULTS: There is no qualitative interaction of cardiac therapies: thrombolytics, beta‐blockers, acetylsalicylic acid (ASA), and statins are efficacious in all clinically relevant patient subgroups, including older people. However, there are consistent gaps between usual care and best care, particularly among older patients (in whom there is also a concomitantly higher mortality risk). Repeated multivariate analyses confirm older age to be an independent contributor to increased risk. Use of efficacious medications is, in contrast, consistently associated with increased survival. Analysis of temporal trends suggests beneficial changes in practice patterns and outcomes are possible to achieve. However, “best care” has not been rapidly or completely achieved. Review of strategies to close these care gaps suggests that audit and feedback, critical pathways, and multifactorial interventions involving patients and other members of the healthcare team as well as physicians may be the most efficacious strategies for change. CONCLUSIONS: Despite equal or enhanced efficacy, there is consistently less prescription of proven drugs among older cardiac patients. These care patterns may contribute to their enhanced risk. The causes underlying these practice patterns are complex, and their population impact may be undervalued by clinicians and managers. Improvement of these patterns is difficult, but ultimately it would be beneficial for this presently disadvantaged, readily identified, high risk patient population. J Am Geriatr Soc 47: 811–818, 1999.