Treatment approach and outcomes of patients with accelerated/blast-phase myeloproliferative neoplasms in the current era.

Progression of myeloproliferative neoplasms (MPNs) to accelerated or blast-phase is associated with poor survival outcomes. Since 2017 there have been several therapies approved for use in acute myeloid leukemia (AML); these therapies have been incorporated into the management of accelerated/blast-phase MPNs (MPN-AP/BP). We performed a multi-center analysis to investigate outcomes of patients diagnosed with MPN-AP/BP in 2017 or later. Two-hundred two patients were identified; median overall survival (OS) was 0.86 years. We also analyzed patients based on first-line treatment; the three most common approaches were intensive chemotherapy (IC) (n=65), DNA methyltransferase inhibitor (DNMTi)-based regimens (n=65), and DNMTi + venetoclax (VEN)-based regimens (n=54). Median OS was not significantly different by treatment type. In addition, we evaluated response by 2017 European LeukemiaNet (ELN) AML criteria and 2012 MPN-BP criteria in an effort to understand the association of response with survival outcomes. We also analyzed outcomes in 65 patients that received allogeneic hematopoietic stem cell transplant (allo-HCT); median OS was 2.30 years from time of allo-HCT. Our study demonstrates that survival amongst patients with MPN-AP/BP is limited in the absence of allo-HCT even in the current era of therapeutics and underscores the urgent need for new agents and approaches.

Molecular ontogeny underlies the benefit of adding venetoclax to hypomethylating agents in newly diagnosed AML patients.

The clinical impact of molecular ontogeny in acute myeloid leukemia (AML) was defined in patients treated with intensive chemotherapy. In a cohort of 314 newly diagnosed AML patients, we evaluated whether molecular ontogeny subgroups have differential benefit of venetoclax (VEN) added to hypomethylating agents (HMA). In secondary ontogeny (n = 115), median overall survival (OS)(14.1 vs. 6.9 months, P = 0.0054), composite complete remission (cCR 61% vs. 18%, P < 0.001) and allogeneic hematopoietic stem cell transplant (alloHCT) (24% vs. 6%, P = 0.02) rates were better in patients treated with HMA + VEN vs. HMA. In contrast, in TP53 AML(n = 111) median OS (5.7 vs. 6.1, P = 0.93), cCR (33% vs. 37%, P = 0.82) and alloHCT rates (15% vs. 8%, P = 0.38) did not differ between HMA + VEN vs. HMA. The benefit of VEN addition in the secondary group was preserved after adjustment for significant clinicopathologic variables (HR 0.59 [95% CI 0.38-0.94], P = 0.025). The OS benefit of HMA + VEN in secondary ontogeny was similar in those with vs. without splicing mutations (P = 0.92). Secondary ontogeny AML highlights a group of patients whose disease is selectively responsive to VEN added to HMA and that the addition of VEN has no clinical benefit in TP53-mutated AML.

Hypomethylating agents plus venetoclax compared with intensive induction chemotherapy regimens in molecularly defined secondary AML.

Molecularly defined secondary acute myeloid leukemia is associated with a prior myeloid neoplasm and confers a worse prognosis. We compared outcomes of molecularly defined secondary AML patients (n = 395) treated with daunorubicin and cytarabine (7 + 3, n = 167), liposomal daunorubicin and cytarabine (CPX-351, n = 66) or hypomethylating agents (HMA) + venetoclax (VEN) (n = 162). Median overall survival (OS) was comparable between treatment groups among patients aged >60 years. In a multivariable model HMA + VEN vs. 7 + 3 was associated with better OS (hazard ratio [HR] 0.64 [95% confidence interval (CI) 0.42-0.98, p = 0.041]), whereas CPX-351 vs. 7 + 3 was not (HR 0.79 [CI 95% 0.50-1.25, p = 0.31]). Allogeneic hematopoietic stem cell transplantation, BCOR and IDH mutations were associated with improved OS; older age, prior myeloid disease, NRAS/KRAS mutations, EZH2 mutation, and monosomal karyotype were associated with worse OS. When analyzed in each treatment separately, the IDH co-mutations benefit was seen with 7 + 3 and the detrimental effect of NRAS/KRAS co-mutations with HMA + VEN and CPX-351. In pairwise comparisons adjusted for age, HMA + VEN was associated with improved OS vs. 7 + 3 in patients with SF3B1 mutation and improved OS vs. CPX-351 in those with RNA splicing factor mutations. In molecularly defined secondary AML treatment with HMA + VEN might be preferred but could further be guided by co-mutations.

Tri-ing to decipher trisomy AML.

Lam et al. compared trisomy acute myeloid leukaemia (AML) patients (inclusive of single trisomy, double trisomy or tetrasomy cases) with cytogenetically normal AML to uncover distinguishing molecular and prognostic features of trisomy AML. The study contributes to our understanding of trisomy AML, but the heterogeneity of trisomy subtypes remains a barrier to its study. Commentary on: Lam et al. Distinct karyotypic and mutational landscape in trisomy AML. Br J Haematol 2024;204:939-944.

Immunotherapy for Acute Myeloid Leukemia: Current Trends, Challenges, and Strategies.

BACKGROUND: In the past decade, there have been significant breakthroughs in immunotherapies for B-cell lymphoid malignancies and multiple myeloma, but progress has been much less for acute myeloid leukemia (AML). Nevertheless, challenge begets innovation and several therapeutic strategies are under investigation. SUMMARY: In this review, we review the state of the art in AML immunotherapy including CD33- and CD123-targeted agents, immune checkpoint inhibition, and adoptive cell therapy strategies. We also share conceptual frameworks for approaching the growing catalog of investigational AML immunotherapies and propose future directions for the field. KEY MESSAGES: Immunotherapies for AML face significant challenges but novel strategies are in development.

Spectrum From Clonal Hematopoiesis to Myelodysplastic Neoplasm/Syndromes and Other Myeloid Neoplasms.

ABSTRACT: Clonal hematopoiesis (CH) confers a high risk of aging-related diseases and hematologic malignancy. There are still significant knowledge gaps in identifying high-risk patients with CH and managing such patients. In this review, we focus on 3 areas: (1) the natural history of CH; (2) the risks of progression of CH, including CH of indeterminate potential, clonal cytopenia of undetermined significance, and therapy-related CH, to myeloid malignancy; and (3) the challenges and unmet needs of CH management and research.

Targeted Therapy for MPNs: Going Beyond JAK Inhibitors.

PURPOSE OF REVIEW: JAK inhibition is an effective means of controlling symptom burden and improving splenomegaly in patients with myeloproliferative neoplasms (MPNs). However, a majority of patients treated with JAK inhibition will have disease progression with long-term use. In In this review, we focus on the investigation of novel targeted agents beyond JAK inhibitors both in the chronic phase of disease and in the accelerated/blast phase of disease. RECENT FINDINGS: Relevant targeted therapies in MPNs include BET inhibitors, BCL inhibitors, LSD1 inhibitors, PI3K inhibitors, IDH inhibitors, telomerase inhibitors, and MDM2 inhibitor. Agents within these classes have been investigated either as monotherapy or in combination with a JAK inhibitor. We summarize the prospective data for these agents along with detailing the ongoing phase III trials incorporating these agents. While JAK inhibition has been a mainstay of therapy in MPNs, a majority of patients will have disease of progression. JAK inhibitors also have limited anti-clonal effect and do not impact the rate of progression to the blast phase of disease. The novel therapies detailed in this review not only show promise in ameliorating the symptom burden of MPNs but may be able to alter the natural history of disease.

Targeting MET and FGFR in Relapsed or Refractory Acute Myeloid Leukemia: Preclinical and Clinical Findings, and Signal Transduction Correlates.

PURPOSE: Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and require new therapies. In AML, autocrine production of hepatocyte growth factor (HGF) drives MET signaling that promotes myeloblast growth and survival, making MET an attractive therapeutic target. MET inhibition exhibits activity in AML preclinical studies, but HGF upregulation by the FGFR pathway is a common mechanism of resistance. PATIENTS AND METHODS: We performed preclinical studies followed by a Phase I trial to investigate the safety and biological activity of the MET inhibitor merestinib in combination with the FGFR inhibitor LY2874455 for patients with R/R AML. Study Cohort 1 underwent a safety lead-in to determine a tolerable dose of single-agent merestinib. In Cohort 2, dose-escalation of merestinib and LY2874455 was performed following a 3+3 design. Correlative studies were conducted. RESULTS: The primary dose-limiting toxicity (DLT) observed for merestinib alone or with LY2874455 was reversible grade 3 transaminase elevation, occurring in 2 of 16 patients. Eight patients had stable disease and one achieved complete remission (CR) without measurable residual disease. Although the MTD of combination therapy could not be determined due to drug supply discontinuation, single-agent merestinib administered at 80 mg daily was safe and biologically active. Correlative studies showed therapeutic plasma levels of merestinib, on-target attenuation of MET signaling in leukemic blood, and increased HGF expression in bone marrow aspirate samples of refractory disease. CONCLUSIONS: We provide prospective, preliminary evidence that MET and FGFR are biologically active and safely targetable pathways in AML.

Prognostication in myelodysplastic syndromes (neoplasms): Molecular risk stratification finally coming of age.

Accurate risk prognostication is central to the management of myelodysplastic syndromes, given the widely heterogeneous clinical outcomes of these bone marrow failure disorders. Over the past decade, the rapidly expanding compendium of molecular lesions in myelodysplastic syndrome (MDS) has offered unprecedented insight into MDS pathobiology. Recently, molecular prognostic models such as the Molecular International Prognostic Scoring System (IPSS-M) have leveraged the wellspring of genetic data to improve upon traditional risk models such as the Revised IPSS (IPSS-R), but also added substantial complexity. In this review, we highlight early MDS prognostic models, the significant advancements in MDS genomics since then, and the recent advent of molecular based prognostic models. We conclude by discussing important opportunities and challenges in the management of MDS as we arrive at the molecular frontier.

Emicizumab for the treatment of acquired hemophilia A: Retrospective review of a single-institution experience.

INTRODUCTION: Acquired haemophilia A (AHA) is a rare and potentially life-threatening bleeding disorder arising from autoantibodies that inhibit coagulation factor VIII (FVIII). Treatment entails achieving haemostasis with bypassing agents or factor replacement, and eradication of the inhibitor with immunosuppressive therapy (IST). Due to the rarity of AHA, there are few prospective data to guide management. METHODS: We present a retrospective report of 11 AHA patients treated with emicizumab, a FVIII-mimetic bispecific antibody, administered at 3 mg/kg weekly for 4 weeks in conjunction with rituximab-based immunosuppressive therapy. The chromogenic FVIII inhibitor assay was used to assess for inhibitor eradication. RESULTS: The median follow-up was 13.9 months. The median number of days of additional haemostatic therapy or red blood cell transfusions after initiating emicizumab was 2 (range 0-15). The median was 0 days (range 0-8) for patients who did not require vascular embolization to achieve haemostasis. Eight patients achieved a complete remission (defined as recovery of FVIII activity to > 50% with a negative inhibitor test in the absence of haemostatic and IST); two patients achieved a partial remission (FVIII activity > 50% but with detectable inhibitor); one patient experienced refractory disease. One patient experienced rebleeding and two patients experienced inhibitor recurrence. No thrombotic, thrombotic microangiopathic or infectious complications occurred. CONCLUSION: Our observations suggest emicizumab can facilitate haemostasis for AHA patients and be combined with safer, lower-intensity immunosuppressive therapies to achieve remission.

Outcomes of antifungal prophylaxis for newly diagnosed AML patients treated with a hypomethylating agent and venetoclax.

Antifungal prophylaxis (AFP) is recommended for acute myeloid leukemia (AML) patients receiving the combination of venetoclax (VEN) and a hypomethylating agent (HMA), but the benefit of this practice is unclear. We identified 131 patients with newly diagnosed AML who received frontline VEN/HMA and evaluated the use of AFP and its association with invasive fungal infections (IFIs) and AML outcomes. Seventeen percent of our patients received AFP at any time. Overall incidence of any IFI ('possible,' 'probable,' or 'proven' infection, as defined by the European Mycoses Study Group) was 13%, and the incidence did not differ based on AFP use (p=.74). Median overall survival did not differ based on AFP use or lack thereof (8.1 vs. 12.5 months, respectively; p=.14). Our findings suggest that, at an institution where the incidence of fungal infections is low, there does not appear to be a role for AFP in newly diagnosed AML patients receiving VEN/HMA.

Erythroid nuclear dysplasia is associated with inferior outcomes for patients with myelodysplastic syndrome undergoing allogeneic hematopoietic cell transplantation.

Disease burden prior to hematopoietic cell transplantation (HCT) is difficult to assess in myelodysplastic syndrome (MDS), particularly in patients without excess blasts. We assessed whether morphologic dysplasia at the time of transplant can be a metric of disease burden that is associated with post-transplant outcomes in MDS patients. We identified 84 MDS patients undergoing allogeneic HCT at our institution between 2010 and 2017 who received a bone marrow evaluation immediately prior to HCT. Dysplasia was independently determined by two hematopathologists blinded to existing pathology reports. Erythroid nuclear dysplasia, but not megakaryocytic or myeloid, was associated with post-HCT outcomes. Presence compared to absence of erythroid nuclear dysplasia was associated with lower 2-year progression-free survival (PFS; 34 % vs 62 %, p = 0.0495) and 2-year overall survival (OS; 34 % vs 62 %, p = 0.042). In a multivariate analysis including age, IPSS-R at the time of transplant, pre-HCT therapy, and donor type as covariates, erythroid nuclear dysplasia remained associated with lower PFS (HR 2.6, p = 0.036) and OS (HR 2.7, p = 0.028). Dysplasia assessment prior to transplant may serve as an estimate of disease burden in MDS and identify high-risk patients who merit additional therapies pre- or post-transplant.

Outcomes for Patients With IDH-Mutated Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation.

Disease relapse after hematopoietic cell transplantation (HCT) is a major cause of treatment failure for patients with acute myeloid leukemia (AML). Maintenance therapy after HCT for patients with targetable mutations such as mutated IDH1 or IDH2 may improve outcomes, and clinical trials evaluating this strategy are ongoing. However, clinical outcomes of IDH1- and IDH2-mutated AML patients after HCT have not been well described. The primary objective of this study was to describe the clinical characteristics and post-HCT outcomes of IDH-mutated AML patients. Survival outcomes included progression-free survival (PFS), overall survival, and cumulative incidences of relapse and nonrelapse mortality. In this multicenter retrospective analysis, 112 adult patients with IDH1- or IDH2-mutated AML who underwent HCT and did not receive an IDH inhibitor as maintenance therapy after HCT were identified at Massachusetts General Hospital, Dana Farber Cancer Institute, and Ohio State University. Mutation testing was performed using next-generation sequencing panels. Patient characteristics were collected retrospectively, and their survival outcomes were analyzed. Univariate and multivariate analyses were performed. The median patient age was 64.1 years. The median follow-up was 27.5 months. Among patients, 78.5% had intermediate- or adverse-risk disease by European LeukemiaNET criteria. Fifty-eight percent of patients received intensive induction chemotherapy, 82% of patients underwent HCT during first complete remission (CR) or CR with incomplete hematologic recovery (CRi), and 34% of patients received myeloablative conditioning. Frequently detected co-mutations were DNMT3A (35.7%), NPM1 (33.1%), and FLT3-ITD (13.4%); TP53 mutations were detected in 3.6% of patients. For IDH1-mutated patients transplanted during first CR/CRi, the 1- and 2-year PFS was 75% and 58%, respectively. For IDH2-mutated patients transplanted in first CR/CRi, the 1- and 2-year PFS was 64% and 58%, respectively. The 2-year cumulative incidence of relapse was 31% and 25% for IDH1- and IDH2-mutated cohorts, respectively. Multivariable analysis suggested first CR/CRi and age ≤60 was associated with improved outcomes for IDH2-mutated patients. To date, this is the largest multicenter study of outcomes of IDH-mutated AML patients after HCT. Our analysis provides important benchmarks for analysis and interpretation of results emerging from clinical trials evaluating maintenance IDH1 and IDH2 inhibitor therapy for AML patients after HCT.

Does patient fitness play a role in determining first-line treatment of acute myeloid leukemia?

The treatment choice for newly diagnosed patients with acute myeloid leukemia (AML) is no longer straightforward. Historically, patient fitness has been a major driver of the initial therapy decision based on the belief that intensive chemotherapy would be the optimal choice if a patient were "fit" enough to receive it. Tools based on chronological age, performance status, and comorbidities have been developed to help estimate patient fitness. With newer approved therapies that include nonintensive options such as IDH1 inhibition or less intensive options such as hypomethylating agent (HMA)- or low-dose cytarabine (LDAC)-based combinations with venetoclax, the choice of frontline AML therapy places more emphasis on disease-specific features, including cytogenetics and mutational profile. Moreover, newer treatments have higher response rates than what has been expected with older nonintensive options such as LDAC or HMA monotherapy. We present cases of three patients with AML with varying cytogenetic and molecular risks to demonstrate the important but changing role of patient fitness in the current era of expanding therapeutic options.

Approach to the Patient with COVID-19-Associated Thrombosis: A Case-Based Review.

Coronavirus disease 2019 (COVID-19) is a current global pandemic caused by the novel coronavirus SARS-CoV-2. Alongside its potential to cause severe respiratory illness, studies have reported a distinct COVID-19-associated coagulopathy that is characterized by elevated D-dimer levels, hyperfibrinogenemia, mild thrombocytopenia, and slight prolongation of the prothrombin time. Studies have also reported increased rates of thromboembolism in patients with COVID-19, but variations in study methodologies, patient populations, and anticoagulation strategies make it challenging to distill implications for clinical practice. Here, we present a practical review of current literature and uses a case-based format to discuss the diagnostic approach and management of COVID-19-associated coagulopathy. IMPLICATIONS FOR PRACTICE: Coronavirus disease 2019 (COVID-19)-associated coagulopathy is characterized by elevated D-dimer levels, hyperfibrinogenemia, and increased rates of thromboembolism. Current management guidelines are based on limited evidence from retrospective studies that should be interpreted carefully. At this time, all hospitalized patients with suspected or confirmed COVID-19 should receive coagulation test surveillance and standard doses of prophylactic anticoagulation until prospective randomized controlled trials yield definitive information in support of higher prophylactic doses.

Chemotherapy-sparing treatment of haemophagocytic lymphohistiocytosis with intravenous immunoglobulins and corticosteroids.

Haemophagocytic lymphohistiocytosis (HLH) can be a rapidly fatal disease. Current treatment in adults is extrapolated from the HLH-2004 protocol that specifies a regimen of etoposide, dexamethasone and cyclosporine. However, HLH presents as a spectrum of disease severity. A therapeutic challenge arises for milder cases where the harms of potent chemotherapy such as etoposide may outweigh its benefit. We present a case of an adult with HLH who developed significant pancytopenia but was otherwise not critically ill and who responded to treatment with a chemotherapy-sparing approach consisting of intravenous immunoglobulins and corticosteroids alone. The case illustrates that tailored therapy may allow effective treatment of the disorder while minimising therapy-related toxicities.