Search

Introduction: Myeloid malignancies are a heterogeneous group of clonal bone marrow disorders that are complex to manage in the community and therefore often referred to subspecialists at tertiary oncology referral centers. Many patients do not live in close proximity to tertiary referral centers and are unable to commute long distances due to age, comorbidities, and frailty. Interventions that minimize the travel time burden without compromising quality of care are an area of unmet need. We describe a cancer care delivery model for patients with myeloid malignancies that is built around telehealth and enables this vulnerable population access to care at an NCI-designated cancer center while receiving majority of their care close to home. Methods and Materials: We report on a cohort of patients with myeloid malignancies who were co-managed by a general community oncologist and an academic leukemia subspecialist at Montefiore Einstein Cancer Center in New York. Patients were initially referred to our institute for a second opinion by community practices that are in partnership with Montefiore Health System, and initial visits were in-person or via telehealth. Treatment plans were made after discussion with patient’s local community oncologist. Patients then continued to receive majority of their treatment and supportive care including transfusion support with their local oncologist, and follow-up visits were mainly via telehealth with the academic leukemia subspecialist. Results: Our cohort of 12 patients had a median age of 81 years (range, 59–88 years). Patients remained on active treatment for a median time of 357 days (range, 154–557 days). Most of our patients had a performance status of ECOG 2 or higher. Three patients had myelodysplastic syndromes, 7 patients had acute myeloid leukemia, and 2 patients had myelofibrosis. The median number of hospitalizations over the total treatment time period was one. Conclusion: We demonstrate a shared academic and community care co-management model for the treatment of myeloid malignancies in elderly, frail patients using telehealth as a backbone with a very low hospitalization rate.

Purpose: Thrombocytopenia is a serious complication of myelodysplastic syndromes (MDS) associated with an increased bleeding risk and worse prognosis. Eltrombopag (ELT), a thrombopoietin receptor agonist, can increase platelet counts and reverse anti-megakaryopoietic effects of lenalidomide (LEN) in preclinical studies. We hypothesized ELT would reduce the incidence of thrombocytopenia in MDS. Patients and Methods: We conducted a Phase II multicenter trial of ELT and LEN in adult patients with low- or intermediate-1–risk MDS with symptomatic or transfusion-dependent anemia or thrombocytopenia (NCT01772420). Thrombocytopenic patients were started on ELT and subsequently treated with LEN after platelets were increased. Patients without thrombocytopenia were started on LEN monotherapy and treated with ELT if they became thrombocytopenic. Results: Fifty-two patients were enrolled; mean age was 71 years (range 34–93). Overall response rate (ORR) in the intention-to-treat population was 35% (18/52). ELT monotherapy led to ORR of 33.3% (7/21), 29% achieving hematologic improvement (HI)-Platelets, and 24% bilineage responses. LEN monotherapy had 38% ORR (6/16) with all responders achieving HI-Erythroid. Fifteen patients received both ELT and LEN with ORR of 33.3%, 20% achieved HI-Erythroid, and 20% HI-Platelets with 13% bilineage responses. Median duration of response was 40 weeks for ELT (range 8–ongoing), 41 weeks (25–ongoing) for LEN, and 88 weeks (8.3–ongoing) for ELT/LEN. Non-hematologic grade 3–4 treatment-related adverse events were infrequent. Among patients on ELT, 2 had major bleeding events, 1 had a reversible increase in peripheral blasts, and 1 developed marrow fibrosis after 6 years on ELT. Conclusions: ELT and LEN are well tolerated and effective in achieving hematologic improvement in patients with low-/intermediate-risk MDS.

Supplemental Figure 1. Overall Survival Responders vs Non-Responders Supplemental Figure 2. Overall Survival Among Groups

Purpose:Thrombocytopenia is a serious complication of myelodysplastic syndromes (MDS) associated with an increased bleeding risk and worse prognosis. Eltrombopag (ELT), a thrombopoietin receptor agonist, can increase platelet counts and reverse anti-megakaryopoietic effects of lenalidomide (LEN) in preclinical studies. We hypothesized ELT would reduce the incidence of thrombocytopenia in MDS.Patients and Methods:We conducted a Phase II multicenter trial of ELT and LEN in adult patients with low- or intermediate-1–risk MDS with symptomatic or transfusion-dependent anemia or thrombocytopenia (NCT01772420). Thrombocytopenic patients were started on ELT and subsequently treated with LEN after platelets were increased. Patients without thrombocytopenia were started on LEN monotherapy and treated with ELT if they became thrombocytopenic.Results:Fifty-two patients were enrolled; mean age was 71 years (range 34–93). Overall response rate (ORR) in the intention-to-treat population was 35% (18/52). ELT monotherapy led to ORR of 33.3% (7/21), 29% achieving hematologic improvement (HI)-Platelets, and 24% bilineage responses. LEN monotherapy had 38% ORR (6/16) with all responders achieving HI-Erythroid. Fifteen patients received both ELT and LEN with ORR of 33.3%, 20% achieved HI-Erythroid, and 20% HI-Platelets with 13% bilineage responses. Median duration of response was 40 weeks for ELT (range 8–ongoing), 41 weeks (25–ongoing) for LEN, and 88 weeks (8.3–ongoing) for ELT/LEN. Non-hematologic grade 3–4 treatment-related adverse events were infrequent. Among patients on ELT, 2 had major bleeding events, 1 had a reversible increase in peripheral blasts, and 1 developed marrow fibrosis after 6 years on ELT.Conclusions:ELT and LEN are well tolerated and effective in achieving hematologic improvement in patients with low-/intermediate-risk MDS.

Knockdown of Angpt1 does not lead to inhibition of leukemic cell viability

MDS Patient Characteristics

Proposed model of efficacy of dual inhibitor of Tie2 and p38 MAPK in MDS and AML

Supp Fig 1-3 Legends

Gene sets differentially expressed in Angpt-1 high MDS samples

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) suppress normal hematopoietic activity in part by enabling a pathogenic inflammatory milieu in the bone marrow. In this report, we show that elevation of angiopoietin-1 in myelodysplastic CD34+ stem-like cells is associated with higher risk disease and reduced overall survival in MDS and AML patients. Increased angiopoietin-1 expression was associated with a transcriptomic signature similar to known MDS/AML stem-like cell profiles. In seeking a small-molecule inhibitor of this pathway, we discovered and validated pexmetinib (ARRY-614), an inhibitor of the angiopoietin-1 receptor Tie-2, which was also found to inhibit the proinflammatory kinase p38 MAPK (which is overactivated in MDS). Pexmetinib inhibited leukemic proliferation, prevented activation of downstream effector kinases, and abrogated the effects of TNFα on healthy hematopoietic stem cells. Notably, treatment of primary MDS specimens with this compound stimulated hematopoiesis. Our results provide preclinical proof of concept for pexmetinib as a Tie-2/p38 MAPK dual inhibitor applicable to the treatment of MDS/AML. Cancer Res; 76(16); 4841–9. ©2016 AACR.

Heatmap and GSEA analysis of Angpt1 high and low expressing MDS samples

Adult T-cell leukemia/lymphoma (ATLL) remains challenging to treat and has dismal outcome. Allogeneic stem-cell transplantation (allo-SCT) has promising results, but data remain scarce. In this single-center retrospective analysis of 100 patients with ATLL from north America (67 acute, 22 lymphomatous), 17 underwent allo-SCT and 5 autologous SCT (ASCT), with a median follow-up of 65 months. Post-transplant 3-years relapse incidence (RI) and non-relapse mortality (NRM) were 51% and 37%, respectively, and 3-year progression-free survival (PFS) and overall survival (OS) were 31% and 35%, respectively. ASCT 1-year RI was 80% compared to 30% in allo-SCT (p = 0.03). After adjusting for immortal-time bias, allo-SCT had significantly improved OS (HR = 0.4, p = 0.01). In exploratory multivariate analysis, patients achieving first complete response and Karnofsky score ≥ 90 had significantly better outcomes, as did Black patients, compared to Hispanics, who had worse outcome. In transplanted patients, 14 died within 2 years, 4 of which ASCT recipients. Our data are the largest ATLL transplant cohort presented to date outside of Japan and Europe. We show that allo-SCT, but not ASCT, is a valid option in select ATLL patients, and can induce long term survival, with 40% of patients alive after more than 5 years.

Purpose Research suggests better survival among Hispanics with diffuse large B-cell lymphoma (DLBCL) compared to non-Hispanic Whites (NHW); however, less is known about racial/ethnic survival differences in follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). Methods We identified incident FL and CLL cases diagnosed between 2005 and 2016 at Montefiore Medical Center in the Bronx, NY. Cox proportional hazards regression assessed the association between race/ethnicity and all-cause mortality among FL and CLL separately. Results Of the 201 FL patients, 39.3% were NHW, 19.4% non-Hispanic Black (NHB), and 41.3% Hispanic, with a similar distribution among CLL patients. After adjusting for International Prognostic Index factors, sex, and chemotherapy, Hispanics with FL had lower all-cause mortality compared to NHWs (HR = 0.22; 95% CI 0.08-0.63), similar to prior DLBCL findings. All-cause mortality did not differ between NHBs and NHWs for FL or by any race/ethnicity for CLL. Conclusion In our diverse, urban population, we found that Hispanic diagnosed with FL had lower all-cause mortality compared to NHWs. We found no significant difference in all-cause mortality between Hispanics and NHWs diagnosed with CLL. Our study adds to the growing literature on racial and ethnic differences in survival among Hispanics with hematologic malignancies.

Thrombocytopenia is a serious complication of MDS associated with an increased bleeding risk and worse prognosis. Eltrombopag (ELT), a thrombopoietin receptor agonist, can increase platelet counts and reverse anti-megakaryopoietic effects of lenalidomide (LEN) in preclinical studies. We hypothesized ELT would reduce the incidence of thrombocytopenia in MDS.We conducted a phase 2 multicenter trial of ELT and LEN in adult patients with low or intermediate-1-risk MDS with symptomatic or transfusion-dependent anemia or thrombocytopenia (NCT01772420). Thrombocytopenic patients were started on ELT and subsequently treated with LEN after platelets were increased. Patients without thrombocytopenia were started on LEN monotherapy and treated with ELT if they became thrombocytopenic.52 patients were enrolled; mean age was 71 years (range 34-93). ORR in the ITT population was 35% (18/52). ELT monotherapy led to ORR of 33.3% (7/21), 29% achieving HI-Platelets, and 24% bilineage responses. LEN monotherapy had 38% ORR (6/16) with all responders achieving HI-Erythroid. 15 patients received both ELT and LEN with ORR of 33.3%, 20% achieved HI-Erythroid, and 20% HI-Platelets with 13% bilineage responses. Median duration of response was 40 weeks for ELT (range 8-ongoing), 41 weeks (25-ongoing) for LEN, and 88 weeks (8.3-ongoing) for ELT/LEN. Non-hematological grade 3-4 treatment-related adverse events were infrequent. Among patients on ELT, 2 had major bleeding events, 1 had a reversible increase in peripheral blasts, and 1 developed marrow fibrosis after 6 years on ELT.ELT and LEN are well tolerated and effective in achieving hematological improvement in patients with low/intermediate-risk MDS.

Cancer patients show increased morbidity with COVID-19 and need effective immunization strategies. We demonstrate that a 3rd dose of COVID-19 vaccine leads to seroconversion in 57% of patients that were seronegative after primary vaccination. The immune response is durable as assessed by anti-S antibody titers, T-cell activity and neutralization activity against wild-type SARS-CoV2 and BA1.1.529 at 6 months of follow up. A subset of severely immunocompromised hematologic malignancy patients were unable to mount adequate immune response after the 3rd dose and were treated with a 4th dose in a prospective clinical trial which led to adequate immune-boost in 67% of patients. Low baseline IgM levels and CD19 counts were associated with inadequate seroconversion. Booster doses induced limited neutralization activity against the Omicron variant. These results indicate that vaccine booster-induced immunity is durable in cancer patients and additional doses can further stimulate immunity in a subset of hematologic malignancy patients.Statement of significanceWe demonstrate that a 3rd dose of vaccine leads to seroconversion in 57% of negative patients with durable immune responses at 6 months. A 4th dose of vaccine can seroconvert hematologic malignancy patients with higher baseline IgM and CD19 levels.

Outcomes for patients with hematologic malignancy infected with COVID-19 have not been aggregated. The objective of this study was to perform a systematic review and meta-analysis to estimate the risk of death and other important outcomes for these patients. We searched PubMed and EMBASE up to 20 August 2020 to identify reports of patients with hematologic malignancy and COVID-19. The primary outcome was a pooled mortality estimate, considering all patients and only hospitalized patients. Secondary outcomes included risk of intensive care unit admission and ventilation in hospitalized patients. Subgroup analyses included mortality stratified by age, treatment status, and malignancy subtype. Pooled prevalence, risk ratios (RRs), and 95% confidence intervals (CIs) were calculated using a random-effects model. Thirty-four adult and 5 pediatric studies (3377 patients) from Asia, Europe, and North America were included (14 of 34 adult studies included only hospitalized patients). Risk of death among adult patients was 34% (95% CI, 28-39; N = 3240) in this sample of predominantly hospitalized patients. Patients aged ≥60 years had a significantly higher risk of death than patients, Key Points • Adult patients with hematologic malignancy and COVID-19 found a 34% risk of death, whereas pediatric patients had a 4% risk of death. • Patients on systemic anticancer therapy had a similar risk of death to patients on no treatment (RR, 1.17; 95% CI, 0.83-1.64).

Racial/ethnic differences in diffuse large B-cell lymphoma (DLBCL) survival have focused on non-Hispanic Whites (NHW) and non-Hispanic Blacks (NHB), often excluding Hispanics/Latinos. To further assess these racial/ethnic survival differences, we identified incident DLBCL cases diagnosed between 2005 and 2016 (n=404; NHW=136, NHB=106, Hispanic/Latino=162) at Montefiore Medical Center (Bronx, NY). All-cause mortality survival curves were assessed by the Kaplan-Meier method and log-rank test. Cox proportional hazards regression assessed the association between demographic/clinical factors and all-cause mortality. Hispanic/Latino patients experienced 52% lower risk of mortality compared to NHWs (HR=0.48, 95%CI=0.28–0.83), after adjusting for clinical prognostic factors. This reduced risk experienced by Hispanics/Latinos was similarly observed by age at diagnosis (≤60 years, >60 years), stage (I/II, III/IV), and receipt of chemotherapy. NHBs and NHWs experienced similar risk of mortality (HR=0.85, 95%CI=0.52–1.40). Overall, Hispanic/Latino patients had improved survival compared to NHWs. Additional research should seek to identify the drivers of this survival benefit.

The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49–8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9–8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1–7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.

It is well established that COVID-19 carries a higher risk of morbidity and mortality in patients with hematologic malignancies, however, very little data on ethnicity specific responses in this particular patient population currently exist. We established a program of rapid vaccination and evaluation of antibody-mediated response to all EUA COVID-19 vaccines in an inner city minority population to determine the factors that contribute to the poor seroconversion to COVID-19 vaccination in this population. We conducted a cross-sectional cohort study of 126 patients with hematologic malignancies in the outpatient practices of our institution who completed their vaccination series with one of the three FDA EUA COVID-19 vaccines, Moderna, Pfizer, or Johnson & Johnson (J&J). We qualitatively measured Spike IgG production in all patients using the AdviseDx SARS-CoV-2 IgG II assay and quantitatively in 106 patients who completed their vaccination series with at least 14 days after the 2nddose of the Moderna or Pfizer vaccines or 28d after the single J&J vaccine. Patient characteristics were analyzed using standard descriptive statistics and associations between patient characteristics, cancer subtypes, treatments, and vaccine response were assessed using Fisher Exact test or Kruskal-Wallis Rank Sum test. The majority of patients (74%) were minorities. Seventy patients (60%) received Pfizer, 36 patients (31%) Moderna, and 10 patients (9%) J&J. We observed a high-rate of seropositivity (86%) with 16 pts (14%) having a negative Spike IgG. Of the 86 minority patients included, 94% Blacks (30/32) and 87% (39/45) Hispanics showed seropositivity. The factors that contributed to significantly lower seroconversion rates included patients with Non-Hodgkin lymphoma (p=0.005), those who received cytotoxic chemotherapy (p=0.002), IVIG (p=0.01), CAR-T cell therapy (p=0.00002), and CD20 monoclonal antibodies (Ab) (p=0.0000008). Plasma cell neoplasms (p=0.02), immunomodulatory agents (p=0.01), and proteasome inhibitors (p=0.01) had significantly higher seroconversion rates, and those with a history of prior COVID-19 (11%, 12/106) had significantly higher antibody titers (p=0.0003). The positivity rate was 86% (37 seropositive, 6 seronegative) for autologous HSCT and 75% (3 seropositive, 1 seronegative) for allogeneic HSCT. No life-threatening AE were observed. We show high seroconversion rates after SARS-CoV-2 vaccination in non-White patients with hematologic malignancies treated with a wide spectrum of therapeutic modalities. Vaccination is safe, effective, and should be encouraged in most patients with hematologic malignancies. Our minorities based study could be employed as an educational tool to dispel myths and provide data driven evidence to overcome vaccine hesitancy.