Final phase I substudy results of ivosidenib in patients with mutant IDH1 relapsed/refractory myelodysplastic syndrome.

Ivosidenib is a first-in-class mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor and has shown efficacy and tolerability in patients with advanced mIDH1 hematologic malignancies, leading to approval in front-line and relapsed/refractory (R/R) mIDH1 AML populations. We report final data from a phase I single-arm substudy (NCT02074839) of patients with R/R mIDH1 MDS following failure of standard-of-care therapies. Oral ivosidenib was taken once daily on days 1-28 in 28-day cycles. Primary objectives were to determine safety, tolerability, and clinical activity. The primary efficacy endpoint was the complete remission + partial remission (CR+PR) rate. Nineteen patients were enrolled; 18 were included in the efficacy analysis. Treatment-related adverse events occurred in eight (42.1%) patients, including a grade 1 QT interval prolongation in one (5.3%) patient and grade 2 differentiation syndrome in two (10.5%) patients. Rates of CR+PR and objective response (CR +PR+marrow CR) were 38.9% (95% confidence interval [CI]: 17.3, 64.3) and 83.3% (95% CI: 58.6, 96.4), respectively. Kaplan-Meier estimates showed a 68.6% probability of patients in CR achieving a remission duration of >=5 years, and a median OS of 35.7 months. Of note, 71.4% and 75.0% baseline red blood cell (RBC) and platelet transfusion-dependent patients, respectively, became transfusion independent (TI; no transfusion >=56 days); 81.8% and 100% of baseline RBC and platelet TI patients, respectively, remained TI. One (5.3%) patient proceeded to a hematopoietic stem cell transplant by data cut-off. In conclusion, ivosidenib is clinically active, with durable remissions and a manageable safety profile observed in patients with mIDH1 R/R MDS.

Venetoclax in combination with hypomethylating agent for the treatment of advanced myeloproliferative neoplasms and acute myeloid leukemia with extramedullary disease.

The combination of venetoclax and hypomethylating agent (HMA/venetoclax) has emerged as a treatment option for patients with de novo acute myeloid leukemia (AML) who are unfit to receive intensive chemotherapy. In this single-center retrospective study, we evaluated clinical outcomes following treatment with HMA/venetoclax in 35 patients with advanced myeloproliferative neoplasms, myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes or AML with extramedullary disease. The composite complete remission (CR) rate (including confirmed/presumed complete cytogenetic response, acute leukemia response-complete, CR and CR with incomplete hematologic recovery) was 42.9% with median overall survival (OS) of 9.7 months. Complex karyotype was associated with inferior median OS (3.7 versus 12.2 months; p = 0.0002) and composite CR rate (22% versus 50.0%; p = 0.2444). Although SRSF2 mutations were associated with higher composite CR rate (80.0% versus 28.0%; p = 0.0082), this was not associated with longer median OS (10.9 versus 8.0 months; p = 0.2269). Future studies should include these patient subgroups.

Allogeneic Blood or Marrow Transplantation with High-Dose Post-Transplantation Cyclophosphamide for Acute Lymphoblastic Leukemia in Patients Age ≥55 Years.

Patients age ≥55 years with acute lymphoblastic leukemia (ALL) fare poorly with conventional chemotherapy, with a 5-year overall survival (OS) of ∼20%. Tyrosine kinase inhibitors and novel B cell-targeted therapies can improve outcomes, but rates of relapse and death in remission remain high. Allogeneic blood or marrow transplantation (alloBMT) provides an alternative consolidation strategy, and post-transplantation cyclophosphamide (PTCy) facilitates HLA-mismatched transplantations with low rates of nonrelapse mortality (NRM) and graft-versus-host disease (GVHD). The transplantation database at Johns Hopkins was queried for patients age ≥55 years who underwent alloBMT for ALL using PTCy. The database included 77 such patients. Most received reduced-intensity conditioning (RIC) (88.3%), were in first complete remission (CR1) (85.7%), and had B-lineage disease (90.9%). For the entire cohort, 5-year relapse-free survival (RFS) and overall survival (OS) were 46% (95% confidence interval [CI], 34% to 57%) and 49% (95% CI, 37% to 60%), respectively. Grade III-IV acute GVHD occurred in only 3% of patients, and chronic GVHD occurred in 13%. In multivariable analysis, myeloablative conditioning led to worse RFS (hazard ratio [HR], 4.65; P = .001), whereas transplantation in CR1 (HR, .30; P = .004) and transplantation for Philadelphia chromosome-positive (Ph+) ALL versus T-ALL (HR, .29; P = .03) were associated with improved RFS. Of the 54 patients who underwent RIC alloBMT in CR1 for B-ALL, the 5-year RFS and OS were 62% (95% CI, 47% to 74%) and 65% (95% CI, 51% to 77%), respectively, with a 5-year relapse incidence of 16% (95% CI, 7% to 27%) and an NRM of 24% (95% CI, 13% to 36%). RIC alloBMT with PTCy in CR1 represents a promising consolidation strategy for B-ALL patients age ≥55 years.

Genomic landscape of myelodysplastic/myeloproliferative neoplasm can predict response to hypomethylating agent therapy.

There are currently no known predictors of myelodysplastic syndrome (MDS)/myeloproliferative overlap neoplasm (MPN) patients' response to hypomethylating agents (HMA). Forty-three patients with MDS/MPN who were treated with HMA during chronic phase and had next-generation sequencing using the established 63-genes panel were identified. Complete and partial remission and marrow response were assessed based on the MDS/MPN International Working Group response criteria. On univariate analysis, younger age, higher number of mutations, and mutations in SETBP1, RUNX1, or EZH2 were associated with no response. Multivariable analysis for modeling response were conducted via least absolute shrinkage and selection operator logistic regression approach, and showed that mutations in SETBP1, RUNX1, or EZH2 predict lack of HMA response. While limited by sample size, our findings suggest that genomic landscape can potentially identify MDS/MPN patients with lower likelihood of response to HMA.

Phase II Trial of Pembrolizumab after High-Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia.

Immune suppression, exhaustion, and senescence are frequently seen throughout disease progression in acute myeloid leukemia (AML). We conducted a phase II study of high-dose cytarabine followed by pembrolizumab 200 mg i.v. on day 14 to examine whether PD-1 inhibition improves clinical responses in relapsed/refractory (R/R) AML. Overall responders could receive pembrolizumab maintenance up to 2 years. Among 37 patients enrolled, the overall response rate, composite complete remission (CRc) rate (primary endpoint), and median overall survival (OS) were 46%, 38%, and 11.1 months, respectively. Patients with refractory/early relapse and those receiving treatment as first salvage had encouraging outcomes (median OS, 13.2 and 11.3 months, respectively). Grade ≥3 immune-related adverse events were rare (14%) and self-limiting. Patients who achieved CRc had a higher frequency of progenitor exhausted CD8+ T cells expressing TCF-1 in the bone marrow prior to treatment. A multifaceted correlative approach of genomic, transcriptomic, and immunophenotypic profiling offers insights on molecular correlates of response and resistance to pembrolizumab. SIGNIFICANCE: Immune-checkpoint blockade with pembrolizumab was tolerable and feasible after high-dose cytarabine in R/R AML, with encouraging clinical activity, particularly in refractory AML and those receiving treatment as first salvage regimen. Further study of pembrolizumab and other immune-checkpoint blockade strategies after cytotoxic chemotherapy is warranted in AML.See related commentary by Wei et al., p. 551. This article is highlighted in the In This Issue feature, p. 549.

A phase II study of azacitidine in combination with granulocyte-macrophage colony-stimulating factor as maintenance treatment, after allogeneic blood or marrow transplantation in patients with poor-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

Relapse is the most common cause of treatment failure following allogeneic blood or marrow transplantation (alloBMT) for AML or MDS. Post-transplant maintenance therapies may prevent relapse. We conducted a phase II trial combining azacitidine (AZA) with GM-CSF in non-relapsed, post-transplant patients with AML or MDS. Patients received escalating doses of AZA to a maximum of 75 mg/m2 for 5 days per cycle for up to 12 cycles. GM-CSF was given on days 1-10 of each cycle. Eighteen patients were treated following non-myeloablative (17) and myeloablative (1) alloBMT for AML (61.1%), MDS (27.7%), or therapy-related myeloid neoplasm (11.1%). The majority of patients (72%) received their graft from an HLA-haploidentical donor. The treatment was well-tolerated with rare grade 3-4 hematologic toxicities. One patient suffered an exacerbation of GVHD. The 24-month relapse-free and overall survivals were 47 and 57%, respectively, with a median of 18.6 and 29 months.

Immunomodulation with pomalidomide at early lymphocyte recovery after induction chemotherapy in newly diagnosed AML and high-risk MDS.

An immunosuppressive microenvironment promoting leukemia cell immune escape plays an important role in the pathogenesis of AML. Through its interaction with cereblon, a substrate receptor for the E3 ubiquitin ligase complex, pomalidomide leads to selective ubiquitination of transcription factors Aiolos and Ikaros thereby promoting immune modulation. In this phase I trial, 51 newly diagnosed non-favorable risk AML and high-risk MDS patients were enrolled and treated with AcDVP16 (cytarabine 667 mg/m2/day IV continuous infusion days 1-3, daunorubicin 45 mg/m2 IV days 1-3, etoposide 400 mg/m2 IV days 8-10) induction therapy followed by dose- and duration-escalation pomalidomide beginning at early lymphocyte recovery. Forty-three patients (AML: n = 39, MDS: n = 4) received pomalidomide. The maximum tolerated dose of pomalidomide was 4 mg for 21 consecutive days. The overall complete remission (CR + CRi) rate, median overall survival, and disease-free survival were 75%, 27.1 and 20.6 months, respectively. Subset analyses revealed 86% CR/CRi rate in AML patients with unfavorable-risk karyotype treated with pomalidomide. Pomalidomide significantly decreased Aiolos expression in both CD4+ and CD8+ peripheral blood and bone marrow T cells, promoted T cell differentiation, proliferation, and heightened their cytokine production. Finally, pomalidomide induced distinct gene expression changes in immune function-related ontologies in CD4+ and CD8+ T cells.

Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia.

Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI], 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #NCT02074839.

Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML.

BACKGROUND: Mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1. METHODS: We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up. RESULTS: Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting co-occurring single gene mutation predicted clinical response or resistance to treatment. CONCLUSIONS: In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).

Pilot trial of K562/GM-CSF whole-cell vaccination in MDS patients.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies. Currently, approved drugs are given with non-curative intent as the only known cure is allogeneic bone marrow transplantation, which relies on the donor's immune system driving an allogeneic effect. Previous efforts to harness the endogenous immune system have been less successful. We present the results of a pilot study of K562/GM-CSF (GVAX) whole-cell vaccination in MDS patients. The primary objective of safety was met as there were no serious adverse events. One patient had a decrease in transfusion requirements and another demonstrated hematologic improvement suggesting a signal for clinical activity. In vitro correlative studies indicated biological effects on immune cells following vaccination. Although only a pilot study, results are encouraging that an immunotherapeutic approach with a whole-cell vaccine may be feasible in MDS patients.

Outcomes of Nonmyeloablative HLA-Haploidentical Blood or Marrow Transplantation With High-Dose Post-Transplantation Cyclophosphamide in Older Adults.

PURPOSE: Recent advances in nonmyeloablative (NMA), related HLA-haploidentical blood or marrow transplantation (haplo-BMT) have expanded the donor pool. This study evaluated the effect of age on NMA haplo-BMT outcomes in patients age 50 to 75 years. PATIENTS AND METHODS: A retrospective analysis was performed of 271 consecutive patients with hematologic malignancies, age 50 to 75 years, who received NMA, T-cell-replete haplo-BMT with high-dose post-transplantation cyclophosphamide. RESULTS: The median age was 61 years, with 115 patients (42%) age 50 to 59, 129 (48%) age 60 to 69, and 27 (10%) age 70 to 75 years. Overall, 84% of patients had intermediate- or high-/very high-risk disease. The 6-month probabilities of grade 3 or 4 acute graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) were 3% and 8%, respectively. Patients in their 50s, 60s, and 70s had 6-month NRM probabilities of 8%, 9%, and 7%, respectively (P=.20). With a median follow-up of 4 years, corresponding 3-year progression-free survival probabilities were 39%, 35%, and 33% (P=.65), and corresponding 3-year overall survival probabilities were 48%, 45%, and 44% (P=.66). Three-year progression-free survival probabilities were 40% in acute myeloid leukemia (n=65), 39% in aggressive non-Hodgkin lymphoma (n=83), and 37% in indolent or mantle-cell lymphoma (n=65). Older patient age was associated with a significantly higher risk of grade 2 to 4 acute GVHD but not grade 3 to 4 acute or chronic GVHD. No statistically significant associations were found between older age (relative to age 50 to 59 years or as a continuous variable) and NRM, relapse, or survival. CONCLUSION: NMA haplo-BMT with post-transplantation cyclophosphamide has encouraging safety and survival outcomes in patients age 50 to 75 years. In patients otherwise fit for BMT, the results support consideration of this approach despite advanced age.

Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide.

Related HLA-haploidentical blood or marrow transplantation (BMT) with high-dose posttransplantation cyclophosphamide (PTCy) is being increasingly used because of its acceptable safety profile. To better define outcomes of nonmyeloablative (NMA) HLA-haploidentical BMT with PTCy, 372 consecutive adult hematologic malignancy patients who underwent this procedure were retrospectively studied. Risk-stratified outcomes were evaluated using the refined Disease Risk Index (DRI), developed to stratify disease risk across histologies and allogeneic BMT regimens. Patients received uniform conditioning, T-cell-replete allografting, then PTCy, mycophenolate mofetil, and tacrolimus. Six-month probabilities of nonrelapse mortality and severe acute graft-versus-host disease were 8% and 4%. With 4.1-year median follow-up, 3-year probabilities of relapse, progression-free survival (PFS), and overall survival (OS) were 46%, 40%, and 50%, respectively. By refined DRI group, low (n = 71), intermediate (n = 241), and high/very high (n = 60) risk groups had 3-year PFS estimates of 65%, 37%, and 22% (P < .0001), with corresponding 3-year OS estimates of 71%, 48%, and 35% (P = .0001). On multivariable analyses, the DRI was statistically significantly associated with relapse, PFS, and OS (each P < .001). This analysis demonstrates that the DRI effectively risk stratifies recipients of NMA HLA-haploidentical BMT with PTCy and also suggests that this transplantation platform yields similar survivals to those seen with HLA-matched BMT.