Project description:This study investigated the efficacy and safety of azacitidine maintenance in the posttransplant setting based on the encouraging phase 1/2 reports for azacitidine maintenance in patients with acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). Between 2009 and 2017, a total of 187 patients aged 18 to 75 years were entered into a randomized controlled study of posttransplant azacitidine if they were in complete remission. Patients randomized to the treatment arm (n = 93) were scheduled to receive azacitidine, given as 32 mg/m2 per day subcutaneously for 5 days every 28 days for 12 cycles. The control arm (n = 94) had no intervention. Eighty-seven of the 93 patients started azacitidine maintenance. The median number of cycles received was 4; a total of 29 patients relapsed on study, and 23 patients withdrew from the study due to toxicity, patient's preference, or logistical reasons. Median relapse-free survival (RFS) was 2.07 years in the azacitidine group vs 1.28 years in the control group (P = .43). There was also no significant difference for overall survival, with a median of 2.52 years vs 2.56 years in the azacitidine and control groups (P = .85), respectively. Multivariate Cox regression analysis revealed no improvement in RFS or overall survival with the use of azacitidine as maintenance compared with the control group (hazard ratios of 0.73 [95% confidence interval, 0.49-1.1; P = .14] and 0.84 [95% confidence interval, 0.55-1.29; P = .43]) [corrected]. This randomized trial with azacitidine maintenance showed that a prospective trial in the posttransplant setting was feasible and safe but challenging. Although RFS was comparable between the 2 arms, we believe the strategy of maintenance therapy merits further study with a goal to reduce the risk of relapse in patients with AML/MDS. This trial was registered at www.clinicaltrials.gov as #NCT00887068.
Project description:Glasdegib is a Hedgehog pathway inhibitor. This ongoing, open-label, phase 2 study (NCT01546038) evaluated glasdegib plus cytarabine/daunorubicin in patients with untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). Patients received glasdegib 100 mg orally, once daily in continuous 28-day?cycles from day -3, with intravenous cytarabine 100?mg/m2 on days 1-7 and daunorubicin 60?mg/m2 on days 1-3. Patients in remission then received consolidation therapy (2-4 cycles of cytarabine 1 g/m2 twice daily on days 1, 3, 5 of each cycle), followed by maintenance glasdegib (maximum 6 cycles). Primary endpoint was complete remission (CR) in patients aged ?55?years. Secondary endpoints included overall survival (OS), safety and outcome by mutational status. Patients had a median (range) age of 64.0 (27-75) years, 60.0% were male, and 84.5% were white. In 69 evaluable patients, 46.4% (80% confidence interval [CI]: 38.7-54.1) achieved investigator-reported CR. Among patients ?55?years old (n =?60), 40.0% (80% CI 31.9-48.1) achieved CR. Among all 69 patients, median OS was 14.9 (80% CI 13.4-19.3) months, with 12-month survival probability 66.6% (80% CI 58.5-73.4). The most common treatment-related adverse events (?50% patients) were diarrhea and nausea. There were no significant associations between mutational status (12 genes) and clinical response, suggesting potential benefit across diverse molecular profiles. Glasdegib plus cytarabine/daunorubicin was well tolerated and associated with clinical activity in patients with untreated AML or high-risk MDS. A randomized phase 3 trial of glasdegib in combination with chemotherapy (7 + 3 schedule) is ongoing.
Project description:Relapse after allogeneic hematopoietic stem cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Infusion of unselected donor lymphocytes (DLIs) enhances the graft-versus-leukemia (GVL) effect. However, because the infused lymphocytes are not selected for leukemia specificity, the GVL effect is often accompanied by life-threatening graft-versus-host disease (GVHD), related to the concurrent transfer of alloreactive lymphocytes. Thus, to minimize GVHD and maximize GVL, we selectively activated and expanded stem cell donor-derived T cells reactive to multiple antigens expressed by AML/MDS cells (PRAME, WT1, Survivin, and NY-ESO-1). Products that demonstrated leukemia antigen specificity were generated from 29 HCT donors. In contrast to DLIs, leukemia-specific T cells (mLSTs) selectively recognized and killed leukemia antigen-pulsed cells, with no activity against recipient's normal cells in vitro. We administered escalating doses of mLSTs (0.5 to 10 × 107 cells per square meter) to 25 trial enrollees, 17 with high risk of relapse and 8 with relapsed disease. Infusions were well tolerated with no grade >2 acute or extensive chronic GVHD seen. We observed antileukemia effects in vivo that translated into not-yet-reached median leukemia-free and overall survival at 1.9 years of follow-up and objective responses in the active disease cohort (1 complete response and 1 partial response). In summary, mLSTs are safe and promising for the prevention and treatment of AML/MDS after HCT. This trial is registered at www.clinicaltrials.com as #NCT02494167.
Project description:This study evaluated azacitidine as treatment of minimal residual disease (MRD) determined by a sensitive donor chimerism analysis of CD34(+) blood cells to pre-empt relapse in patients with CD34(+) myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT). At a median of 169 days after HSCT, 20/59 prospectively screened patients experienced a decrease of CD34(+) donor chimerism to <80% and received four azacitidine cycles (75?mg/m(2)/day for 7 days) while in complete hematologic remission. A total of 16 patients (80%) responded with either increasing CD34(+) donor chimerism to ?80% (n=10; 50%) or stabilization (n=6; 30%) in the absence of relapse. Stabilized patients and those with a later drop of CD34(+) donor chimerism to <80% after initial response were eligible for subsequent azacitidine cycles. A total of 11 patients (55%) received a median of 4 (range, 1-11) additional cycles. Eventually, hematologic relapse occurred in 13 patients (65%), but was delayed until a median of 231 days (range, 56-558) after initial decrease of CD34(+) donor chimerism to <80%. In conclusion, pre-emptive azacitidine treatment has an acceptable safety profile and can substantially prevent or delay hematologic relapse in patients with MDS or AML and MRD after allogeneic HSCT.
Project description:The heterogeneity of acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) has led to a multiplicity of treatments, from cytotoxic agents to signal transduction modulators, cell-cycle inhibitors and epigenetic therapies. While some have shown promising initial results, the outlook for AML patients, particularly older and relapsed patients, as well as patients whose cells exhibit certain adverse chromosomal abnormalities or mutant oncoproteins, continues to be grim. Combination chemotherapy using new agents that act at a number of different levels may provide the greatest potential for successful future therapies. A select number of new agents, approaches and combinations are reviewed here.
Project description:The use of low dose hypomethylating agents for patients with myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (AML) has had made a significant impact. In the past, therapies for these diseases were limited and patients who elected to receive treatment were subject to highly toxic, inpatient chemotherapeutics, which were often ineffective. In the era of hypomethylating agents (azacitidine and decitabine), a patient with high grade MDS or AML with multilineage dysplasia can be offered the alternative of outpatient, relatively low-toxicity therapy. Despite the fact that CR (CR) rates to such agents remain relatively low at 15-20%, a much larger percentage of patients will have clinically significant improvements in hemoglobin, platelet, and neutrophil counts while maintaining good outpatient quality of life. As our clinical experience with azanucleotides expands, questions regarding patient selection, optimal dosing strategy, latency to best response and optimal duration of therapy following disease progression remain, but there is no question that for some patients these agents offer, for a time, an almost miraculous clinical benefit. Ongoing clinical trials in combination and in sequence with conventional therapeutics, with other epigenetically active agents, or in conjunction with bone marrow transplantation continue to provide promise for optimization of these agents for patients with myeloid disease. Although the mechanism(s) responsible for the proven efficacy of these agents remain a matter of some controversy, activity is thought to stem from induction of DNA hypomethylation, direct DNA damage, or possibly even immune modulation; there is no question that they have become a permanent part of the armamentarium against myeloid neoplasms.
Project description:Allogeneic hematopoietic cell transplant (allo-HCT) for eligible patients with acute myeloid leukemia (AML) in first complete remission is a central treatment paradigm to achieve durable remission. However, disease relapse after allo-HCT remains a significant concern and generally portends a poor prognosis. There is significant interest regarding the role for maintenance therapy after allo-HCT for patients with high risk of relapse, regardless of the presence of measurable residual disease. While there are currently no therapies approved for maintenance therapy for AML after allo-HCT, there are a number of ongoing investigations examining the role of maintenance therapies that include targeted agents against FLT3-ITD or IDH mutations, hypomethylating agents, immunomodulatory therapies and cellular therapies. In this review, we examine the current landscape and future strategies for maintenance therapy for AML after allo-HCT.
Project description:Autologous stem cell transplant (ASCT) has been an important component of therapy for myeloma patients eligible for high-dose chemotherapy. Recent studies comparing early transplant to low-dose chemotherapy support the continued use of ASCT as consolidation following induction therapy, even in the era of immunomodulatory drugs, proteasome inhibitors, and other novel agents. Despite the marked improvements in outcomes with this approach, most patients will eventually experience disease progression. Thus, inclusion of post-ASCT consolidation/maintenance strategies is used to improve long-term disease control. Multiple randomized studies support the use of lenalidomide maintenance therapy following ASCT. The next generation of clinical trials will incorporate novel agents such as monoclonal antibodies, proteasome inhibitors, and other novel pathway modulatory agents into post-ASCT treatment strategies with the goal of achieving even deeper responses and longer durations of disease control.
Project description:Activating mutations in FLT3 in acute myeloid leukemia (AML) portend a poor prognosis, and targeting FLT3 with a tyrosine kinase inhibitor has been an area of intense research recently. Most FLT3 mutated AML patients undergo hematopoietic stem cell transplantation (HSCT) as standard of care but a significant proportion of patients relapse. Although the use of FLT3 inhibitors in the pre-HSCT perspective is more clearly defined, its use in the post-HSCT scenario, when most relapses occur, remains unclear. In this review, we comprehensively present the data on the recent and ongoing studies evaluating the role of various FLT3 inhibitors in AML with a particular focus in the post-HSCT setting.