scholarly journals A Phase 2 Study of the Hedgehog Pathway Smoothened Inhibitor PF-04449913 to Reduce Relapse in High Risk Acute Leukemia and MDS Patients Following Allogeneic Stem Cell Transplantation

2015 ◽  
Vol 21 (2) ◽  
pp. S286
Author(s):  
Jonathan A. Gutman ◽  
Emily Denoncourt ◽  
Derek Schatz ◽  
Clayton Smith ◽  
Daniel Aaron Pollyea
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Hedgehog Pathway ◽  
Phase 2 ◽  
Phase 2 Study

Phase I Trial of High-Dose Clofarabine and Busulfan as a Myeloablative Regimen Prior to Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Relapsed or Refractory Acute Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 198-198 ◽  
Author(s):  
Sherif Farag ◽  
Lisa L Wood ◽  
Jennifer E. Schwartz ◽  
Shivani Srivastava ◽  
Robert P. Nelson ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Phase I ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Phase I Trial ◽  
High Dose ◽  
Dose Levels

Abstract Abstract 198 Fludarabine in combination high-dose busulfan (Bu) is an effective myeloablative preparative regimen for allogeneic stem cell transplantation. At doses used, however, fludarabine has only modest anti-leukemic activity. Clofarabine (Clo) is a second-generation purine nucleoside antimetabolite with significant single agent activity in patients with AML and ALL. The novel combination of Clo with Bu may provide improved disease activity safely. Therefore, we conducted a phase I trial to determine the maximum tolerated dose (MTD) of Clo in combination with Bu in patients with high-risk acute leukemia. Patients received i.v. Bu (Busulfex) 0.8 mg/kg q 6 hrs on days −6 to −3 and Clo at 30–60 mg/m2/day on days −6 to −2 in successive cohorts. Stem cells were infused day 0. GvHD prophylaxis included sirolimus plus tacrolimus starting day −2 to day 100, tapering to day 180. Patients were eligible if they were 18–60 years, had primary refractory or relapsed and refractory AML or ALL, or were in CR2 or higher, had Karnofsky performance status ≥70%, and adequate organ function. Donors were HLA-matched related (5/6 or 6/6 antigen-matched) or unrelated (10/10 allele-matched). Toxicity was scored using the Common Terminology Criteria for Adverse events, version 3.0. Dose limiting toxicity (DLT) was defined as any grade 3–4 non-hematologic toxicity that did not resolve to grade 2 or less by day 30. A total of 15 patients were treated at 4 Clo dose levels, 30 (n=3), 40 (n=3), 50 (n=3), and 60 mg/m2 (n=6). Seven males and 8 females of median age 48 (30–58) years, with AML (n=13) or ALL (n=2) were treated. At transplant, leukemia was relapsed and refractory (n=8), primary refractory (n=6), or in CR2 (n=1). Median number of lines of treatment failed before transplant was 2 (1–3). Median marrow blasts at transplant was 12% (3%–83%). Hematopoietic cell transplants were from related (n=9) and unrelated (n=6) donors. All patients engrafted. Median time to neutrophils >0.5×109/l was 16 (12–20) days, and to platelets >20×109/l was 15 (10–42) days. One patient treated at the 30 mg/m2 dose level failed to achieve platelets > 20×109/l. No DLT was observed. Transient Grades 3–4 non-hematological toxicities were evenly distributed across all 4 dose levels, and included vomiting (n=3), mucositis (n=9), hand-foot syndrome (n=1), and elevation of AST/ALT (n=10). Grades 3–4 elevation of AST/ALT occurred in 2 of 3 patients treated at 30 mg/m2, 3 of 3 at 40 mg/m2, 2 of 3 at 50 mg/m2, and 3 of 6 patients at 60 mg/m2 dose levels. AST/ALT peaked at day −1 or 0 and returned to baseline in all patients by day 10, with no long-term sequelae. There was no correlation between Clo dose and peak AST/ALT. One patient developed acute renal failure at the 60 mg/m2 dose on day +12 in association with elevated tacrolimus levels, although the creatinine subsequently normalized. Two patients, both at the 30 mg/m2 dose, developed mild veno-occlusive disease of the liver which was self-limiting. One treatment-related death due to sepsis was observed at day +104 in a patient treated at the 30 mg/m2 dose. Thirteen of 15 patients were in CR by day 30; 2 patients, treated at 40 mg/m2 and 50 mg/m2, respectively, failed to achieve CR. Day 100 mortality was 0. With a median follow-up of 313 days, the 1-year relapse-free survival was 51% ± 15%, and the 1-year overall survival was 61% ± 14%. Clo at doses as high as 60 mg/m2/day × 5 days in combination with Bu 3.2 mg/kg/day × 4 days is well tolerated and demonstrates promising efficacy in a very-high risk acute leukemia population. The MTD has not been reached. We recommend Phase II testing of Clo 60 mg/m2/day × 5 days in combination with high-dose Bu as a myeloablative regimen for allogeneic stem cell transplantation in patients with acute leukemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Repetitively Administered Low-Dose Donor Lymphocyte Infusion for Prevention of Relapse after Allogeneic Stem Cell Transplantation in Patients with High-Risk Acute Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2699
Author(s):  
Panagiotis Tsirigotis ◽  
Konstantinos Gkirkas ◽  
Vassiliki Kitsiou ◽  
Spiros Chondropoulos ◽  
Theofilos Athanassiades ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Low Dose ◽  
Acute Gvhd ◽  
Donor Lymphocyte Infusion

Background: Patients with high-risk acute leukemia have a high risk of relapse after allogeneic stem cell transplantation (allo-SCT). In an effort to reduce the relapse rate, various therapeutic methods have been implemented into clinical practice. Among them, prophylactic donor lymphocyte infusion (pro-DLI) has shown significant efficacy. However, the widespread application of pro-DLI has been restricted mostly due to concerns regarding the development of graft versus host disease (GVHD). In the present study, we tested the safety and efficacy of a novel method of prophylactic-DLI based by repetitive administration of low lymphocyte doses. Methods: DLI was administered to patients with high-risk acute leukemia at a dose of 2 × 106/kg CD3-positive cells. DLI at the same dose was repeated every two months for at least 36 months post-allo-SCT, or until relapse or any clinical or laboratory feature suggested GVHD, whichever occurred first. Forty-four patients with a median age of 53 years (range 20–67) who underwent allo-SCT between 2011 and 2020 were included in our study. Thirty-three patients with high-risk acute myeloid leukemia (AML) and 11 with high-risk acute lymphoblastic leukemia (ALL) after allo-SCT from a matched sibling (MSD, no = 38 pts) or a matched-unrelated donor (MUD, no = 6 pts) received pro-DLI. Twenty-three patients were in CR1, all with unfavorable genetic features; 12 patients were in CR2 or beyond; and 9 patients had refractory disease at the time of transplant. Ten out of 23 patients in CR1 had detectable minimal residual disease (MRD) at the time of allo-SCT. Disease risk index (DRI) was high and intermediate in 21 and 23 patients, respectively. Conditioning was myeloablative (MAC) in 36 and reduced intensity (RIC) in 8 patients, while GVHD prophylaxis consisted of cyclosporine-A in combination with low-dose alemtuzumab in 39 patients or with low-dose MTX in 5 patients, respectively. Results: Thirty-five patients completed the scheduled treatment and received a median of 8 DLI doses (range 1–35). Fifteen out of 35 patients received all planned doses, while DLI was discontinued in 20 patients. Reasons for discontinuation included GVHD development in nine, donor unavailability in seven, disease relapse in three, and secondary malignancy in one patient, respectively. Nine patients were still on treatment with DLI, and they received a median of four (range 2–12) doses. Fourteen percent of patients developed transient grade-II acute GVHD while 12% developed chronic GVHD post-DLI administration. Acute GVHD was managed successfully with short course steroids, and four out of five patients with cGVHD were disease-free and off immunosuppression. With a median follow-up of 44 months (range 8–120), relapse-free (RFS) and overall survival (OS) were 74%, (95% CI, 54–87%) and 78%, (95% CI, 58–89%) respectively, while the cumulative incidence of non-relapse mortality (NRM) was 13% (95% CI, 4–28%). The cumulative incidence of relapse in patients with intermediate and high DRI is 7% and 15%, respectively. Conclusion: Prolonged—up to three years—low-dose pro-DLI administered every two months is safe and effective in reducing relapse rate in patients with high-risk acute leukemia. The low-dose repetitive administration DLI strategy reduced the risk of DLI-mediated GVHD, while the prolonged repeated administration helped in preventing relapse, possibly by inducing a sustained and prolonged immunological pressure on residual leukemic cells. This novel strategy deserves testing in larger cohort of patients with high-risk acute leukemia.

Sequential Azacitidine and High-Dose Lenalidomide for Relapsed and Refractory High-Risk MDS and AML: Interim Analysis of a Phase 2 Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3746-3746
Author(s):  
Daniel A Pollyea ◽  
Clayton A. Smith ◽  
Vu H. Nguyen ◽  
Aaron Fullerton ◽  
Derek Schatz ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Renal Insufficiency ◽  
Stem Cell Transplantation ◽  
Disease Progression ◽  
Cell Transplantation ◽  
Median Number ◽  
High Dose ◽  
Phase 2 ◽  
Phase 2 Study

Abstract Introduction: Relapsed/refractory high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have a dismal prognosis with few conventional treatment options. Intensive therapies are often intolerable or ineffective. Previously, Pollyea et al reported a phase 1/2 study for elderly, newly diagnosed AML patients (pts) who were administered sequential azacitidine with high-dose lenalidomide; the maximum tolerated dose of lenalidomide was 50 mg for 21 days of a 6-week cycle, and the ORR was 40% with a 28% CR/CRi rate (Leukemia 2012 893 and Haematologica 2013 591). Based on the efficacy and tolerability of this regimen, we designed a single-center phase 2 study for high-risk MDS and AML pts with relapsed/refractory disease. Methods: The primary objective was to evaluate the efficacy of this regimen in this population. Secondary objectives included safety, response duration, progression-free survival/overall survival, the number of eligible pts able to proceed to transplantation, and correlative outcomes. The schema involved azacitidine 75 mg/m2 d1-7 followed by lenalidomide 50 mg d8-28; d29-42 was a recovery period for a total 42-day cycle. Cycles could be repeated indefinitely in the absence of excessive toxicity or disease progression. Pts were ≥18 with relapsed/refractory high-risk MDS or AML. The study was designed to maximize inclusion to approximate a real-world clinical population, but pts with extensive organ dysfunction or hyperproliferative disease that was not controllable with hydroxyurea were excluded. Using a Simon two-stage minimax design, 37 pts are required to double the null hypothesis, a 15% CR/CRi rate. At least 2 of the first 18 pts must achieve a CR/CRi to justify proceeding to the second stage of the study; interim results are presented here. Results: Nineteen pts have been enrolled as of July 1 2014, with a median follow-up of 78 days. 16 are evaluable; 3 did not complete a full cycle, the protocol-defined minimum to be evaluable, due to disease progression. The median age was 73 (18-86). 16 were male; 16 had AML and 3 had high-risk MDS. The median number of prior therapies was 1 (range 1-5). All MDS patients had failed a hypomethylator. Three had relapsed after allogeneic stem cell transplantation. Using European LeukemiaNet cytogenetic and molecular prognostic data, 1 pt was considered favorable, 2 were intermediate-1, 4 were intermediate-2 and 12 were adverse. Five had a monosomal karyotype; 1 had a del(5q) as part of a complex karyotype. The median number of cycles received was 1 (0-4). Adverse events (AEs) were reported according to the NCI CTCAE v4.0. There were 114 independent possibly related AEs; the most common AEs (>25% of pts) were constipation (9/19, 47%), anemia (7/19, 37%), diarrhea (7/19, 37%), dizziness (7/19, 37%), abdominal pain (6/19, 32%), hypoxia (6/19, 32%), injection site reactions (6/19, 32%), anorexia (6/19, 32%), pruritus (6/19, 32%), pneumonia (5/19, 26%), nausea (5/19, 26%), thrombocytopenia (5/19, 26%) and hypotension (5/19, 26%). The possibly related ≥ grade 3 AEs (reported as total number of events) were: thrombocytopenia (n=9), febrile neutropenia (n=6), anemia (n=6), leukopenia (n=4), neutropenia (n=4), weakness (n=4), renal insufficiency (n=1) and pruritus (n=1). Three pts required a 50% dose reduction of lenalidomide for renal insufficiency (n=1), rash/GVHD flare (n=1) and fatigue (n=1), and 8 held lenalidomide for at least 2 days during at least 1 treatment cycle. The ORR was 50% (8/16) for evaluable patients and 42% (8/19) for all patients. 43% (7/16) of evaluable patients had a CR/CRi (n=2 CR, including 1 complete cytogenetic remission, n=5 CRi). There was 1 PR. 2/3 high-risk MDS patients responded (both CRi). The median time to achieve best response was 1.5 months. Lower baseline bone marrow blasts were predictive of response. Median OS was 91 days; 569 days for responders and 71 days for non-responders. 12 pts died; 1 was treatment related (renal failure) and 11 were disease related. Early death rate (death in the first 30 days) was 17% (2/12). 2/6 pts felt to be eligible for a stem cell transplantation were able to use this regimen as a bridge to this therapy. Conclusions: The requisite number of responders to proceed to the second phase of the study was reached. Sequential azacitidine and high-dose lenalidomide has activity in relapsed/refractory AML and high-risk MDS; updated clinical results and correlative studies will be presented. Disclosures Pollyea: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Lenalidomide for AML/non del-5q MDS.

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