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Nonmyeloablative allogeneic stem-cell transplantation can induce sustained regression of metastatic renal-cell carcinoma in patients who have had no response to conventional immunotherapy.

Background Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations are common in acute myeloid leukemia (AML) and are associated with rapid relapse and short survival. In relapsed/refractory (R/R) AML, the clinical benefit of FLT3 inhibitors has been limited by rapid generation of resistance mutations, especially FLT3-D835. Gilteritinib is a potent, highly selective oral FLT3/AXL inhibitor with preclinical activity against FLT3-ITD and FLT3-D835 mutations. The aim of this Phase 1/2 study was to assess the safety, tolerability, and pharmacokinetic (PK) effects of gilteritinib in FLT3 mutation-positive (FLT3mut+) R/R AML. Methods This ongoing pharmacodynamic-driven Phase 1/2 trial (NCT02014558) enrolled subjects from October 2013 to August 2015 who were aged ≥18 years and were either refractory to induction therapy or had relapsed after achieving remission with prior therapy. Subjects were enrolled in one of seven dose-escalation or dose-expansion cohorts that were assigned to receive once-daily doses of oral gilteritinib (20, 40, 80, 120, 200, 300, or 450 mg). Cohort expansion was based on safety/tolerability, FLT3 inhibition in correlative assays, and antileukemic activity; the 120 and 200 mg dose cohorts were further expanded to include FLT3mut+ patients only. Safety and tolerability, and PK effects were the primary endpoints; antileukemic response was the main secondary endpoint. Safety and tolerability were assessed by monitoring dose-limiting toxicities and treatment-emergent adverse events, and safety assessments (eg, clinical laboratory evaluations, electrocardiograms) in the Safety Analysis Set. Findings A total of 252 adults with R/R AML, including 58 with wild-type FLT3 and 194 with FLT3 mutations (FLT3-ITD, n=162; FLT3-D835, n=16; FLT3-ITD and -D835, n=13; other, n=3), received oral gilteritinib (20–450 mg) once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated in this heavily pretreated population; Grade 3 diarrhea and hepatic transaminase elevation limited dosing above 300 mg/d. The most common Grade 3/4 adverse events were febrile neutropenia (39%; n=97/252), anemia (24%; n=61/252), thromobocytopenia (13%; n=33/252), sepsis (11%; n=28/252), and pneumonia (11%; n=27/252). Serious adverse events in ≥5% of patients were febrile neutropenia (31%; n=78/252), progressive disease (17%; n=43/252), sepsis (14%; n=36/252), pneumonia (11%; n=27/252), and acute renal failure (10%; n=25/252), pyrexia (8%; n=21/252), bacteremia (6%; n=14/252), and respiratory failure (6%; n=14/252). Gilteritinib demonstrated consistent, potent inhibition of FLT3 phosphorylation at doses ≥80 mg/d in correlative assays. While responses were observed across all dose levels regardless of FLT3 mutation status (overall response rate [ORR]=40%), response rate was improved in FLT3mut+ patients at doses ≥80 mg/d (ORR=52%). Among patients with FLT3-ITD, the additional presence of FLT3-D835 did not alter response rate; patients with only FLT3-D835 respond...

The unique immunomodulatory properties of mesenchymal stem cells (MSCs) make them a rationale agent to investigate for graft-versus-host disease (GVHD). Human MSCs were used to treat de novo acute GVHD (aGVHD). Patients with grades II-IV GVHD were randomized to receive 2 treatments of human MSCs (Prochymal(R)) at a dose of either 2 or 8 million MSCs/kg in combination with corticosteroids. Patients received GVHD prophylaxis with tacrolimus, cyclosporine, (CsA) or mycophenolate mofetil (MMF). Study endpoints included safety of Prochymal administration, induction of response to Prochymal, and overall response of aGVHD by day 28, and long-term safety. Thirty-two patients were enrolled, with 31 evaluable: 21 males, 10 females; median age 52 years (range: 34-67). Twenty-one patients had grade II, 8 had grade III, and 3 had grade IV aGVHD. Ninety-four percent of patients had an initial response to Prochymal (77% complete response [CR] and 16% partial response [PR]). No infusional toxicities or ectopic tissue formations were reported. There was no difference with respect to safety or efficacy between the low and high Prochymal dose. In conclusion, Prochymal can be infused safely into patients with aGVHD and induces response in a high proportion of GVHD patients.

Key Points• A sensitive and specific assay was developed for detection of MRD in patients with AML who harbor FLT3-ITD mutations.• This standardized assay is readily available and may be used to guide therapy decisions in patients with AML.

Although this study was a nonrandomized, single-treatment study, 34% of patients treated with antithymocyte globulin became transfusion independent. Response was associated with a statistically significant longer survival and an almost significant decreased time to disease progression. Treatment with antithymocyte globulin did not seem to be detrimental because historical overall median survival times were similar to those of nonresponders.

Nonmyeloablative allogeneic stem cell transplantation has recently been explored as a safer alternative to conventional high-dose transplant regimens. Although a high incidence of mixed chimerism after nonmyeloablative procedures has been reported, the exact kinetics of engrafting donor cells in specific cellular lineages has yet to be defined. We investigated lineage-specific chimerism in 15 patients receiving an allogeneic peripheral blood stem cell (PBSC) transplant from an HLA-identical (n = 14) or a 5/6 antigen-matched sibling donor after a preparative regimen of cyclophosphamide and fludarabine. Donor chimerism was assessed weekly in T lymphocytes and myeloid cells by polymerase chain reaction (PCR) of minisatellite regions. Eight patients survived between 121 to 409 days after transplant. Ten of 14 patients surviving more than 30 days (71.4%) had delayed disease regression consistent with a graft-versus-malignancy (GVM) effect. One patient rejected the transplant with subsequent recovery of autologous hematopoiesis. Hematological recovery was rapid (median, 11 days to ≥500 neutrophils/μL) and was initially predominantly recipient in origin. Donor myeloid chimerism gradually supplanted recipient hematopoiesis and became fully donor in all survivors by 200 days after transplantation. In contrast, T-cell engraftment was more rapid, with full chimerism in 7 patients by day 30 and in 6 further patients by day 200 after cyclosporine withdrawal and donor lymphocyte infusion. Full donor T-cell engraftment preceded donor myeloid engraftment, acute graft-versus-host disease, and disease regression, consistent with a requirement for 100% donor T-cell chimerism for full expression of the alloresponse. These results emphasize the importance of lineage-specific chimerism analysis to successfully manipulate engraftment after nonmyeloablative allogeneic PBSC transplantation.

Nonmyeloablative allogeneic stem cell transplantation has recently been explored as a safer alternative to conventional high-dose transplant regimens. Although a high incidence of mixed chimerism after nonmyeloablative procedures has been reported, the exact kinetics of engrafting donor cells in specific cellular lineages has yet to be defined. We investigated lineage-specific chimerism in 15 patients receiving an allogeneic peripheral blood stem cell (PBSC) transplant from an HLA-identical (n = 14) or a 5/6 antigen-matched sibling donor after a preparative regimen of cyclophosphamide and fludarabine. Donor chimerism was assessed weekly in T lymphocytes and myeloid cells by polymerase chain reaction (PCR) of minisatellite regions. Eight patients survived between 121 to 409 days after transplant. Ten of 14 patients surviving more than 30 days (71.4%) had delayed disease regression consistent with a graft-versus-malignancy (GVM) effect. One patient rejected the transplant with subsequent recovery of autologous hematopoiesis. Hematological recovery was rapid (median, 11 days to ≥500 neutrophils/μL) and was initially predominantly recipient in origin. Donor myeloid chimerism gradually supplanted recipient hematopoiesis and became fully donor in all survivors by 200 days after transplantation. In contrast, T-cell engraftment was more rapid, with full chimerism in 7 patients by day 30 and in 6 further patients by day 200 after cyclosporine withdrawal and donor lymphocyte infusion. Full donor T-cell engraftment preceded donor myeloid engraftment, acute graft-versus-host disease, and disease regression, consistent with a requirement for 100% donor T-cell chimerism for full expression of the alloresponse. These results emphasize the importance of lineage-specific chimerism analysis to successfully manipulate engraftment after nonmyeloablative allogeneic PBSC transplantation.