Phase I Trial of Lithium and Tretinoin for Treatment of Relapsed and Refractory Non-promyelocytic Acute Myeloid Leukemia.

Glycogen synthase kinase-3 (GSK3) inhibitors induce differentiation and growth inhibition of acute myeloid leukemia (AML) cells. Our pre-clinical studies showed GSK3 inhibition leads to sensitization of AML cells to tretinoin-mediated differentiation. We conducted a phase I trial of lithium, a GSK3 inhibitor, plus tretinoin for relapsed, refractory non-promyelocytic AML. Nine patients with median (range) age 65 (42-82) years were enrolled. All subjects had relapsed leukemia after prior therapy, with a median (range) of 3 (1-3) prior therapies. Oral lithium carbonate 300 mg was given 2-3 times daily and adjusted to meet target serum concentration (0.6 to 1.0 mmol/L); tretinoin 22.5 or 45 mg/m2/day (two equally divided doses) was administered orally on days 1-7 and 15-21 of a 28-day cycle. Four patients attained disease stability with no increase in circulating blasts for ≥4 weeks. Median (range) survival was 106 days (60-502). Target serum lithium concentration was achieved in all patients and correlated with GSK3 inhibition in leukemic cells. Immunophenotypic changes associated with myeloid differentiation were observed in five patients. The combination treatment led to a reduction in the CD34+ CD38- AML stem cell population both in vivo and in vitro. The combination of lithium and tretinoin is well-tolerated, induces differentiation of leukemic cells, and may target AML stem cells, but has limited clinical activity in the absence of other antileukemic agents. The results of this clinical trial suggest GSK3 inhibition can result in AML cell differentiation and may be a novel therapeutic strategy in this disease, particularly in combination with other antileukemic agents. Lithium is a weak GSK3 inhibitor and future strategies in AML treatment will probably require more potent agents targeting this pathway or combinations with other antileukemic agents. This trial is registered at ClinicalTrials.gov NCT01820624.

Comparison of 2 Carmustine-Containing Regimens in the Rituximab Era: Excellent Outcomes Even in Poor-Risk Patients.

High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) improves outcomes in relapsed lymphoma, but the relative efficacy of different preparative regimens is not well defined. We included patients undergoing autologous HCT using BEAM (carmustine, 300 mg/m(2), etoposide, cytarabine, and melphalan) or BEP (carmustine 600 mg/m(2), etoposide, and cisplatin) between January 2004 and December 2013; 65 patients received BEP and 64 patients BEAM. Both cohorts were similar for advanced-stage disease, extranodal and bulky disease, and prior therapies. Median neutrophil and platelet engraftment was 10 and 20 days for both regimens, respectively. Febrile neutropenia, serum creatinine concentration increase, and electrolyte abnormalities were more frequent with BEP. Incidence of carmustine pneumonitis was not higher with BEP, likely the result of corticosteroid prophylaxis, although 2 cases of fatal pneumonitis were observed after BEP. One-year nonrelapse mortality was 6.8% after BEP and 0% after BEAM (P = .379). After a median follow-up of 39.4 months (range, 1 to 128), 4-year rates of overall survival (OS) after BEP and BEAM were 80.4% and 72.3%, respectively (P = .611). Diffuse large B cell lymphoma patients transplanted after early relapse post-rituximab-based first-line therapy presented 3-year rates of OS and progression-free survival (PFS) of 73.8% and 65%, respectively. There were no statistically significant differences in the OS and PFS of follicular lymphoma, mantle cell lymphoma, or Hodgkin lymphoma. BEP is a valid alternative to BEAM in autologous HCT. Although associated with more renal and electrolytic toxicities, BEP results in similar disease control and long-term survival as BEAM. Prospective studies are needed to confirm whether intensification of conditioning regimens for autologous HCT can improve disease control in high-risk relapsed lymphoma patients.

A phase I study of midostaurin and azacitidine in relapsed and elderly AML patients.

BACKGROUND: Midostaurin is a novel, orally available Fms-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitor that induces cell cycle arrest and apoptosis of leukemic cells expressing mutant and wild type FLT3 receptors, and has shown potential synergism with cytotoxic chemotherapy. PATIENTS AND METHODS: We conducted a phase I study of azacitidine (intravenous 75 mg/m(2) daily for 7 days) with escalating doses of oral midostaurin (25 mg twice per day [b.i.d.], 50 mg b.i.d., and 75 mg b.i.d.) on days 8 to 21 of a 28-day cycle in untreated acute myeloid leukemia (AML) in older patients and/or relapsed AML. Patients were eligible regardless of FLT3 mutation status. Trough blood samples for pharmacokinetics were obtained on days 8, 15, and 21 before midostaurin dosing. RESULTS: Seventeen patients with a median age of 73 (range, 57-83) years were enrolled; 5 patients had previous conventional treatment and none of the patients had FLT3 mutations. Dose-limiting toxicities were not observed. Hospitalizations, primarily for infections, occurred in one-third of treatment cycles. Fourteen patients were evaluable for response: 3 attained complete remission and 2 had hematologic improvement. Median (range) survival from enrollment was 6 (1 to ≥ 19) months. Three patients died within 60 days of enrollment (2 progressive disease, 1 non-dose-limiting toxicity, treatment-related). Pharmacokinetic data at 75 mg orally b.i.d. showed increased trough levels of midostaurin during cycle 2 compared with cycle 1 and persistent and increasing levels of its active metabolite, CGP52421. CONCLUSION: The combination of sequential azacitidine and midostaurin is safe and tolerable with response rates comparable with azacitidine alone and should be studied further in FLT3 mutation-positive AML.

Spontaneous autologous graft-versus-host disease in plasma cell myeloma autograft recipients: flow cytometric analysis of hematopoietic progenitor cell grafts.

Nine plasma cell myeloma patients spontaneously developed histologically proven autologous graft-versus-host disease (GVHD) limited predominantly to the gastrointestinal tract within 1 month of initial autologous hematopoietic cell transplantation (AHCT) using high-dose melphalan conditioning. All recipients responded promptly to systemic and nonabsorbable oral corticosteroid therapy. All patients previously received systemic therapy with thalidomide, lenalidomide, or bortezomib before AHCT. Using enzymatic amplification staining-enhanced flow cytometry, we evaluated expression of selected transcription regulators, pathway molecules, and surface receptors on samples of the infused hematopoietic cell grafts. We demonstrated significantly enhanced expression of GATA-2, CD130, and CXCR4 on CD34(+) hematopoietic progenitor cells of affected patients compared with 42 unaffected AHCT controls. These 3 overexpressed markers have not been previously implicated in autologous GVHD. Although we did not specifically evaluate T cells, we postulate that exposure over time to the various immunomodulating therapies used for induction treatment affected not only the CD34(+) cells but also T cells or relevant T cell subpopulations capable of mediating GVHD. After infusion, the affected hematopoietic progenitor cells then encounter a host that has been further altered by the high-dose melphalan preparative regimen; such a situation leads to the syndrome. These surface markers could be used to develop a model to predict development of this syndrome. Autologous GVHD potentially is a serious complication of AHCT and should be considered in plasma cell myeloma patients with otherwise unexplained gastrointestinal symptoms in the immediate post-AHCT period. Prompt recognition of this condition and protracted treatment with nonabsorbable or systemic corticosteroids or the combination may lead to resolution.

Influence of human leucocyte antigen disparity and graft lymphocytes on allogeneic engraftment and survival after umbilical cord blood transplant in adults.

The dose of graft-nucleated cells and CD34(+) haematopoietic progenitor cells are predictors of allogeneic engraftment and survival in umbilical cord blood (UCB) recipients. In this single institution prospective phase II trial, flow cytometric analyses of CD34(+) progenitor and lymphocyte populations in unmodified single unit human leucocyte antigen (HLA)-disparate UCB grafts infused into 31 consecutive adults (median age 41 years, range 20-64) receiving myeloablative conditioning were compared with clinical outcomes. Median infused UCB graft-nucleated cells and CD34(+) dose was 2.2 x 10(7)/kg and 1.2 x 10(5)/kg respectively. Day to absolute neutrophil count >/=0.5 x 10(9)/l with full donor chimerism averaged 27 d (range 12-41). Univariate analyses demonstrated that UCB graft-infused cell doses of CD34(+) (P = 0.015), CD3(+) (P = 0.024) and CD34(+)HLADR(+)CD38(+) progenitors (P = 0.043) correlated with neutrophil engraftment. This same analysis did not demonstrate a correlation between CD34(+) (P = 0.11), CD3(+) (P = 0.28) or CD34(+)HLADR(+)CD38(+) (P = 0.108) cell dose and event-free survival (EFS). High-resolution matching for HLA-class II (DRB1) resulted in improved EFS (P = 0.02) and decreased risk for acute graft-versus-host disease (GVHD) (P = 0.004). Early mortality (prior to post-transplant day +28) occurred in three patients, while 26 patients achieved myeloid engraftment. These results suggest that UCB graft matching at DRB1 is an important risk factor for acute GVHD and survival, while higher UCB graft cell doses of CD34(+), committed CD34(+) progenitors and CD3(+) T cells favourably influence UCB allogeneic engraftment.

High-dose carmustine, etoposide, and cisplatin for autologous stem cell transplantation with or without involved-field radiation for relapsed/refractory lymphoma: an effective regimen with low morbidity and mortality.

Over a 10-year period (January 1993 to October 2002), 101 relapsed or refractory non-Hodgkin lymphoma patients were treated at our center with high-dose chemotherapy and autologous transplantation. The median patient age was 54 years (range, 25-70 years). Thirty-two patients had indolent (low-grade), 42 had aggressive (intermediate-grade), and 27 had very aggressive (high-grade) non-Hodgkin lymphoma. Thirty-six patients had primary refractory disease, 20 had a chemoresistant relapse, 35 patients had a chemosensitive relapse, and 10 patients were "initial high risk" patients. The median number of prior chemotherapy regimens was 2 (range, 1-5). The preparative regimen (BEP) was bischloroethylnitrosourea (BCNU) 600 mg/m 2 , etoposide 2400 mg/m 2 , and Platinol (cisplatin) 200 mg/m 2 given intravenously over 5 days. Within 3 weeks before transplantation, 70 patients received involved-field radiotherapy (IFR) 20 Gy to sites of currently active (>2 cm) or prior bulky (>5 cm) disease. Most patients (n = 93) received mobilized peripheral blood stem cells (median CD34 + cell dose, 6.7 x 10 6 /kg). Median neutrophil (>500/microL) and platelet (>20 000/microL, untransfused) recoveries were 11 days (range, 7-19 days) and 14 days (range, 7-36 days), respectively. At a median follow-up of 41 months (range, 4 to 118 months) for survivors, Kaplan-Meier 5-year probabilities of overall survival (OS) and disease-free survival (DFS) were 58.6% and 51.1%, respectively. Four patients (4%) died within 30 days of stem cell infusion (1 pulmonary embolism, 2 septicemias with multiorgan failure, and 1 progressive lymphoma). Two patients (2%) developed interstitial pneumonitis most likely secondary to high-dose BCNU. Three cases (3%) of secondary acute myelogenous leukemia occurred. On multivariate analysis, age (<60 or > or =60 years), histologic grade (low versus intermediate or high), the use of IFR, and chemotherapy response at baseline did not affect OS or DFS. Of 70 patients given IFR, 27 relapsed: 10 (37%) within and 17 (63%) outside the radiation field. The use of IFR did not affect either OS or DFS, probably because IFR was offered to patients with bulky or chemoresistant disease. BEP with or without IFR is a highly effective and well-tolerated regimen in the relapsed/refractory lymphoma setting. It has low morbidity and transplant-related mortality and a low incidence (3%) of posttransplantation malignancy.

A phase I and pharmacodynamic study of fludarabine, carboplatin, and topotecan in patients with relapsed, refractory, or high-risk acute leukemia.

PURPOSE: A novel regimen designed to maximize antileukemia activity of carboplatin through inhibiting repair of platinum-DNA adducts was conducted in poor prognosis, acute leukemia patients. EXPERIMENTAL DESIGN: Patients received fludarabine (10 to 15 mg/m(2) x 5 days), carboplatin (area under the curve 10 to 12 by continuous infusion over 5 days), followed by escalated doses of topotecan infused over 72 hours (fludarabine, carboplatin, topotecan regimen). Twenty-eight patients had acute myelogenous leukemia (7 untreated secondary acute myelogenous leukemia, 11 in first relapse, and 10 in second relapse or refractory), 1 patient had refractory/relapsed acute lymphoblastic leukemia, and 2 patients had untreated chronic myelogenous leukemia blast crisis. Six patients had failed an autologous stem cell transplant. Patients ranged from 19 to 76 (median 54) years. Measurement of platinum-DNA adducts were done in serial bone marrow specimens. RESULTS: Fifteen of 31 patients achieved bone marrow aplasia. Clinical responses included 2 complete response, 4 complete response with persistent thrombocytopenia, and 2 partial response. Prolonged myelosuppression was observed with median time to blood neutrophils >/=200/microl of 28 (0 to 43) days and time to platelets >/=20,000/microl (untransfused) of 40 (24 to 120) days. Grade 3 or greater infections occurred in all of the patients, and there were 2 infection-related deaths. The nonhematologic toxicity profile was acceptable. Five patients subsequently received allografts without early transplant-related mortality. Maximum tolerated dose of fludarabine, carboplatin, topotecan regimen was fludarabine 15 mg/m(2) x 5, carboplatin area under the curve 12, and topotecan 2.55 mg/m(2) over 72 hours. An increase in bone marrow, platinum-DNA adduct formation between the end of carboplatin infusion and 48 hours after the infusion correlated with bone marrow response. CONCLUSIONS: Fludarabine, carboplatin, topotecan regimen is a promising treatment based on potential pharmacodynamic interactions, which merits additional study in poor prognosis, acute leukemia patients.

Renal dysfunction during high-dose cisplatin therapy and autologous hematopoietic stem cell transplantation: effect of aminoglycoside therapy.

PURPOSE: Renal dysfunction is a common cause of morbidity after cancer therapy and bone marrow transplantation. In this study, we evaluated the effects of aminoglycosides and other nephrotoxic antibiotics on the occurrence of renal dysfunction in patients who received high-dose cisplatin-containing chemotherapy regimens. PATIENTS AND METHODS: The subjects of this analysis were 102 consecutive patients, studied from September 1985 to February 1991, who received high-dose cisplatin, administered as 40 mg/m2 for 5 consecutive days in 3% saline with saline hydration and mannitol diuresis, followed by autologous stem cell transplantation. Renal dysfunction was defined as an increase in serum creatinine greater than or equal to 44.2 mumol/L above baseline. RESULTS: Characteristics of the 43 patients who were given aminoglycosides were similar to those in patients who did not receive aminoglycosides with respect to initial renal function, age, cancer type, and previous exposure to cisplatin. Patients who experienced serious treatment-related toxicities such as hemorrhage or septicemia were more likely to have received aminoglycoside antibiotics (p = 0.005). A multivariate analysis showed that increased duration of neutropenia, advanced patient age, and amphotericin B use were predictors of renal failure. Aminoglycoside therapy did not significantly increase the risk of renal dysfunction. CONCLUSIONS: Our data suggest that with appropriate supportive care measures, aminoglycosides can safely be administered to febrile, neutropenic patients who recently have received high-dose cisplatin therapy.