Dose escalation of lenalidomide in relapsed or refractory acute leukemias.
ABSTRACT Lenalidomide is effective in myeloma and low-risk myelodysplastic syndromes with deletion 5q. We report results of a phase I dose-escalation trial of lenalidomide in relapsed or refractory acute leukemia.
Thirty-one adults with acute myeloid leukemia (AML) and four adults with acute lymphoblastic leukemia (ALL) were enrolled. Lenalidomide was given orally at escalating doses of 25 to 75 mg daily on days 1 through 21 of 28-day cycles to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD), as well as to provide pharmacokinetic and preliminary efficacy data.
Patients had a median age of 63 years (range, 22 to 79 years) and a median of two prior therapies (range, one to four therapies). The DLT was fatigue; 50 mg/d was the MTD. Infectious complications were frequent. Plasma lenalidomide concentration increased proportionally with dose. In AML, five (16%) of 31 patients achieved complete remission (CR); three of three patients with cytogenetic abnormalities achieved cytogenetic CR (none with deletion 5q). Response duration ranged from 5.6 to 14 months. All responses occurred in AML with low presenting WBC count. No patient with ALL responded. Two of four patients who received lenalidomide as initial therapy for AML relapse after allogeneic transplantation achieved durable CR after development of cutaneous graft-versus-host disease, without donor leukocyte infusion.
Lenalidomide was safely escalated to 50 mg daily for 21 days, every 4 weeks, and was active with relatively low toxicity in patients with relapsed/refractory AML. Remissions achieved after transplantation suggest a possible immunomodulatory effect of lenalidomide, and results provide enthusiasm for further studies in AML, either alone or in combination with conventional agents or other immunotherapies.
Article: Elevated levels of serum macrophage colony-stimulating factor in normotensive pregnancies complicated by intrauterine fetal growth restriction.[show abstract] [hide abstract]
ABSTRACT: Macrophage colony-stimulating factor (M-CSF) is considered an essential cytokine for placental growth and maintenance. M-CSF also may regulate trophoblast invasion into the placental bed. The aim of the present study was to evaluate whether serum M-CSF levels were altered in normotensive pregnancies complicated by intrauterine growth restriction (IUGR) arising from unknown factors. Plasma thrombin-antithrombin complex (TAT) levels and the pulsatility index (PI) values also were measured. This study enrolled 47 Japanese women experiencing normotensive pregnancies with single fetuses. Of these pregnancies, 20 were complicated by IUGR arising from unknown factors; these women later delivered small-for-gestational-age (SGA) infants. The other 27 women later delivered appropriate-for-gestational-age infants (controls). The women's ages and gestational ages did not differ significantly between the two groups. Maternal peripheral blood was collected, and the levels of serum M-CSF and plasma TAT were compared between two groups. The M-CSF level was determined by the sandwich enzyme-linked immunosorbent assay method and the TAT level by the enzyme immunoassay method. The PI value for the middle cerebral artery of the fetuses was calculated. Serum levels of M-CSF were significantly higher (p < 0.005) in pregnancies complicated by IUGR that produced SGA infants than in controls. Plasma levels of TAT also were significantly higher (p < 0.02) in pregnancies that produced SGA infants than in controls. The PI values were significantly lower (p < 0.05) in pregnancies that produced SGA infants than in controls. This study demonstrated significant increases in serum M-CSF levels in women with normotensive pregnancies complicated by IUGR arising from unknown factors who later delivered SGA infants. To the best of our knowledge, this is the first such report. Elevated serum M-CSF levels may be related to placental hypoxia leading to pregnancies complicated by IUGR.Experimental Hematology 05/2002; 30(5):388-93. · 2.90 Impact Factor
Article: Impact of disease burden at time of allogeneic stem cell transplantation in adults with acute myeloid leukemia and myelodysplastic syndromes.[show abstract] [hide abstract]
ABSTRACT: The impact of disease burden on the outcome of patients with acute myeloid leukemia (AML) undergoing allogeneic stem cell transplantation (SCT) has not been well defined. Data from several retrospective series suggest that overt leukemia at the time of transplant increases the risk of relapse. We reviewed the outcomes of 68 consecutive adults with AML (n=60) or myelodysplastic syndromes (MDS) (n=8) who received an allogeneic SCT at the University of Chicago between May 1986 and October 2002 to confirm the importance of currently recognized risk factors for overall survival (OS) and progression-free survival (PFS). In addition, we wanted to determine whether quantification of residual disease by blast percentage or cytogenetic abnormalities at the time of SCT was correlated with outcome. AML subtypes based on the FAB classification were as follows: M0=9, M1=9, M2=16, M3=2, M4=16, M5=3, M6=5. Cytogenetic analysis was available from 52 patients. Using standard morphologic criteria, 34 patients were in complete remission (CR) and 34 had visible leukemia present. The majority of donors were HLA-identical siblings (n=55). In all, 56 patients received myeloablative conditioning regimens and 12 received a reduced-intensity, fludarabine-based conditioning regimen. OS and PFS times were 7.1 months (95% CI, 4.8-10.4) and 5.1 months (95% CI, 3.2-7.8), respectively. Median follow-up from SCT was 4.6 years (range, 0.6-17.0) for survivors. In multivariate analysis, the following factors were found to be associated with worse survival: (1) increased percentage of blasts in the bone marrow at the time of SCT, (2) presence of acute graft-versus-host disease, (3) mismatched donor, (4) Zubrod performance score of >/=2, and (5) age >/=45 years. We also found a trend towards improved outcome among patients in cytogenetic remission as compared to those who had residual cytogenetic abnormalities and those in overt relapse. These data support an association between pre-transplant disease burden and poor outcome after SCT.Bone Marrow Transplantation 05/2005; 35(10):965-70. · 3.75 Impact Factor