Abraham Kneller

Phase I Safety and Pharmacokinetic Study of CT-011, a Humanized Antibody Interacting with PD-1, in Patients with Advanced Hematologic Malignancies

Purpose: CT-011 is a humanized IgG1 monoclonal antibody that modulates the immune response through interaction with PD-1, a protein belonging to the B7 receptor family present on lymphocytes. The objectives of this phase I study were to assess the dose-limiting toxicities, to determine the maximum tolerated dose, and to study the pharmacokinetics of CT-011 administered once to patients with advanced hematologic malignancies. Experimental Design: Seventeen patients were treated with escalating doses of CT-011 ranging from 0.2 to 6 mg/kg. For pharmacokinetic analysis, blood samples were withdrawn from the patients before and immediately after treatment and at 24 hours, 48 hours, and on days 7, 14, and 21. CT-011 blood levels were assessed with a specific ELISA and derived concentrations were used to calculate pharmacokinetic parameters. Activation of the immune system was assessed by measuring peripheral blood CD4+, CD8+, and CD69+ lymphocytes. Results: The study showed the antibody to be safe and well tolerated in this patient population. No single maximum tolerated dose was defined in this study. Clinical benefit was observed in 33% of the patients with one complete remission. Pharmacokinetic analyses show that serum Cmax and the AUC of CT-011 increased proportionally with dose. The median t1/2 of CT-011 ranged from 217 to 410 hours. Sustained elevation in the percentage of peripheral blood CD4+ lymphocytes was observed up to 21 days following CT-011 treatment. Conclusions: A single administration of 0.2 to 6.0 mg/kg of CT-011 is safe and well tolerated in patients with advanced hematologic malignancies.

Chronic myeloid leukaemia following 131I treatment for thyroid carcinoma: a report of two cases and review of the literature

Leukaemia is an uncommon late complication of exposure to the Ionizing radiation of radioactive Iodine (131I). Most cases reported have been of acute ieukaemias developing after high doses of 131I. Only a few cases of chronic myeloid leukaemia (CML) have been reported in this setting to date.

BCR-ABL transcripts are not detected in cord blood or the peripheral blood of the newborn child whose mother developed chronic myeloid leukemia while pregnant

BACKGROUND AND OBJECTIVES The treatment of choice for the pregnant woman with CML has not been defined. Exposure to imatinib while pregnant may cause serious fetal malformations and interferon-alpha is sometimes associated with side effects. Furthermore, little is known of the possibility that BCR/ABL-positive cells might be passed to the fetus and the role of the treatment given to the pregnant mother. DESIGN AND METHODS Detection of BCR-ABL transcripts in the peripheral blood of the mother, the newborn and the cord blood was performed by quantitative real time PCR and FISH. RESULTS A patient with CML diagnosed at the beginning of pregnancy was treated with leukapheresis at 31 weeks of gestation until delivery without any untoward effects. Since no tyrosine kinase inhibitor was administered BCR-ABL transcripts contamination of the cord blood and peripheral blood of the newborn was a reasonable concern. In practice no transcripts were detected in the cord blood or in the peripheral blood of the newborn at birth, at 1 month or 3 at months of age despite the fact that throughout her pregnancy and on the day of delivery the mother had 90% BCR/ABL positive cells in her blood. INTERPRETATION AND CONCLUSIONS Leukapheresis does not eliminate the malignant clone; however the absence of BCR-ABL transcripts in the peripheral blood of the neonate and in the cord blood supports the view that transmission of CML to a fetus is improbable even if the mothers treatment during pregnancy is suboptimal.

Calreticulin mutation burden--is it a stable clone in patients with essential thrombocythemia and myelofibrosis?

Calreticulin mutation represents the second most frequent mutation after JAK2 V617F in myeloproliferative disorder and is considered to be a driving mutation. Herein the mutation burden was evaluated in patients with essential thrombocythemia or myelofibrosis and found to increase by 5.7% over time unrelated to the time elapsed from the initial to the final positive test. The longer the course of the disease when first tested (range 0-30 years, mean 7.9 years) the lower mutation burden was observed. The mutated clone was larger in type II in comparison with type I mutation when first tested but the difference in mutation burden from the final to the first positive test was significantly higher in those with type I. Similarly, the difference in mutation burden was higher in patients with essential thrombocythemia reaching almost 8% in comparison to 1.3% in post-essential thrombocythemia myelofibrosis. Thus a repeat calreticulin quantitative test is not warranted.

Post-essential thrombocythemia myelofibrosis and chronic myelomonocytic leukemia can co-exist with complex cytogenetic abnormalities.

Cytogenetic abnormalities are detected in approximately 50% of atients with post-essential thrombocythemia myelofibrosis (postTMF) or post-polycythemia vera myelofibrosis (post-PVMF). ytogenetic abnormalities in these diseases are associated with sigificantly different survival outcomes. Isolated deletion 13q or 20q as favorable outcome similar to the presence of normal karyotype, hereas other cytogenetic abnormalities are unfavorable. [1–4]. lonal chromosomal evolution is frequently observed in post-PVMF nd less frequently in post-ETMF. Chronic myelomonocytic leukemia (CMML) is a rare disease. ccording to the new WHO classification, CMML is a myelodyslastic/myeloproliferative disorder (MDS/MPD) [5]. Furthermore, MML is divided into 2 prognostic categories, CMML-1 when ewer than 5% blasts are present in the peripheral blood (PB) nd less than 10% in the bone marrow (BM) or CMML-2 when % or more of blasts are present in the PB or 10% or more in the M. CMML can occur de novo, following chemotherapy or after mmunosuppressive drugs [6]. Here we present an unusual course of a patient who has postTMF and CMML for the last seven years. The clinical course of the ombined two hematological diseases, each one by itself being an ndication for stem cell transplantation, is presented along with the omplex cytogenetic abnormalities.