Repurposing the Bis-Biguanide Alexidine in Combination with Tyrosine Kinase Inhibitors to Eliminate Leukemic Stem/Progenitor Cells in Chronic Myeloid Leukemia.

Background & Aims: In CML, Leukemic Stem Cells (LSCs) that are insensitive to Tyrosine Kinase Inhibitors are responsible for leukemia maintenance and relapses upon TKI treatment arrest. We previously showed that downregulation of the BMI1 polycomb protein that is crucial for stem/progenitor cells self-renewal induced a CCNG2/dependent proliferation arrest leading to elimination of Chronic Myeloid Leukemia (CML) cells. Unfortunately, as of today, pharmacological inhibition of BMI1 has not made its way to the clinic.

Additional prognostic impact of the percentage of erythroid cells in the bone marrow of patients with myelodysplastic syndromes.

In patients with myelodysplastic syndromes (MDS) the impact of the percentage of erythroid precursors in the bone marrow has been the subject of considerable debate, especially with regard to prognosis. We examined the prognostic impact of the percentage of erythroid cells in the bone marrow (bmery) in 2453 primary untreated MDS patients in a retrospective multi-center analysis. Bmery were quantified in bone marrow smears at the time of diagnosis and were correlated with overall survival (OS) and AML evolution.

Evolving characteristics and outcome of secondary acute promyelocytic leukemia (APL): A prospective analysis by the French-Belgian-Swiss APL group.

Background: Reports of patients with secondary acute promyelocytic leukemia (APL) have increased in recent years, particularly for those who received treatment with mitoxantrone, and retrospective studies have suggested that their characteristics and outcomes were similar to those of patients with de novo APL.

Methods: The authors investigated patients with de novo and secondary APL who were included in the ongoing APL-2006 trial. Patients with secondary APL who were included in that trial also were compared with a previous retrospective cohort of patients with secondary APL.

Phosphorylation of spleen tyrosine kinase at tyrosine 348 (pSyk³⁴⁸) may be a marker of advanced phase of Chronic Myeloid Leukemia (CML).

We investigated Syk as a potential marker of CML progression. We observed a significant over-expression of Syk mRNA and constitutive phosphorylation of Syk Y348 in blast cells from six AP or BP-CML, but not in 15 CML in chronic phase. We could follow in vivo the recurrence of pSyk(348) throughout blast cell escape, despite observing storage of dasatinib in blast cells.

Azacitidine in untreated acute myeloid leukemia: a report on 149 patients.

Limited data are available on azacitidine (AZA) treatment and its prognostic factors in acute myeloid leukemia (AML). One hundred and forty-nine previously untreated AML patients considered ineligible for intensive chemotherapy received AZA in a compassionate patient-named program. AML diagnosis was de novo, post-myelodysplastic syndromes (MDS), post-MPN, and therapy-related AML in 51, 55, 13, and 30 patients, respectively.

Measurement of imatinib uptake by flow cytometry.

One of the essential parameters of targeted therapy efficiency in cancer treatment is the amount of drug reaching the therapeutic target area. Imatinib (IM) was the first specifically targeted drug to be developed and has revolutionized the treatment of patients with chronic myeloid leukemia (CML). To evaluate cellular uptake of IM, we developed a method based on the chemical structure of the molecule and using the natural UV fluorescence that we quantified by flow cytometry.

Outcome of acute promyelocytic leukemia (APL) in children and adolescents: an analysis in two consecutive trials of the European APL Group.

Purpose: Acute promyelocytic leukemia (APL) is rare in children. All-trans-retinoic acid (ATRA) combined with chemotherapy, the reference treatment of APL, is generally considered to produce similar results in children and adults. However, previously published childhood APL studies have generally analyzed all patients age < 18 years as a group, without further dividing according to age.

Treatment by Lenalidomide in lower risk myelodysplastic syndrome with 5q deletion--the GFM experience.

We treated 95 RBC transfusion dependent lower risk MDS with del 5q with Lenalidomide (10mg/day, 3 weeks/4 weeks). Median age was 70.4, median interval from diagnosis 29 months.

Characteristics and outcome of myelodysplastic syndromes (MDS) with isolated 20q deletion: a report on 62 cases.

Isolated 20q deletion is common in MDS and considered of good prognosis, but no large series have been reported. We compared characteristics of 62 MDS patients with isolated del 20q, 36 patients with del 20q and other cytogenetic abnormalities, and 1335 MDS patients without del20q. Significant differences between MDS with isolated del 20q and patients without del 20q were lower platelet count (mean 144 vs.

The addition of daunorubicin to imatinib mesylate in combination with cytarabine improves the response rate and the survival of patients with myeloid blast crisis chronic myelogenous leukemia (AFR01 study).

Background: The median survival of patients with chronic myelogenous leukemia in myeloid blast crisis (MBC-CML) is poor even for patients treated with tyrosine kinase inhibitors (TKIs).

Design And Methods: We conducted a dose-escalating study of daunorubicin combined to fixed doses of IM (imatinib mesylate, 600 mg/d) and cytarabine (200 mg/d for 7 days), followed by hematopoietic stem cell transplantation or maintenance therapy with single-agent IM in patients with MBC-CML at onset or after failure of therapy excluding TKIs.

Results: Thirty-six patients were evaluated.

Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial.

Background: Imatinib treatment significantly improves survival in patients with chronic myeloid leukaemia (CML), but little is known about whether treatment can safely be discontinued in the long term. We aimed to assess whether imatinib can be discontinued without occurrence of molecular relapse in patients in complete molecular remission (CMR) while on imatinib.

Methods: In our prospective, multicentre, non-randomised Stop Imatinib (STIM) study, imatinib treatment (of >2 years duration) was discontinued in patients with CML who were aged 18 years and older and in CMR (>5-log reduction in BCR-ABL and ABL levels and undetectable transcripts on quantitative RT-PCR).

Pegylated IFN-α2a combined to imatinib mesylate 600mg daily can induce complete cytogenetic and molecular responses in a subset of chronic phase CML patients refractory to IFN alone or to imatinib 600mg daily alone.

This phase I/II study was designed to demonstrate the tolerance and the efficacy of a combination of pegylated interferon-α 2a to Imatinib mesylate (IM) 600mg daily in cytogenetically IM-resistant but in CHR chronic phase CML patients. The combination was generally well tolerated in the 15 evaluable patients. A significant reduction of the Ph1(+) BM metaphases was observed in these poor prognosis patients, with 2 long-term CCyR including 2 MMR.

Early introduction of ESA in low risk MDS patients may delay the need for RBC transfusion: a retrospective analysis on 112 patients.

ESAs are increasingly used to treat anemia of lower risk MDS, even before RBC transfusion requirement. From a previously published patient cohort treated with ESAs, we selected 112 patients with de novo low or int-1 IPSS MDS with Hb<10 g/dl, serum EPO<500 UI/l and who had never been transfused. Erythroid response rate at 12 weeks was 63.

Does iron chelation therapy improve survival in regularly transfused lower risk MDS patients? A multicenter study by the GFM (Groupe Francophone des Myélodysplasies).

Background: Iron chelation therapy (CT) improves survival in thalassemia major but its beneficial effects on survival in MDS patients remain uncertain.

Methods: We analyzed, by multivariate analysis, survival and causes of deaths in 97 low or intermediate 1 IPSS patients regularly transfused as outpatients, chelated or not, who were included during a month period and followed for 2.5 years.

Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience.

Acute promyelocytic leukemia (APL) is highly curable with the combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy (CT), but very long-term results of this treatment, when CT should be added to ATRA and the role of maintenance treatment, remain uncertain. In our APL93 trial that included 576 newly diagnosed APL patients, with a median follow-up of 10 years, 10-year survival was 77%. Maintenance treatment significantly reduced 10-year cumulative incidence of relapses, from 43.

Daily practice management of myelodysplastic syndromes in France: data from 907 patients in a one-week cross-sectional study by the Groupe Francophone des Myelodysplasies.

Background: There is little published information on the everyday clinical management of myelodysplastic syndromes in real world practice.

Design And Methods: We conducted a cross-sectional study of all patients with myelodysplastic syndromes attending 74 French centers in a 1-week period for inpatient admission, day-hospital care or outpatient visits.

Results: Nine hundred and seven patients were included; 67.

Improved outcome of acute promyelocytic leukemia with high WBC counts over the last 15 years: the European APL Group experience.

Purpose: Acute promyelocytic leukemia (APL) with pretreatment WBC counts greater than 10,000/microL is still considered to carry a poorer prognosis than APL with WBC lower than 10,000/mL. We evaluated outcome improvement in such patients in recent years.

Patients And Methods: Nine hundred two patients with APL, including 204 patients and 68 patients with WBC counts more than 10,000/microL and more than 50,000/microL, respectively, were enrolled between 1993 and 2005 in two successive randomized trials of the European APL group (APL 93 and APL 2000) that tested, in particular, the modalities of combination of all-trans retinoic acid (ATRA) and chemotherapy, maintenance treatment, escalating doses of cytarabine, early administration of dexamethasone, and CNS prophylaxis.

Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results.

All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) LPA 99 trial, where patients received no AraC in addition to ATRA, high cumulative dose idarubicin, and mitoxantrone, and APL 2000 trial, where patients received AraC in addition to ATRA and lower cumulative dose daunorubicin. In patients with white blood cell (WBC) count less than 10 x 10(9)/L, complete remission (CR) rates were similar, but 3-year cumulative incidence of relapse (CIR) was significantly lower in LPA 99 trial: 4.

Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group.

Purpose: Several phase II studies have suggested that cytarabine (AraC) was not required in the treatment of newly diagnosed acute promyelocytic leukemia (APL) patients receiving all-trans-retinoic acid (ATRA), an anthracycline, and maintenance therapy, and we aimed at confirming this finding in a randomized trial.

Patients And Methods: Newly diagnosed APL patients younger than age 60 years with a WBC count of less than 10,000/microL were randomly assigned to receive either ATRA combined with and followed by three daunorubicin (DNR) plus AraC courses and a 2-year maintenance regimen (AraC group) or the same treatment but without AraC (no AraC group). Patients older than age 60 years and patients with initial WBC count of more than 10,000/microL were not randomly assigned but received risk-adapted treatment, with higher dose of AraC and CNS prophylaxis in patients with WBC counts more than 10,000/microL.