Analysis of Early Events during the First Year of Tyrosine Kinase Inhibitor Therapy in Patients with Chronic Phase - Chronic Myeloid Leukemia: A "Campus CML" Study

Tyrosine kinase inhibitors (TKIs) revolutionized treatment of chronic myeloid leukemia (CML). However, the rst months of therapy are crucial, as optimal response is dened as the achievement of molecular milestones at 3, 6 and 12 months (mo.) and as many toxicities, also causing a TKI switch, are more frequent in the 1st yea

Cloning and Gene Mapping of the Chromosome 13q14 Region Deleted in Chronic Lymphocytic Leukemia

Frequent deletions and loss of heterozygosity in a segment of chromosome 13 (13q14) in cases of B-cell chronic lymphocytic leukemia (CLL) have suggested that this malignancy is caused by inactivation of an unknown tumor suppressor gene located in this region. Toward the identification of the putative CLL tumor suppressor, we have constructed a high-resolution physical map of YAC, PAC, and cosmid contigs covering 600 kb of the 13q14 genomic region. In addition to densely positioned genetic markers and STSs, this map was further annotated by localization of 32 transcribed sequences (ESTs) using a combination of exon trapping, direct cDNA selection, sample sequencing of cosmids and PACs, and homology searches. On the basis of these mapping data, allelic loss analyses at 13q14 using CLL tumor samples allowed narrowing of the genomic segment encompassing the putative CLL gene to <300 kb. Twenty-three ESTs located within this minimally deleted region are candidate exons for the CLL-associated tumor suppressor gene

Early response does not predict outcome in children and adolescents with chronic myeloid leukaemia treated with high-dose imatinib

We investigated the predictive value of the 3-month BCR-ABL1 transcript levels in terms of responses and outcome of 44 children and adolescents (<18 years at diagnosis) with chronic myeloid leukemia (CML) treated with high-dose imatinib (IM) (340 mg/m2/day). The transcript cutoff levels of 1% and 10% BCR-ABL1 IS were not predictive of either complete cytogenetic response at any time, overall molecular response (MR) and complete MR (CMR), and progression-free survival probabilities at 5 years. The 3-month transcript levels in children and adolescents with CML treated with high-dose IM do not appear to be informative for the prediction of outcomes

Long-term results of high-dose imatinib in children and adolescents with chronic myeloid leukaemia in chronic phase: The Italian experience

Imatinib mesylate (IM) is used for the management of childhood chronic myeloid leukaemia (CML). The most effective dosage of IM and its long-term efficacy in children are not well defined. The purpose of this multicentre study is to report on the long-term results of high-dose IM (340 mg/m2 /d) in CML patients in chronic phase (CP-CML) aged <18 years at diagnosis. A total of 47 CP-CML patients with a median age at diagnosis of 11 years 9 months were enrolled in nine Italian centres. Complete cytogenetic response was achieved in 91.5% of the evaluable patients at a median time of 6 months. BCR-ABL1 International Scale 64 0.1% (major molecular response; MMR) and 640.01% (molecular response; MR) at 12 months were 66.6% and 33%, respectively. During follow-up, MMR and MR were achieved in 78.6% and 61% of children, respectively. IM was safely discontinued in 3 long-term treated children with a durable MR. Twelve patients (eight cytogenetic/molecular responders) underwent stem cell transplantation. The progression-free survival probabilities at 96 months for responding patients who continued IM and for those transplanted were 60% and 50%, respectively. After a median follow-up of 52 months (range 3-146), all patients are alive. High-dose IM is a long-term effective therapy in children and adolescents with CP-CML

High Dose Imatinib Is Effective In Children and Adolescents With Chronic Myelogenous Leukemia In Chronic Phase. The Italian Experience

Imatinib (IM) is an established first-line treatment for children with chronic myeloid leukemia (CML). However, the most effective dosage and duration of IM treatment are not well defined. This study was designed to evaluate the response to high-dose IM and long-term outcome in pediatric CML patients, previously untreated or resistant to IFN. Patients aged &lt;18 years with a diagnosis of CML in chronic phase (CP) were treated with IM at a dosage of 340 mg/m2/day. Cytogenetic analysis was performed on bone marrow (BM) cells before and during IM therapy, at planned intervals; quantitative RT-PCR was assessed on peripheral blood (PB) monthly and on BM every 3 months, according to the European LeukemiaNet recommendations for minimal residual disease quantification. Major molecular response (MMR) is defined as &lt;0.1% BCR-ABLIS, while complete MR (CMR) is considered as &lt;0.01% BCR-ABLIS. From March 2001 to February 2013, 45 CML patients in CP (18 females, 27 males; median age: 119/12 years) were recorded from 9 Italian pediatric centers. Eight patients had previously received IFN. IM was started in all patients, including 16 with an HLA-matched sibling. The dosage was modulated according to hematologic toxicity and/or appearance of WHO &gt;2 side- effects, mostly during the first 6 months of treatment (median administered dose: 309 mg/m2/day). Hematologic toxicity (medullary hypoplasia[n=1], neutropenia [n=11] and/or thrombocytopenia [n=6], anemia [n=1]) was observed in14/44 evaluable patients (32%); 13 patients (29.5%) experienced isolated or combined side effects: arthralgia/myalgia (n=10), nausea (n=1), vomiting (n=1), diarrhea (n=1), hepatitis (n=1), edema (n=1). After 3 months of IM treatment, 7/25 of tested patients (28%) obtained complete cytogenetic response (CCyR). Overall, 34/36 evaluable patients (94%) obtained a CCyR at a median time of 6 months. A molecular response (&lt;0.1% BCR-ABLIS) was achieved in 21/26 tested patients (81%) on PB and in 30/33 evaluable patients (91%) on BM. Seventeen of 26 patients (65%), including 2 with a HLA-matched sibling, obtained a CMR on PB cells and 19/33 (55%) on BM cells at a median time of 15 and 19 months, respectively. With the aim of reducing the risk of longitudinal growth impairment or to improve treatment compliance, 9 patients with sustained CMR and 2 adolescents with MMR lasting &gt;12 months received IM at the same daily dosage for 3 weeks a month (intermittent therapy). IM given without interruption was resumed in 3 of these 9 patients because of an increased BCR-ABL transcript. The growth rate showed a delay in height, which recovered over time, in 6 children who received IM prior to puberty. Overall, IM was stopped in 22/44 evaluable patients (50%) because of various reasons: stem cell transplant (SCT) in 8 patients (3 in CP, 1 in CCyR, 3 in MMR, 1 in CMR); hematologic (n=2) or extra-hematologic toxicity (n=2) (WHO grading &gt;3) during the first 6 months in 4; recurrent disease in 6 (3 increased BCR-ABL transcript, 2 cytogenetic relapse,1 blast crisis [BC]); no response in 1; CMR ( &lt;0.0032% BCR-ABL IS) lasting &gt;88 months in 2 and pancreatitis in 1 patient in CMR for 75 months. Twelve patients underwent a SCT after a median time of 8 months: 8 from an identical siblings (5 responders to IM [1 CMR, 3 MMR, 1 CCyR]), 3 MUD (2 in CCyR and 1 in MMR) and 1 cord blood in CCyR after chemotherapy for CB. Three patients, transplanted from an identical sibling, had disease recurrence after 24 (molecular relapse), 36 (cytogenetic relapse) and 83 (BC) months, respectively. At the last follow-up, all patients are alive (CMR= 25; MMR=14; CCyR=3; minor CyR=2; too early=1) at a median of 52 months (range: 3-146). Of 42 patients evaluable for treatment, 23 are receiving IM at a dosage of 340 mg/m2 (4 intermittent IM); 11 are in CMR without any treatment (8 after SCT; 3 at 32, 33 and 50 months after IM discontinuation); 4 are in treatment with dasatinib, 3 with nilotinib and 1 with IFN. In our experience, higher dose IM is an effective treatment for childhood CP CML, associated with sustained responses. Moreover, IM can be safely discontinued in pediatric CML patients with a deep CMR lasting more than 7 years. For patients candidates to a SCT, IM provides a safe bridging option to transplant, at no increased risk. Since patients may lose their response, a close and regular monitoring should be performed, mostly for those who stop IM, as SCT and new TK inhibitors may be successfully employed in patients failing IM