BCR Gene Breakpoint and Type of BCR/ABL-Transcript in Children with Chronic Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4863-4863
Author(s):  
Meinolf Suttorp ◽  
Susanne Viehmann ◽  
Alexander Claviez ◽  
Yvonne Martiniak ◽  
Jochen Harbott
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Pediatric Leukemia ◽  
Total Study Population ◽  
Exon 2 ◽  
Study Population ◽  
The Impact

Abstract The hallmark of chronic myeloid leukemia (CML) is the reciprocal translocation t(9;22)(q34;q11) which creates a hybrid BCR/ABL gene that is transcribed into a chimeric mRNA. In the 8.5-kb mRNA either exon b2 or exon b3 of the major breakpoint cluster region (M-bcr) is coupled to C-ABL exon 2. These two junction variants (b2a2 or b3a2) differ in size by 75 nucleotides and can be selectively amplified by semi-nested PCR. A controversy exists whether or not the type of transcript and/or the breakpoint site exerts an influence on the clinical course of CML in adult patients (Mills KI 1991; Foiretos T 1993; Melo JV 1996). CML is a rare disease in childhood contributing only 2 – 3 % of all pediatric leukemia cases. This may be the reason why there are only scant data from small series of children with CML giving information on the transcript variant present at diagnosis. During an 11 year period (1995 – 2005) 203 pts younger than 19 years (median age: 11.4 yrs; 101 boys, 102 girls) with Philadelphia-chromosome positive CML were treated within the multicenter GPOH-trial “CML-paed”. 85% of the pts were diagnosed in chronic phase (CP). Treatment was performed by hydroxyurea +/− interferon and pts were scheduled for stem cell transplantation (SCT) from an HLA-matched family donor within 6 months after diagnosis and from an unrelated donor within 12 months. Bone marrow and/or peripheral blood specimen for molecular analysis were collected at diagnosis and during follow-up examinations at 3 – 6 months intervals. RT-PCR with analysis of the breakpoint and transcript type was performed in 154 pts (77.4 % of the total study population). 133 pts exhibited a Major-BCR rearrangement, 5 pts a minor-BCR rearrangement and in 16 pts both rearrangements were present. In pts with M-BCR either 55 pts expressed the b2a2 transcript (37 %) or the b3a2 transcript (37 %), respectively. Both types of transcripts were found either simultaneously or alternately during follow-up examinations in 38 pts (25 %). One pt showed an atypical rearrangement which is awaiting further classification. No statistical significant differences (p > 0.05) could be found with respect to hematological parameters at diagnosis (white cell count, platelets count, percentage of basophils in peripheral blood), clinical findings (liver size, spleen size) and disease status (CP versus advanced phase). The impact of either transcript upon the course of the disease (e.g. duration of chronic phase) was not analyzed because 70 % of the study population was transplanted early within 1 year after diagnosis. We conclude that in contrast to some reports in adults the type of BCR breakpoint seems to have no impact in pediatric pts with CML.

Impact of baseline mutations on response to ponatinib and end of treatment mutation analysis in patients with chronic myeloid leukemia.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7001-7001 ◽  
Author(s):  
Michael W. N. Deininger ◽  
Jorge E. Cortes ◽  
Dong-Wook Kim ◽  
Franck E. Nicolini ◽  
Moshe Talpaz ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Single Mutation ◽  
Mutation Status ◽  
End Of Treatment ◽  
The Impact

7001 Background: BCR-ABL kinase domain mutations frequently cause tyrosine kinase inhibitor (TKI) failure in chronic myeloid leukemia (CML). Ponatinib, a potent oral pan-BCR-ABL TKI, has shown preclinical activity against all single mutants tested, including T315I. The impact of baseline (BL) mutations on response to ponatinib (45 mg once daily) and end of treatment (EOT) mutations in pts discontinuing treatment were evaluated in the phase II PACE trial. Methods: Heavily pretreated chronic phase (CP) CML pts (93% received ≥2 prior TKIs, 60% ≥3) resistant or intolerant to dasatinib or nilotinib (N=203) or with T315I confirmed at BL (N=64) were enrolled. The primary endpt was major cytogenetic response (MCyR). Min follow up at analysis (9 Nov 2012) was 12 mos (median 15 [0.1-25]). Sanger sequencing was done at one central laboratory. Results: At BL, no mutations were detected in 51% of pts, 1 mutation in 39%, and ≥2 mutations in 10%; 26 unique mutations were observed. Responses were observed regardless of BL mutation status. MCyR rates were: 56% overall, 49% in pts with no mutations, 64% 1 mutation, 62% ≥2 mutations; 57% in pts with mutation(s) other than T315I, 74% T315I only, 57% T315I + other mutation(s). Responses were seen against each of the 15 mutations present in >1 pt at BL, including T315I, E255V, F359V, Y253H. 99 pts discontinued, 56 had EOT mutations assessed. 5 pts lost a mutation, 46 had no change, 5 gained mutations (Table). 11 pts lost MCyR (none with T315I); of the 6 discontinuing, 4 had EOT mutations assessed and no changes from BL were seen. Conclusions: Responses to ponatinib were observed regardless of BL mutation status. No single mutation conferring resistance to ponatinib in CP-CML has been observed to date. Data with a minimum follow up of 18 mos, including pts with advanced disease, will be presented. Clinical trial information: NCT01207440. [Table: see text]

Adoptive Donor T-Cell Infusions Are Necessary and Efficient To Induce Lasting Molecular Remissions after Highly Purified CD34+ Sibling Donor Transplants for First Chronic Phase Chronic Myeloid Leukemia - Final Report and Long-Term Follow-Up of a Phase II Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3017-3017
Author(s):  
Ahmet Elmaagacli ◽  
Rudolf Peceny ◽  
Michael Koldehoff ◽  
Hellmut Ottinger ◽  
Rudolf Trenschel ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Secondary Malignancy ◽  
Molecular Remission ◽  
Transcript Levels ◽  
Peripheral Blood Cd34

Abstract Since September 1998, we prospectively studied the feasibility of transplantation using purified peripheral blood CD34+ cells from HLA-identical sibling donors in first chronic phase chronic myeloid leukemia (CML). A total of 60 patients (pts) with a median pretransplant risk score of 2 (range 1–4) has been included in this study. One patient received an unmanipulated graft due to poor CD34+ donor cell mobilization, while three pts (5%) were successfully retransplanted with an unmanipulated graft from the primary donor after secondary graft failure (n=2) or from an unrelated donor after hematologic relapse (n=1). As part of the study protocol, all pts were closely monitored for BCR-ABL transcripts using real-time RT-PCR analysis of peripheral blood cells as well as BCR-ABL-interphase FISH and metaphase karyotyping of marrow cells. Of the 60 pts, 56 were eligible for the application of donor lymphocyte infusions (DLI), but 7 pts did not receive DLI due to sustained molecular remission and complete chimerism. Thirty-one pts (52%) received DLI because of increasing BCR-ABL transcript levels or hematologic relapse, and 18 pts (30%) as programmed T-cell add-back. The median starting dose was 0.33 (0.01 – 10) x 106 CD3+ cells per kg with a median maximum dose 3.3 (0.17 – 100) x 106 CD3+ cells per kg. DLI induced a lasting reduction of median BCR-ABL transcript levels (BCR-ABL/GAPDH ratio) of more than 3 log10 and the estimate of being in a complete molecular remission at 7 years is 83% ± 5%. Six pts. (10%) did not respond to DLI, but 4 of these pts. attained a cytogenetic and molecular response by imatinib and/or interferon treatment. The cumulative risk of grades II-IV acute GvHD is 15% ± 5% for all study pts, and the risk of chronic GvHD is 25% ± 6%, respectively. After a median follow-up period of 46 (range 6 – 86) months for all pts, the cumulative 7-year survival estimate is 91% ± 4% (survival rate 92%). Causes of death were disease progression, secondary malignancy, liver failure, septicemia, and systemic capillary leak syndrome in one patient each. In conclusion, the concept of highly purified peripheral blood CD34+ cell transplantation in conjunction with adoptive DLI is associated with a particularly low risk of non-relapse mortality and allows induction of lasting molecular disease control in the majority of first chronic phase CML patients.

scholarly journals Efficacy and Tolerability after Unusually Low Doses of Dasatinib in Chronic Myeloid Leukemia Patients Intolerant to Standard-Dose Dasatinib Therapy

2010 ◽  
Vol 4 ◽  
pp. CMO.S6413 ◽  
Author(s):  
Mariana Serpa ◽  
Sabri S. Sanabani ◽  
Israel Bendit ◽  
Fernanda Seguro ◽  
Flávia Xavier ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
Chronic Phase ◽  
Patient Treatment ◽  
Hematological Toxicity ◽  
Drug Discontinuation ◽  
Once Daily ◽  
Starting Dose

We report our experience in 4 patients with chronic myeloid leukemia (CML) who had discontinued imatinib as a result of adverse events and had switched to dasatinib. The chronic phase ( n 2) and accelerated phase ( n 2) CML patients received dasatinib at starting dose of 100 and 140 mg once daily, respectively. Reappearance of hematological toxicity was observed in 3 patients and pancreatitis in one patient. Treatment was given at a lower dose and patients were followed. The median follow-up was 13 months and the median dose of dasatinib until achievement of complete cytogenetic remission (CCyR) was 60 mg daily (range = 20 to 120 mg). All four patients had achieved CCyR at a median of 4 months (range = 3 to 5 months) and among them, three had also achieved major molecular remission. We conclude that low-dose dasatinib therapy in intolerant patients appears safe and efficacious and may be tried before drug discontinuation.

Real-Life Management of Children and Adolescents with Chronic Myeloid Leukemia: The Italian Experience

2018 ◽  
Vol 140 (2) ◽  
pp. 105-111 ◽  
Author(s):  
Fiorina Giona ◽  
Michelina Santopietro ◽  
Giuseppe Menna ◽  
Maria Caterina Putti ◽  
Concetta Micalizzi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Real Life ◽  
Chronic Phase ◽  
Optimal Management ◽  
Molecular Monitoring ◽  
Italian Experience ◽  
Adults And Children

Background: To date, no data on the adherence to specific guidelines for children with chronic myeloid leukemia (CML) in chronic phase (CP) have been reported. Methods: Since 2001, guidelines for treatment with imatinib mesylate (IM) and monitoring in patients younger than 18 years with CP-CML have been shared with 9 pediatric referral centers (P centers) and 4 reference centers for adults and children/adolescents (AP centers) in Italy. In this study, the adherence to these guidelines was analyzed. Results: Thirty-four patients with a median age of 11.4 years and 23 patients with a median age of 11.0 years were managed at 9 P and at 4 AP centers, respectively. Evaluations of bone marrow (BM) and/or peripheral blood (PB) were available for more than 90% of evaluable patients. Cytogenetics and molecular monitoring of PB were more consistently performed in AP centers, whereas molecular analysis of BM was carried out more frequently in P centers. Before 2009, some patients who responded to IM underwent a transplantation, contrary to the guidelines’ recommendations. Conclusions: Our experience shows that having specific guidelines is an important tool for an optimal management of childhood CP-CML, together with exchange of knowledge and proactive discussions within the network.

scholarly journals Side-effects profile and outcomes of ponatinib in the treatment of chronic myeloid leukemia

2020 ◽  
Vol 4 (3) ◽  
pp. 530-538 ◽  
Author(s):  
Onyee Chan ◽  
Chetasi Talati ◽  
Leidy Isenalumhe ◽  
Samantha Shams ◽  
Lisa Nodzon ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Inverse Correlation ◽  
Cancer Center ◽  
Molecular Response ◽  
Starting Dose ◽  
Dose Dependent Fashion ◽  
Dose Dependent

Abstract Ponatinib is associated with cardiovascular adverse events (CAEs), and its frequency in the real world is limited. In this retrospective study, we examined the survival outcomes and associated toxicities in 78 consecutive ponatinib-treated patients with chronic myeloid leukemia (CML) at the Moffitt Cancer Center from January 2011 through December 2017. The most common non-CAE was thrombocytopenia (39.7%), occurring in a dose-dependent fashion. Eighteen patients (23.1%) experienced some form of CAE, with the most common being arrhythmia (9%) and hypertension (7.7%), whereas 3 patients experienced myocardial infarction (3.8%). Before 2014, most patients were started on ponatinib 45 mg daily. There was an inverse correlation between cardio-oncology referral and the number of CAEs (P = .0440); however, a lower ponatinib starting dose, more frequent dose reduction, and increased cardio-oncology referral all were likely to have contributed to the observed decrease in CAEs after 2014. The response rate and 5-year overall survival (OS) were higher than those observed in the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial (major molecular response, 58.7% vs 40% and OS, 76% vs 73%; median follow-up of 32.5 months). Ponatinib-treated patients with chronic phase–CML did not show a significant improvement with allogeneic stem cell transplantation, whereas those with accelerated phase/blast phase–CML had a much better outcome (median OS of 32.9 months vs 9.2 months; P = .01). These results demonstrate that ponatinib is highly effective. Dose adjustments and increased awareness of the cardiotoxicities associated with ponatinib may help maximize its benefits.

Chronic phase chronic myeloid leukemia patients who failed interferon alpha and switched to imatinib: Long-term 9-year follow-up of 134 patients

2015 ◽  
Vol 90 (5) ◽  
pp. E95-E96
Author(s):  
Massimo Breccia ◽  
Roberto Latagliata ◽  
Matteo Molica ◽  
Gioia Colafigli ◽  
Marco Mancini ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Interferon Alpha ◽  
Myeloid Leukemia ◽  
Chronic Phase
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