Chronic Myeloid Leukemia in Pediatrics — First Results From Study CML-PAED II.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 342-342 ◽  
Author(s):  
Meinolf Suttorp ◽  
Christian Thiede ◽  
Josefine T Tauer ◽  
Silja Roettgers ◽  
Petr Sedlacek ◽  
...  
Keyword(s):  
Side Effects ◽  
Chronic Myeloid Leukemia ◽  
Bone Metabolism ◽  
Treatment Response ◽  
Muscle Pain ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Response Rates ◽  
Longitudinal Growth ◽  
Molecular Response

Abstract Abstract 342 Background: Chronic myeloid leukemia (CML) is a rare malignancy in pediatrics. In this decade -like in adults- imatinib meyslate (IMA) has been established also as first line treatment for children with CML while allogeneic stem cell transplantation (SCT) as treatment option is postponed for those cases becoming intolerant or refractory to tyrosine kinase inhibitor (TKI) treatment. However, results from controlled trials in children are lacking so far. We here report an analysis of pediatric data from patients (pts) with newly diagnosed Philadelphia-chromosome positive (Ph+) CML on up-front treatment with IMA. Pts and Methods: According to protocol CML-PAED II pediatric pts with confirmed diagnosis of Ph+ CML were treated in CP with IMA 300 mg/sqm once daily, while in accelerated phase (AP) or in blastic phase (BC) the dose was increased to 400 mg/sqm and 500 mg/sqm (bis daily), respectively. Initial and long-term clinical and laboratory data, treatment response and side effects were reported to the study center on standardized forms by the treating physician. Specimen from peripheral blood (pB) and bone marrow (BM) were assessed by cytogenetics and by quantitative RT-PCR for BCR-ABL transcript rates in central laboratories for standardized monitoring in three months intervals. Results: From 1. Jan 2004 until 31. Mrch 2009 a total of 51 pts (21 female, 30 male; median age: 10.6 yrs [range:1-20 yrs]) were registered: 10 pts with ongoing IMA treatment were recruited and analyzed retrospectively while 41 pts were enrolled prospectively from centers in Austria (n=1), Czech Rep. (n=6), Germany (n=40), Italy (n=1), Netherlands (n=1), Slovak Rep. (n=2). Stages of disease were: CP n=47; AP n=1; BC n=3 (two myeloid). Those four pts diagnosed in AP and BC underwent early SCT. Observed side effects in the whole group included: nausea (n=9), muscle pain (n=7), edema (n=3), rhabdomyolysis (n=1, short interruption of IMA), reduced blood cell count (n=2, short interruption of IMA in one pt), biochemical alterations in bone metabolism [for details see: N Engl J Med 2006;354:2006] (n = 8), impaired longitudinal growth (n=1, [Haematologica 2009;94:1177]). Two pts experienced intolerance (muscle pain) or toxicity (hepatic), respectively, therefore stopped IMA and were put on dasatinib after 4 and 10 months, respectively. Having achieved complete cytogenetic response (CyR) and 2 log-fold reduction of BCR-ABL transcript rate, one pt opted for SCT from her HLA-identical brother after 15 mo of treatment. Response rates in advanced stages of CML were as follows: in BC (n=3) two pts became hematological responders (HR), one pt exhibited partial HR. The only one pt diagnosed in AC exhibited partial CyR but complete HR. A landmark analysis in pts entering CML-paed II in CP exhibited that 2/42 pts (5%) had no complete HR at month 3; 2/28 (7%) had no complete CyR at month 12, and 2/19 (15%) pts achieved no major molecular response (MMR, defined as >0.1% BCR-ABL [Blood 2006;108:28–37]) at month 18 after start of IMA. Each two of those four patients with incomplete response (one pt with no CyR at month 12, one pt with no MMR at month 18) underwent SCT from a sibling donor and the other two pts stopped IMA and were put on dasatinib. With a median follow-up of 19 months (range: 0-63 months) all 47 pts diagnosed in CP are alive. Of note none of the six pts (median age at diagnosis: 5 yrs; range 1–13 years) treated by imatinib meanwhile for >36 months have opted for SCT. Conclusion: Keeping in mind that the number of pediatric pts is still small, IMA treatment for children and adolescents with CML in CP is associated -like in adults- with high treatment response rates. Refractoriness to IMA is uncommon and side effects seem tolerable, as only 10% of the total cohort stopped imatinib and were put on 2nd generation TKI. However, disturbances of bone metabolism and longitudinal growth impairment may be of special concern in this not yet outgrown cohort [N Engl J Med 2006;354:2006, Blood 2008;111:2538; Haematologica 2008;93:1101; Lancet 2008;372:111; Int J Hematol; 2009;89:251; Haematologica 2009;94:1177]. Only 3/47 pts not diagnosed in advanced phases of CML so far underwent SCT thus underlining that also in pediatrics SCT has been shifted to a second-line strategy for high-risk patients and those who failed therapy with IMA. Disclosures: Suttorp: Novartis : Research Funding. Thiede:Novartis: Research Funding.

scholarly journals Targeting Chronic Myeloid Leukemia Stem/Progenitor Cells Using Immunolipsome Loaded Venetoclax

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-39
Author(s):  
Mohammad Houshmand ◽  
Paola Circosta ◽  
Francesca Garello ◽  
Valentina Gaidano ◽  
Alessandro Cignetti ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Side Effects ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Residual Disease ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Number Of Patients

The introduction of different generations of tyrosine kinase inhibitors (TKIs) significantly improved outcome and survival rate in chronic myeloid leukemia (CML) patients. However, long-term use of TKIs is concomitant with many side effects that affect the quality of life in patients. Approximately half of CML patients achieve deep molecular response (DMR), this makes them suitable candidates to discontinue the TKI therapy in a controlled condition, and about half of them will remain in treatment free remission (TFR) after discontinuation. It has been shown that a small population of leukemia stem cells (LSCs) as the residual disease burden is present at diagnosis, during the treatment, and in patients who are in TFR. While CML LSCs have many features in common with HSCs, they express specific markers such as CD25, CD26, IL1-RAP, etc., which can be used for the diagnosis and targeting. Protection by the bone marrow microenvironment and activity of signaling pathways such as WNT/β catenin, Hedgehog, PI3K, JAK/STAT in CML LSCs in a BCR-ABL dependent and independent manner guarantee their survival and elimination of these cells solely using TKIs seems ineffective. Herein we designed a pegylated liposomal nanocarrier conjugated with a specific antibody against CD26 (Begelomab, ADIENNE, Lugano, Switzerland). Then we loaded this immunoliposome with venetoclax, a BCL2 inhibitor, to eliminate CML LSCs selectively and to spare normal HSCs. First, we measured the expression of CD26 in the bone marrow and peripheral blood samples of newly diagnosed patients. We had a high expression of CD26 in CD34+/CD38- of both PB and BM, and a low expression on CD34+/CD38+ (progenitors) cells. Also, the expression of this marker in resistant patients to TKIs was visible while it was absent in normal stem cells. After the synthesis of the liposome, we conjugated Begelomab to the liposome. Then, we tested the selectivity of the designed system in different positive and negative cells. Our designed immunoliposome showed a strong selectivity toward CD26 positive cells. We also tested the selectivity on CML primary cells; in particular, we sorted newly diagnosed CML samples based on CD34+/CD38-/CD26- for HSCs and CD34+/CD38-/CD26+ for LSCs. Based on the confocal and flow cytometry analysis, our designed immunoliposome selectively targets LSCs and spares HSCs. Then we loaded this immunoliposome with venetoclax, and we treated CD26 positive and negative cells with this system. Based on our preliminary results, this immunoliposome loaded venetoclax specifically induced apoptosis in CD26+ cells, with higher activity compared to free venetoclax at the same dose. However, more analysis will be performed to confirm the selectivity of this system. Based on the obtained results, CD26 in newly diagnosed CML patients is expressed by CML LSCs and is a suitable option for diagnosis and targeting. Our preliminary data strongly suggest that we can selectively target CML LSCs. The main advantage of this system is its precision to hit the target. So we expect that after the drug release, the LSCs will be eliminated without any side effects on normal cells. Liposomes are suitable carriers because of their biocompatibility, self-assembly, large drug payload, and minimal toxicity. This strategy may help us to increase the number of patients attaining and maintaining TFR without relapsing. Disclosures Saglio: Ariad: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding.

scholarly journals Prognostic Value of BCR-ABL1 Transcript Type in Chronic Myeloid Leukemia Patients Treated Frontline with Nilotinib

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3070-3070 ◽  
Author(s):  
Fausto Castagnetti ◽  
Gabriele Gugliotta ◽  
Massimo Breccia ◽  
Fabio Stagno ◽  
Mariella D'Adda ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Second Generation ◽  
Response Rates ◽  
Molecular Response ◽  
Prognostic Impact ◽  
Free Survival ◽  
Transcript Type

Abstract Background. The fusion protein encoded by the BCR-ABL1 fusion gene may differ in size, but the great majority of chronic myeloid leukemia (CML) patients have a e13a2 (b2a2) or a e14a2 (b3a2) junction. In CML patients treated frontline with imatinib, the e14a2 transcript has been recently associated to faster and deeper molecular responses; in some studies a better outcome has been also reported. Very limited information on the prognostic impact of the BCR-ABL1 transcript type in CML patients treated frontline with second generation tyrosine kinase inhibitors (TKIs) is still available: a study from MDACC reported lower molecular response rates and a trend for inferior event-free survival in e13a2 patients. Aim. To evaluate if the BCR-ABL1 transcript type (e14a2 vs e13a2) affect the response and the clinical outcome in newly diagnosed adult CML patients treated frontline with nilotinib (NIL). Methods. An analysis of 345 CML patients in early chronic phase (ECP) enrolled within 3 multicentric prospective studies of the GIMEMA CML Working Party (ClinicalTrials.gov NCT00481052, NCT00769327, NCT01535391) was performed. The initial treatment was NIL 300 mg BID or NIL 400 mg BID. Definitions: major molecular response (MMR), BCR-ABL1IS ratio < 0.1%; deep molecular response (MR4.0), BCR-ABL1IS ratio < 0.01% with > 10,000 ABL1 copies; progression, transformation to advanced phases; death, at any time and for any reason. Cumulative incidences of response were estimated under consideration of competing risks (progression, death) and compared by Gray test. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared by log-rank test. Results. Seven patients expressing rare transcripts (e1a2 or e19a2) and 10 patients with unknown transcript type were excluded: 328 out of 345 patients were evaluable, 124 (38%) with e13a2 transcript, 174 (53%) with e14a2 transcript and 30 (9%) expressing both transcripts. The baseline characteristics of patients with e13a2 or e14a2 transcripts were comparable: no significant differences in age, gender, Sokal or EUTOS long-term survival score distribution, presence of clonal chromosomal abnormalities in Ph+ cells, NIL dose were observed; the only difference was a higher platelet count in patients with e14a2 transcript (median 374 vs 313 x 103/µl, p=0.006). The median follow-up was 60 months in both groups (range 24-82 months). The response rates and the survival probabilities were uniformly lower in patients with e13a2 transcript (N=124) compared to patients with e14a2 transcript (N=174), but the differences were not significant: MMR by 12 months, 66% vs 72%, p=0.244; MR4.0 by 36 months, 56% vs 66%, p=0.067; estimated cumulative incidence of MMR, 82% vs 88%, p=0.135; estimated cumulative incidence of MR4.0, 60% vs 69%, p=0.101; estimated PFS, 88% vs 93%, p=0.547; estimated OS, 89% vs 94%, p=0.436 (Figure 1). The responses and the survival probabilities of patients co-expressing the e13a2 and the e14a2 transcripts (N=30) were similar to or even better than the ones of e14a2 patients. Grouping together the patients with e14a2 transcript alone and the patients with co-expression of both transcripts (N=174+30=204), and comparing them to patients with e13a2 transcript alone (N=124), the response differences became significant (cumulative incidence of MMR and MR4.0, p=0.050 and p=0.036, respectively), but no outcome differences emerged (PFS and OS, p=0.340 and p=0.276, respectively). Conclusions. Despite a trend for lower response rates and inferior outcome in patients with e13a2 transcript, the observed differences were small and mostly not significant. Further studies in larger patient cohorts are required to clarify whether nilotinib and other second generation TKIs are able to overcome the adverse prognostic impact of transcript type, potentially affecting the speed and the depth of molecular response, the probability of achieving a treatment-free remission and the patient outcome. Figure 1 Figure 1. Disclosures Castagnetti: Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD Pharmaceuticals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gugliotta:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Breccia:Ariad: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Honoraria; Celgene: Honoraria. Carella:Millenium: Speakers Bureau; Genentech: Speakers Bureau. Tiribelli:Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau. Bocchia:Janssen: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Soverini:Ariad: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Martinelli:ARIAD: Consultancy; Roche: Consultancy; MSD: Consultancy; Novartis: Speakers Bureau; Genentech: Consultancy; Amgen: Consultancy; BMS: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; ARIAD: Consultancy; Roche: Consultancy; MSD: Consultancy; Amgen: Consultancy; Genentech: Consultancy. Rosti:Roche: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

Dasatinib Is Well-Tolerated and Efficacious in Imatinib-Intolerant Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1128-1128 ◽  
Author(s):  
Hanna Jean Khoury ◽  
Michael J. Mauro ◽  
Yousif Matloub ◽  
Tai-Tsang Chen ◽  
Erkut Bahceci ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Median Duration ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Molecular Response

Abstract Abstract 1128 Poster Board I-150 Imatinib (IM), a tyrosine kinase inhibitor (TKI), has been the mainstay of treatment for chronic phase chronic myeloid leukemia (CP-CML). However, IM resistance and intolerance are of considerable clinical relevance. Dasatinib (DAS), a second-line TKI, is effective in the IM-intolerant patient population. The purpose of this study was to determine baseline factors that can affect DAS response and evaluate long term efficacy in this population. Intolerance to IM was defined as ≥ Grade 3 non-hematologic toxicity and/or Grade 4 hematologic toxicity lasting > 7 days. A total of 271 Ph+ CP-CML IM-intolerant patients who received DAS were pooled from two randomized trials (Phase II-trial, CA 180013 and Phase III trial, CA 180034). DAS doses were 50 mg BID (n=43), 70 mg BID (n=141), 100 mg QD (n=43) or 140 mg QD (n=44). At baseline, the median duration of disease for the IM-intolerant patients was 24 months (range: 0.9-182.5) and the median duration of IM therapy was 9 months (range: 0.03-69.06). Of these patients, 46 (17%) had hematologic toxicity and 228 (84.1%) had non-hematologic toxicity to IM. Seventy-nine (29%) patients had prior complete cytogenetic response (CCyR) on IM and 171 (63%) patients did not. The data for prior CyR to IM was not reported for 21 (7.7%) patients. Of the 79 patients who had achieved CCyR on IM, 30 patients had maintained CCyR and 49 patients had lost this response prior to start of DAS. Of the 171 patients who did not achieve CCyR on IM, 62 (36.3%) had been on IM for 3 12 months and 109 (63.7%) for < 12 months. At 2-year follow up of the 271 patients treated with DAS, 121 (44.6%) discontinued DAS (7.4% due to hematologic toxicity and 14% due to non-hematologic toxicity). Of the patients who were intolerant of IM due to hematologic toxicity (n=46), 10 (21.7%) discontinued DAS due to hematologic toxicity, and 3 (6.5%) due to other toxicities. Of the patients with non-hematologic IM-intolerance (n=228), 10 (4.4%) discontinued DAS due to hematologic toxicity, and 35 (15.4%) due to other toxicities. The median average daily dose of DAS was 99 mg/day in the population who achieved CCyR on DAS and 71.5 mg/day in the population who did not achieve CCyR on DAS. The probability of achieving CCyR on DAS was 43.5% in patients with hematologic IM-intolerance versus 78.9% with non-hematologic IM-intolerance. The CCyR, major molecular response (MMR), progression-free survival (PFS) and overall survival (OS) at 2-year follow up for the groups classified by their CCyR status at start of DAS or IM-intolerance status are summarized in Table 1. Conclusions DAS was well-tolerated and associated with high rates of CyR in IM-intolerant patients. Patients with a prior CCyR to IM and those who switched due to non-hematologic imatinib-intolerance had the highest rates of CCyR and MMR on DAS, while patients without CCyR after more than 12 months of IM therapy or IM-intolerance due to hematologic toxicity had the lowest rates of CCyR and MMR. Disclosures Khoury: BMS: Honoraria; Wyeth: Honoraria; Novartis Pharmaceuticals: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. Mauro:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Matloub:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Bahceci:Bristol-Myers Squibb: Employment. Deininger:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Calistoga: Research Funding; Genzyme: Research Funding.

Long Term Adherence to Imatinib Therapy Is the Critical Factor for Achieving Molecular Responses in Chronic Myeloid Leukemia Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3290-3290 ◽  
Author(s):  
Alex Bazeos ◽  
Jamshid Khorashad ◽  
François-Xavier Mahon ◽  
Lina L Eliasson ◽  
Dragana Milojkovic ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Independent Predictor ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Adherence Rate ◽  
Molecular Response ◽  
Molecular Responses ◽  
Adherence To Therapy

Abstract Abstract 3290 Poster Board III-1 There is a great variability in the degree of molecular responses achieved by chronic myeloid leukemia (CML) patients treated with imatinib. These different levels of molecular response could reflect different degrees of adherence to therapy. We measured the adherence to imatinib therapy in 87 consecutive CML chronic phase patients who had received imatinib 400 mg day as first line therapy for a median of 59.7 months before enrolment (range 25–104) and therefore all them were in complete cytogenetic response. Adherence levels were monitored during a 3-month period using microelectronic monitoring devices (MEMS) and were related to levels of molecular response. MEMS consist of an electronic device fitted in the cap of a normal looking medication bottle that automatically records each time the bottle is opened. MEMS are considered as the ‘gold standard' for measuring adherence. We also measured the imatinib plasma level, the presence of TKD mutations and the following prognostic factors measured at diagnosis: hOCT1 transcripts level, polymorphism 1236C&gt;T in ABCB1, Sokal risk group, hemoglobin, leukocytes , BCR-ABL1 transcript type and BCR1-ABL1 ratio and demographic data. The study protocol was approved by the Research Ethics Committee and patients gave written informed consent to participate. The median adherence rate was 97.6% (range 22.6–103.8%). In 23 (26.4%) patients adherence was ≤90% (median 76%) and in 12 (13.8%) ≤80% (median 63%). We found a strong association between adherence rate (≤90% or &gt;90%) and the 6-year probability of major molecular response (MMR) (28.4% vs 94.5%, p&lt;0.0001) and complete molecular response (CMR) (0% vs 43.8%, p=0.002) (Fig 1). Multivariate analysis identified adherence (RR=11.7, p=0.001) and expression of the molecular transporter hOCT1, (RR=1.79, p=0.038) as the only independent predictors for MMR. Adherence was the sole independent predictor for CMR. No molecular responses were observed when the adherence was ≤20% (p=0.0001). In patients whose imatinib dose had been increased (n=32) the adherence was poor (median 86.4%). Adherence was the only independent predictor for failure to achieve a 3-log transcript reduction (RR=17.66, p=0.006) in this subgroup of patients. Patients with CML vary greatly in their response, as demonstrated originally by Sokal et al. in 1984, and the same variation is seen in patients treated with imatinib in the modern era. The basis for this variation is unknown but it has been attributed to the intrinsic biological heterogeneity of the leukemia. In contrast we show here that adherence to therapy is the major factor determining the degree of response that a CML patient treated with imatinib will achieve. Disclosures: Mahon: Novartis: Consultancy, Research Funding. Apperley:Novartis: Consultancy, Honoraria. Rezvani:Novartis: Consultancy, Honoraria, Research Funding. Marin:Novartis: Consultancy, Research Funding.

Specific Drug Transporter Genotypes Are Significantly Associated with Increased Rates of Major and Complete Molecular Responses In Newly Diagnosed Chronic Myeloid Leukemia Patients Treated with Imatinib – A TOPS Correlative Substudy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 670-670
Author(s):  
Simona Soverini ◽  
Sabrina Angelini ◽  
Eleonora Turrini ◽  
Matt Burnett ◽  
Gloria Ravegnini ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase Iii ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
First Line ◽  
Favorable Alleles ◽  
Summary Measures

Abstract Abstract 670 The availability of multiple options for chronic myeloid leukemia (CML) treatment is not paralleled by the availability of biological predictors of outcome allowing to identify patients (pts) who are more likely to benefit from dasatinib or nilotinib rather than imatinib (IM). Pharmacogenetics has proven a potential source of biomarkers given the known influence of polymorphisms in key genes encoding drug transporters and metabolizing enzymes on drug delivery – hence effectiveness. In CML, only two studies had so far explored this field, but both were conducted in heterogeneous populations including pts at different stages of disease, not all receiving IM first-line. We thus aimed to investigate a panel of 20 single nucleotide polymorphisms (SNPs) in ABCB1, ABCG2, SLC22A1, OATP1A2, OCTN1, CYP3A4 and CYP3A5 genes that can be hypothesized to influence IM transport and metabolism in 189 newly diagnosed CML pts enrolled in the TOPS phase III trial (Cortes et al, J Clin Oncol 2010). Pts selection was exclusively based on availability of written informed consent and sufficient amount of archived material. Median age was 46 years; male to female ratio was 103 to 86; 156 (83%) pts were Caucasian and 23 (12%) were Asian; low, intermediate and high Sokal risk pts were 84 (44.4%), 65 (34.4%) and 40 (21.2%), respectively. Baseline demographic/clinical features did not differ significantly from those of the overall population. Treatment outcomes (complete cytogenetic response [CCyR]; major molecular response [MMR] and complete molecular response [CMR]) were compared according to i) each candidate genotype ii) summary measures based on combinations of SNPs in the same gene and iii) summary measures based on combinations of SNPs in functionally related genes (uptake; efflux). CC genotype in OCTN1 had a favorable impact on the achievement of MMR at 12 months (MMR@12m; P = 0.03). With respect to the summary measures, combination of SNPs in the SLC22A1 gene was significantly correlated with MMR@12m (P = 0.03). When considering summary measures of uptake and efflux, the former was found to be associated with both MMR@12m and CMR@12m (P = 0.003 and P = 0.01, respectively). A separate analysis limited to Caucasian pts (n=156) yielded similar results (Table 1). In addition, the analysis in the Caucasian subgroup evidenced a significant association between the CC genotype in ABCB1 rs60023214 and MMR@12m (P = 0.005) (Table 1). Cumulative incidence plots based on the Kaplan-Meier method were also analyzed in the overall population and in Caucasians, with comparable results. Representative plots are shown in Figure 1. There was evidence for difference among MMR cumulative incidence curves for 2 single SNPs and 2 score measures. Presence of the major allele in OCTN1 (CC) and of the minor allele in CYP3A4 rs2740574 (GG) were associated with increased MMR rate (P = 0.028 and P = 0.042, respectively, in the overall population and P = 0.027 and P = 0.038, respectively, in Caucasians). Similarly, an increase in the number of favorable alleles in the SLC22A1 gene was associated with increased MMR rate (P = 0.030 and P = 0.043 in the overall population and in Caucasians, respectively). In addition, the combination of favorable alleles in the genes involved in IM uptake was associated with increased rates of both MMR and CMR (P = 0.004 and P = 0.015, respectively, in the overall population and P = 0.005 and P = 0.009, respectively, in Caucasians). Our results suggest that SNP genotyping might be helpful in selecting pts who are more likely to benefit from first-line use of more potent inhibitors. Further assessment of the SNPs here identified in larger series of pts is warranted. Supported by Novartis Oncology, Clinical Development, TOPS Correlative Studies Network Disclosures: Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria. White:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Rosti:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Hatfield:Novartis: Employment. Martinelli:Novartis: Consultancy, Honoraria; BMS: Honoraria; Pfizer: Consultancy.

Distinct Characteristics of e13a2 versus e14a2 BCR-ABL Chronic Myeloid Leukemia under Upfront Treatment with Imatinib – an Analysis of the German CML Study IV,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3773-3773
Author(s):  
Benjamin Hanfstein ◽  
Philipp Erben ◽  
Susanne Saussele ◽  
Michael Lauseker ◽  
Ulrike Proetel ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Median Time ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Fusion Gene ◽  
Standard Dose ◽  
White Blood Cells ◽  
Molecular Response ◽  
Significant Difference ◽  
Equity Ownership

Abstract Abstract 3773 Introduction: The vast majority of chronic myeloid leukemia (CML) patients express a BCR-ABL fusion gene mRNA encoding a 210 kDa tyrosine kinase which is constitutively activated and hence the mainspring of leukemic transformation. Two typical mRNA variants exist that differ in the presence or absence of the 75 basepair BCR exon 14: the e13a2 (lacking exon 14, also known as “b2a2”) and the e14a2 BCR-ABL transcript (“b3a2”). The significance of the additional 25 amino acid residues of the e14a2 BCR-ABL oncoprotein was extensively studied in the pre-imatinib era. However, the influence of the BCR-ABL transcript variant on the individual disease phenotype and outcome remained controversial and is still undefined in the imatinib era. Patients and methods: A total of 1,104 patients (median age 52 years, range 16–85, 40% female) expressing typical BCR-ABL transcript types (e13a2, n=447; e14a2, n=491; e13a2 and e14a2, n=166) were included in the randomized German CML study IV and treated with an imatinib based therapy consisting of imatinib 400 mg, imatinib 800 mg and combinations of standard dose imatinib with interferon alpha and low-dose cytarabine. The type of BCR-ABL transcript was defined by multiplex PCR. BCR-ABL expression was determined by quantitative RT-PCR and standardized according to the international scale (IS). Cytogenetic response was determined by conventional metaphase analyses. Response landmarks were defined according to European LeukemiaNet criteria, MR4 was defined as BCR-ABL IS ≤ 0.01% Results: No differences regarding age, sex and Euro risk were observed. A significant difference was observed comparing white blood cells (90,400/μl vs. 69,100/μl, p<0.001) and platelets (293,000/μl vs. 424,000/μl, p<0.001) at diagnosis (median, e13a2 vs. e14a2, respectively) indicating a distinct phenotype. No significant difference was observed regarding spleen size, basophils, eosinophils, blasts or adverse events under imatinib. Molecular response as determined by a transcript independent quantitative PCR assay was superior in e14a2 patients as compared to e13a2 patients (median time to major molecular response, MMR 1.5 years vs. 1.2 years, p<0.001; median time to MR4 4.2 years vs. 2.5 years, p<0.001). No difference was observed with regard to the achievement of a complete cytogenetic remission (CCyR). The superior molecular response rate of e14a2 patients did not translate into differences in progression free survival (PFS) or overall survival (OS). Conclusion: Distinct initial blood counts suggest a different phenotype of e13a2 and e14a2 driven CML. MMR and MR4 are achieved earlier by e14a2 patients whereas no difference was observed with regard to PFS and OS. Disclosures: Schnittger: Münchner Leukämie Labor: Equity Ownership. Haferlach:Münchner Leukämie Labor: Equity Ownership. German CML Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; BMBF: Research Funding; EU: Research Funding; Roche: Research Funding; Essex: Research Funding.

Predictive Value of 3-Month Early Molecular Response in New Chronic Phase Chronic Myeloid Leukemia Patients Treated with Radotinib

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4053-4053
Author(s):  
Sung-Eun Lee ◽  
Soo Young Choi ◽  
Jae-Yong Kwak ◽  
Hawk Kim ◽  
Jeong-A Kim ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Predictive Value ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Molecular Response ◽  
Phase 3 ◽  
Qrt Pcr ◽  
Study Therapy

Abstract Background: Recent studies have demonstrated that early molecular milestones were able to identify high-risk chronic myeloid leukemia patients treated with frontline imatinib (IM) and second generation tyrosine kinase inhibitors (2G TKIs) such as nilotinib and dasatinib. However, whether a single measurement of BCR-ABL1 transcripts level after 3 months of treatment is sufficient to define failure necessitating a change of treatment is not confirmed. Radotinib (RAD) is a 2G TKI for BCR-ABL1 tyrosine kinase, which was approved by the Korea FDA for the second-line therapy, and the phase 3 study comparing the efficacy and safety of RAD 300 and 400 mg twice daily and IM 400 mg once daily in patients with newly diagnosed CP CML was performed. The aim of this study was to identify the predictive value of 3-month molecular milestone for an achievement of major molecular response (MMR) by 12 months to RAD therapy. Additionally, in the same population, predictive factors for achieving MMR by 12 months were analyzed. Methods: Among 241 patients who were enrolled in the randomized, open-label, phase 3 study of RAD, 236 patients with available 3-month qRT-PCR on study therapy [RAD 300 mg twice (n = 79), RAD 400 mg twice (n = 79), IM 400 mg once (n = 78)] were evaluated. Molecular responses were monitored using a qRT-PCR assay in 3-month intervals by 12 months. All qRT-PCR were tested with at least 4.5-log sensitivity in the central laboratory (Cancer Research Institute, The Catholic University of Korea, Seoul, Korea) and MMR was defined as a BCR-ABL1 transcript level of 0.1% or lower on the international scale (IS). Results: 236 patients (including 149 men and 87 women) with available 3-month qRT-PCR on study therapy were evaluated. With a median age of 45 years (range, 18-84 years), the distribution of low, intermediate and high Sokal risk scores were 27%, 47% and 26%, respectively. At 3 months, BCR-ABL1 ≤10% [RAD 300 mg twice (n = 68), RAD 400 mg twice (n = 69), IM 400 mg once (n = 55)] and >10% [RAD 300 mg twice (n = 11), RAD 400 mg twice (n = 10), IM 400 mg once (n = 23)] were observed. In the IM 400 mg once group, patients with BCR-ABL1 ≤10% at 3 months showed a significant higher rate of MMR by 12 months compared with that of patients with BCR-ABL1 >10% (38.2% vs 13.0%, P = 0.028). In the RAD 300 and 400 mg twice group, an achievement of 3-month EMR was associated with a higher rate of MMR by 12 months [57.4% vs 18.2%, P = 0.016 (RAD 300 mg twice) and 50.7% vs 10.0%, P = 0.018 (RAD 400 mg twice)]. After adjusting for factors affecting achievement of MMR by 12 months on univariate analyses, multivariate analyses showed that b2a2 transcript type (RR of 0.46, P = 0.023), large spleen size (RR of 0.91, P = 0.001), and no achievement of 3-month EMR (RR of 0.24, P = 0.004) were predictor for not achieving MMR by 12 months. Significance of 3-month EMR for achieving MMR by 12 months was observed in the separated treatment groups: RR of 0.24, P = 0.037 in the IM 400 mg once group, RR of 0.17 P = 0.028 in the RAD 300 mg twice group, and RR of 0.11, P = 0.040 in the RAD 400 mg twice group. Conclusions: Our results suggest that 3-month EMR can play key roles for 12-month MMR achievement in CP CML patients treated with IM and RAD. In addition, some factors for achieving 12-month MMR were detected. To evaluate the long-term prognostic value of 3-month EMR, further clinical investigations in a larger patient population with longer follow-up are needed. Disclosures Kim: IL-YANG Pharm.Co.Ltd: Research Funding. Chung:Alexion Pharmaceuticals: Research Funding.

scholarly journals BCL2L11 (BIM) Deletion Polymorphism Is Associated with Molecular Relapse after ABL Tyrosine Kinase Inhibitor Discontinuation in Patients with Chronic Myeloid Leukemia with Complete Molecular Response

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1797-1797 ◽  
Author(s):  
Seiichiro Katagiri ◽  
Tetsuzo Tauchi ◽  
Yuu Saito ◽  
Tamiko Sugro ◽  
Michiyo Asano ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Molecular Response ◽  
Deletion Polymorphism ◽  
Significant Difference ◽  
Treatment Free Remission ◽  
Tki Discontinuation ◽  
Complete Molecular Response

Abstract Background: The inhibition of BCR-ABL1 kinase with tyrosine kinase inhibitors (TKIs) has markedly improved the prognosis of chronic myeloid leukemia (CML). Recently, it has been recognized that some CML patients with a complete molecular response (CMR) are able to maintain treatment-free remission (TFR) after discontinuation of TKIs. However, no predictive prognostic factors for successful discontinuation of the treatment have yet been identified. We set out to further clarify the role of predictive biomarkers in molecular relapse and non-relapse after ABL TKI discontinuation. Materials and methods: Patients in sustained CMR (MR 4.5) undergoing TKI therapy were eligible for inclusion in the study. Molecular relapse was defined as loss of major molecular response (MMR) of at least one point. Genomic DNA was obtained from whole blood using a DNA Extractor WB Kit (Wako, Osaka, Japan), and was subjected to polymerase chain reaction (PCR) amplification using primers designed to detect a deletion site (2903 bp) in intron two of the BCL2L11 gene (forward: 5′-AATACCACAGAGGCCCACAG-3′; reverse: 5′-GCCTGAAGGTGCTGAGAAAG-3′) and JumpStart RedAccuTaq LA DNA polymerase (Sigma Aldrich, St. Louis, MO, USA). Results: 32 CML patients (17 men, 15 women, median age 58.4 years) were included in this study (Sokal category; low 24, intermediate 7, high 1). Six patients were treated with IFNα before TKI treatment, and 3 were treated with IFNα after stopping TKI. Median duration from TKI initiation to discontinuation was 79.3 months (range; 22 to 138 months); median duration of CMR before TKI discontinuation was 47.3 months (range; 5 to 97 months). Seven patients showed loss of MMR; 6 relapsed within 6 months and one showed late relapse at 25 months after discontinuation. The cumulative incidence of MMR loss was estimated as 18.8% at 12 months and at 24 months. Fluctuation of BCR-ABL transcript levels below the MMR threshold (> two consecutive positive values) was observed in 6.25% of patients at 24 months after ABL TKI discontinuation. Treatment-free remission was estimated as 81.2% at 12 months and at 24 months. The median period of restoration of second CMR was 6.0 months in re-treated patients. No patient died during the follow-up period. TKI-free remission was estimated as 78.1% at 30 months. There was only a significant difference in BCL2L11 (BIM) deletion polymorphism between the patients who maintained and those who lost MMR (p = 0.0253). No significant difference was observed in prior IFNα therapy, time to complete cytogenetic response (CCyR), time to MMR, and time to CMR between relapsing and non-relapsing patients. Conclusion: Our study shows a specific association between BCL2L11 (BIM) deletion polymorphism and clinical outcome after ABL TKI discontinuation in patients with long-lasting molecular undetectable residual disease. BCL2L11 (BIM) deletion polymorphism may predict relapse after ABL TKI discontinuation, which may have an impact on future ABL TKI discontinuation trials. These results further illustrate the importance of single nucleotide polymorphisms in successful long-term treatment of CML. Disclosures Ohyashiki: Bristol-Myers Squibb KK : Research Funding, Speakers Bureau; Novartis KK: Research Funding, Speakers Bureau.

Imatinib in Chronic Myeloid Leukemia - Five Years Single Center Experience.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4558-4558
Author(s):  
Jaroslaw Dybko ◽  
Ewa Medras ◽  
Renata Bednarz ◽  
Donata Urbaniak ◽  
Kazimierz Kuliczkowski
Keyword(s):  
Side Effects ◽  
Chronic Myeloid Leukemia ◽  
Nested Pcr ◽  
Myeloid Leukemia ◽  
Point Mutations ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Line Treatment ◽  
Median Period ◽  
Conventional Cytogenetics

Abstract Background: Chronic myeloid leukemia (CML) treatment standards was completely converted in last decade. This clonal myeloproliferative disease characterized by the Philadelphia (Ph) chromosome genetic abnormality which arises from the chromosomal translocation t(9;22)(q34;q11). This translocation fuses the genes encoding BCR and ABL, resulting in expression of constitutively active protein tyrosine kinase, BCR-ABL. In the pre-Imatinib era CML therapy was focused on decreasing the myeloid line proliferation. Interpheron alpha, nowadays neglected in CML, allowed approximately 30% of patients to achieve cytogenetic remission but it was accompanied by severe side effects. The only known curative therapy in CML was allogeneic stem cell transplantation (alloSCT) but the procedure was restricted to younger patients. The first of tyrosine kinase inhibitors (TKI) introduction was a milestone in CML therapy. Today we are forced to face Imatinib resistance as an expression of point mutations in kinase domains, the second or even the third line treatment is performed, however Imatinib remains the first line, relatively safe and very effective treatment in CML. Patients: 60 patients (F/M-30/30, median age-51) with CML Ph+ BCR-ABL+ diagnosed in our center in last five years were involved in the study. All diagnoses were based on hematological findings, conventional cytogenetics and nested PCR. In all cases 100% Ph+ metaphases were find by the diagnose. The b3a2 transcript type was detected in 34 cases, b2a2 in 26. All but four patients are still receiving Imatinib in dose 400 mg per day. Due to some economic disturbances in early TKI era the median period between the diagnosis of CML and the beginning of Imatinib treatment was 154 days. Three patients were transplanted from allogeneic donor due to NCyR after 12 months of treatment. One death case was related neither to CML nor to treatment toxicity. Definitions: Complete hematologic response (CHR) was defined as white blood cell count in peripheral blood <10x109/L, platelet count <10x109/L, no immature cells in blood, basophils<5% in blood or marrow, spleen non palpable. Cytogenetic response was defined as the percentage of Ph+ metaphases in conventional cytogenetics: complete (CCyR) - no Ph+ metaphases, partial (PCyR) - 1–35%, minor (mCyR) - 36–65% and minor/none (NCyR)≥66%. As for molecular response due to our PCR tools we determined complete molecular response (CMoR) as undetectable BCR-ABL transcript also by nested PCR. Methods: All patients started Imatinib therapy in dose 400 mg per day. Cytogenetic response was determined by conventional cytogenetics and molecular response by nested polymerase chain reaction (PCR). Results: The median period of treatment is 23 months (3–60 months). All patients achieved CHR after 3 months of Imatinib therapy. In the group of 8 patients NCyR was confirmed by 12 months of treatment. In 3 cases of this group allogeneic bone marrow transplantation was performed. One patient of those eight died as was previously mentioned and four of them were included into second-line treatment trial (Nilotinib). 52 patients achieved CCyR (still sustained) after 12 months of therapy. In 13 cases of these 52 CMoR was recognized. Conclusions: The management of CML is constantly changing and developing. TKI are today a group of drugs influencing the point mutations in kinase domain, even the most resistant-T315I. The future of CML treatment seems to rely on the balance between subsequent TKI generations, alloSCT and possible side effects of both therapeutic schedules.

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