Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 884-884

Abstract: Abstract 884 Blast crisis is the terminal phase of chronic myeloid leukemia (CML) with a short median survival of approximately six months. At present, little is known about molecular mechanisms underlying disease progression. We hypothesized that mutations occurring in other myeloid and lymphatic malignancies are acquired during disease progression from chronic phase to blast crisis. Here, in total 40 blast crisis CML cases (n=25 myeloid, n=10 lymphoid, n=5 not specified) were analyzed, all diagnosed between 9/2005 and 7/2009. First, all cases were investigated for IKZF1 deletions by PCR using specific primer pairs for the common intragenic deletions spanning from exon 2–7, or exon 4–7 as published by Iacobucci et al. (Blood, 114:2159-67, 2009). In total, in 17.5% (7/40) of cases intragenic IKZF1 deletions were detected. Secondly, next-generation deep-sequencing (454 Life Sciences, Branford, CT) was used to investigate 11 candidate genes in all 40 patients for a broad molecular screening. Known hotspot regions were sequenced for CBL (exons 8 and 9), NRAS (exons 2 and 3), KRAS (exons 2 and 3), IDH1 (exon 4), IDH2 (exon 4), and NPM1 (exon 12). Complete coding regions were analyzed for RUNX1, TET2, WT1, and TP53. To perform this comprehensive study, amplicon-based deep-sequencing was applied using the small volume Titanium chemistry assay. To cope with the great number of amplicons, in total 59, 48.48 Access Arrays were applied (Fluidigm, South San Francisco, CA), amplifying and barcode-tagging 48 amplicons across 48 samples in one single array (2,304 reactions). In median, 430 reads per amplicon were obtained, thus yielding sufficient coverage for detection of mutations with high sensitivity. Further, ASXL1 exon 12 aberrations were investigated by Sanger sequencing. In summary, after excluding known polymorphisms and silent mutations in 33/40 patients 53 mutations were identified: RUNX1 (16/40; 40.0%), ASXL1 (12/40; 30.0%), WT1 (6/40; 15.0%), NRAS (2/40; 5.0%), KRAS (2/40; 5.0%), TET2 (3/40; 7.5%), CBL (1/40; 2.5%), TP53 (1/40; 2.5%), IDH1 (3/40; 7.5%), IDH2 (0/40), and NPM1 (0/40). Thus, 82.5% of blast crisis CML patients harbored at least one molecular aberration. In median, one affected gene per patient was observed (range 1–5). In detail, RUNX1 was associated with additional mutations in other genes, i.e. 9/16 cases were harboring additional mutations in combination with RUNX1. Similarly, in 8/12 patients with ASXL1 mutations additional aberrations were detected. With respect to myeloid or lymphoid features ASXL1 mutations (n=11) were exclusively observed in patients with myeloid blast crisis (n=1 not specified), in contrast 5/7 IKZF1 cases were detected in cases with lymphoid features (n=1 myeloid, n=1 not specified). Interestingly, besides IKZF1 (n=5) and RUNX1 (n=3) alterations there was no other mutated gene occurring in lymphoid blast crisis CML. In addition, no aberration was detected in NPM1, and in contrast to published data, in our cohort only one patient harbored a mutation in TP53. Moreover, for 8 patients with mutations in IKZF1 (n=3), RUNX1 (n=3), ASXL1 (n=1), WT1 (n=2), and IDH1 (n=2), matched DNA from the initial diagnosis at chronic state was available. In these specimens respective IKZF1 deletions, RUNX1, and ASXL1 mutations were not detectable indicating that IKZF1, RUNX1, and ASXL1 mutations had been developed during disease progression and act as driver mutations in these cases. WT1 and IDH1 mutations occurred at first diagnosis in one case each, indicating these genes would constitute passenger mutations. In conclusion, this comprehensive study on 12 molecular markers enabled to characterize for the first time that 82.5% of blast crisis CML cases harbor specific molecular mutations. IKZF1 and RUNX1 alterations were identified as important markers of disease progression from chronic state to blast crisis. Moreover, technically, a novel combination of a high-throughput sample preparation assay for targeted PCR-based next-generation deep-sequencing was developed and allowed to broaden our molecular understanding in blast crisis CML. Disclosures: Grossmann: MLL Munich Leukemia Laboratory: Employment. Eder:MLL Munich Leukemia Laboratory: Employment. Schindela:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Wille:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.884.884

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1495-1495

Abstract: The approval of three tyrosine kinase inhibitors (TKIs) for the first line treatment of Chronic Myeloid Leukemia (CML) has generated an urgent need for molecular parameters predictive of unfavorable therapeutic outcomes. Recent evidence suggests that failure to achieve early molecular responses (i.e. BCR-ABL/ABLIS levels 〈 10% after 3 months or 〈 1% after 6 months of TKI treatment) results in inferior rates of both overall and progression-free survival. With the current study, we wanted to establish if high BCR-ABL transcripts at diagnosis would be associated with unfavorable responses to Imatinib Mesylate (IM). Thus, we correlated quantitative determinations of BCR-ABL levels at diagnosis with the outcome of 230 newly diagnosed CML patients that were assigned to receive IM 400 mg/die. BCR-ABL transcripts were measured from peripheral blood samples drawn before exposure to any form of treatment. Real-Time Quantitative PCR (RQ-PCR) determinations were subsequently performed in triplicates using glucuronidase-beta (GUS) as the reference gene, since previous evidence has demonstrated that ABL is not a reliable control gene in samples collected at diagnosis. Values were then reported on the International Scale employing a conversion factor obtained from the laboratory of the University of Heidelberg in Mannheim, Germany. Median follow-up of the study population was 50 months. Estimated 5-year cumulative incidences of complete hematologic response, complete cytogenetic response (CCyR) and major molecular response were 97.9%, 89.5% and 64.7%. Five-year probabilities of overall survival (OS), transformation-free survival (TFS: survival without disease transformation to the accelerated phase or blast crisis) and failure-free survival (FFS: survival without IM failure as defined by the 2009 European Leukemia Net recommendations) were 93.8%, 97.8% and 76%. Elevated BCR-ABL/GUSIS correlated with inferior probabilities of optimal response (p 〈 0.001), and lower rates of CCyR after 12 months of IM (p 〈 0.001). Moreover, high BCR-ABL/GUSIS transcripts were associated with lower probabilities of FFS (p 〈 0.001) and TFS (p=0.01). When we employed the 2009 European Leukemia Net criteria to subdivide our patient cohort in optimal responders, suboptimal responders and individuals failing IM, we found that increasingly elevated BCR-ABL/GUSIS transcripts accurately distinguished the three patient groups (optimal vs suboptimal p 〈 0.001; optimal vs resistant p 〈 0.001; suboptimal vs resistant p 〈 0.001). Furthermore, using receiver operating characteristic curves we found that progressively higher BCR-ABL/GUSIS levels at diagnosis defined quantitative transcript thresholds (15.96% for Optimal Response, 16.01% for EFS, 16.09% for FFS, 20.36% for TFS and 22.04% for OS) that separated low risk from high risk patients. Finally, we wanted to determine the concordance rates between BCR-ABL/GUSIS levels at diagnosis and early molecular responses (eMRs) at 3 and 6 months. We therefore employed the 15.96% BCR-ABL/GUSIS threshold to identify subjects with high ( 〈 15.96%) or low ( 〉 15.96%) probabilities of obtaining an Optimal Response and found that 69% of patients displaying 〈 15.96% BCR-ABL/GUSIS achieved 〈 10% BCR-ABL/ABLIS levels after 3 months of IM (p 〈 0.001). Likewise, 78% of subjects presenting 〈 15.96% BCR-ABL/GUSIS at diagnosis attained 〈 1% BCR-ABL/ABLIS after 6 months of therapy (p 〈 0.001). We conclude that high BCR-ABL transcripts at diagnosis measured by RQ-PCR employing GUS as a reference gene allow the identification of CML patients unlikely to benefit from IM that should receive alternative forms of treatment. Disclosures: Muller: Novartis, BMS, ARIAD: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, ARIAD: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.1495.1495

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 96-96

Abstract: The outcome of elderly patients with chronic myeloid leukemia (CML) treated with imatinib has been studied in several trials. However, there are no reports on the effects of different imatinib dosages in older vs. younger CML patients. Methods To evaluate the efficacy of imatinib in the elderly, we analyzed data from the German CML-Study IV, a randomized 5-arm trial designed to optimize imatinib therapy alone or in combination. There was no upper age limit for inclusion. Patients with BCR-ABL positive CML in chronic phase randomized to imatinib 400 mg/d (IM400) or imatinib 800 mg/d (IM800) were compared, stratified according to median age at diagnosis in western populations ≥ 65 years vs. 〈 65 years, regarding effectively administered imatinib dose, time to hematologic, cytogenetic and molecular remissions, adverse events (AEs), rates of progression to accelerated phase (AP) and blast crisis (BC), survival, and causes of death. The full 800 mg dose was given after a 6 weeks run-in period with imatinib 400 mg/d to avoid excessive cytopenias. The dose could then be reduced according to tolerability for maximum patients' compliance. Results From July 2002 through March 2012, 1,551 patients were randomized, 828 of these to IM400 or IM800. Median age of these patients was 52 years (IM400: 53 years; IM800: 51 years). 784 patients were evaluable for follow-up (IM400: 382; IM800: 402). 193 patients were ≥ 65 years, 591 〈 65 years. 110 patients (29%) on IM400 and 83 (21%) on IM800 were ≥ 65 years. Median observation time on IM400 was 63.0 months in the elderly and 67.6 months in the younger group, on IM800 50.9 months in the elderly and 50.1 months in the younger group. The median dose per day was lower for elderly patients on IM800 (421 mg/d for patients ≥ 65 years vs. 556 mg/d for patients 〈 65 years), with the highest median dose in the first year (466mg/d for patients ≥ 65 years vs. 630mg/d for patients 〈 65 years). The median dose for patients on IM400 was 400 mg/d for both age groups. There was no difference between age groups in achieving a complete hematologic remission or a complete cytogenetic remission, neither if IM400 and IM800 were combined, nor in an analysis according to treatment groups. Elderly patients on IM400 achieved major molecular remission (MMR) and deep molecular remission (MR4) significantly later than younger patients (18.1 vs. 15.9 months, p=0.013; 54.4 vs. 33.3 months, p=0.012, respectively) whereas no difference was detected for patients on IM800 (11.9 vs. 10.5 months; 24.2 vs. 26.1 months, respectively). Imatinib was well tolerated in elderly patients with only few WHO grade 3-4 AEs being more frequent in the elderly than in younger patients (dermatologic AEs on IM400: 5.4 vs. 0.4%; infections on IM800: 8.3 vs. 2.5%). There were no significant differences between age groups in probabilities of progression to AP or BC neither if IM400 and IM800 were combined, nor in an analysis according to treatment groups. Five-year age-adjusted relative survival for elderly patients was comparable to that of younger patients. Conclusion We could demonstrate that elderly patients achieved molecular remissions significantly later when treated with standard dose imatinib but not when treated with higher imatinib dosages. As the safety profile of IM800 in senior patients was favorable too we conclude, that the optimal dose for elderly patients could be higher than 400 mg/d. Disclosures: Müller: Ariad: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:Pfizer: Consultancy; ARIAD: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Travel Other. Hehlmann:BMS: Consultancy, Research Funding; Novartis: Research Funding. Saussele:BMS: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria; Novartis: Honoraria, Research Funding, Travel Other.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.96.96

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 355-355

Abstract: Abstract 355 Introduction: The prognostic relevance of variant t(9;22) and additional cytogenetic aberrations (ACA) at diagnosis of chronic myeloid leukemia (CML) is conflicting. Patients and Method: We used baseline and outcome data of 1028 patients (607 male, 421 female, median age 53, range 16–88) with chronic phase CML randomized to the German CML-Study IV (imatinib [IM] 800 mg [n=264] vs IM 400 mg [n=253] vs IM 400 mg + IFN [n=281] vs IM 400 mg after IFN failure [n=108] vs IM 400 mg + AraC [n=122] ) to investigate the impact of variant t(9;22) and of clonal ACA at diagnosis on time to complete cytogenetic remission (CCyR) and major molecular response (MMR), accepted markers of prognosis. Cytogenetic analysis was performed after 24- and/or 48 h culture on G-banded metaphases. If appropriate, fluorescent-in-situ-hybridization on metaphases was used in addition. Since lack of the Y chromosome is regarded as a negligible age-related, not leukemia-associated event, those patients were excluded from evaluation. Result: In total, 123/1028 patients (12%) showed additional cytogenetic findings at diagnosis: 52/1028 patients (5.1%) had variants of the t(9;22), 33/1028 patients (3.2%) lacked the Y chromosome, 38/1028 patients (3.7%) had other additional numerical or structural aberrations. 105/1028 patients (10.2%) had only one type of additional cytogenetic finding, while 18/1028 patients (1.8%) showed ≥ 2 types of additional cytogenetic findings. 905/1028 patients (88%) had no variant t(9;22) or ACA. Median age, sex and treatment were similarly distributed (Table 1). In 45/52 patients (86.5%) with variant t(9;22), one further chromosome was involved (three way translocation), whereas in 7/52 patients (13.5%) ≥ 2 chromosomes were involved (complex variant). No involvement of the chromosomes 10, 18, 20, 21, X, or Y has been found. For patients without variant t(9;22) and ACA, with variant t(9;22), with variant t(9;22) and ACA other than –Y, and with ACA other than -Y and variant t(9;22), median time (years) to CCyR was 0.98, 0.84, 1.08 and 1.34, median time (years) to MMR was 1.4, 1.55, 1.8 and 2.17, and probability (%, confidence interval) for 2 years overall survival was 0.97 (0.96-0.98), 0.96 (0.89-0.99), 0.95 (0.90-0.99) and 0.94 (0.85-0.99), respectively. There was no difference regarding time to CCyR, time to major molecular response (MMR) and 2 years overall survival between patients with variant t(9;22) or ACA compared to those without variant t(9;22) or ACA. Conclusion: We conclude that additional chromosomal abnormalities at diagnosis have no negative prognostic impact. This finding is hypothesis generating. For confirmation of this hypothesis longer observation of the course of patients with variant t(9;22) and ACA is needed. Disclosure: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership, Research Funding. German CML-Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; Roche: Research Funding; BMBF: Research Funding; Essex: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.355.355

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 892-892

Abstract: Abstract 892 Bosutinib (SKI-606) is an orally available, dual Src/Abl tyrosine kinase inhibitor (TKI) with minimal inhibitory activity against PDGFR or c-kit. This open-label, phase 1/2 study evaluated the safety and efficacy of bosutinib as third-line therapy in patients with Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML). Adults (aged ≥18 years) who had failed prior imatinib (IM) therapy and were resistant or intolerant to dasatinib (DAS; n = 35 and n = 51, respectively) or resistant to nilotinib (NIL; n = 28) received oral daily treatment with a starting dose of 500 mg bosutinib. Of the 118 patients enrolled, 46% were male, the median age was 56 years (range, 20–79 years), and the median time from CML diagnosis to start of bosutinib was 6.7 years (range, 0.6–19.2 years). The median daily dose of bosutinib was 446 mg (range, 140–563 mg). At week 24, 26% of patients achieved a major cytogenetic response (MCyR), including 13% with a complete cytogenetic response (CCyR; see Table). Cumulative response rates were 34% for MCyR and 22% for CCyR. The majority (81%) of patients who achieved a MCyR still retained their response as of the data snapshot date (median follow-up duration of 23 months). Comparable rates of response were observed across Bcr-Abl kinase domain mutations, except for the T315I mutation. The most frequently reported treatment-emergent adverse events (TEAEs; ≥20% of patients, all grades) were diarrhea (83%), nausea (45%), vomiting (36%), rash (26%), headache (25%), and fatigue (22%). The incidence of TEAEs was generally similar for DAS-resistant, DAS-intolerant, and NIL-resistant patients. Gastrointestinal events were predominantly grade 1/2, had an early onset, and usually subsided within the first 4 weeks of treatment. The only grade 3/4 TEAE reported in ≥5% of patients was diarrhea (8%). One grade 3 pleural effusion was observed in a patient with concomitant pneumonia and a history of recurrent pleural effusions on DAS. Grade 3/4 hematologic laboratory abnormalities included thrombocytopenia (23%), neutropenia (16%), and anemia (8%); all were usually transient. Other grade 3/4 laboratory abnormalities (≥5% of patients) included elevations of magnesium (12%), alanine transaminase (ALT; 7%), and lipase (5%). Grade 3/4 transaminase elevations were observed more frequently in NIL-resistant patients (ALT, 18% [grade 4, n = 1] ; aspartate transaminase [AST], 11% [grade 4, n = 1] ) compared with DAS-resistant/intolerant patients (ALT, 3–4%; AST, 0–3%). On-treatment QTcF interval prolongation was observed in 13 patients (11%), but was only grade 1/2 (≤500 msec) with a reported rate of arrhythmia of 〈 1%. Adverse events led to treatment discontinuation in 27% of DAS-intolerant patients, 14% of DAS-resistant patients, and 11% of NIL-resistant patients; thrombocytopenia (4%), neutropenia (3%), and increased ALT (3%) were the only events resulting in discontinuation of 〉 2 patients. In conclusion, bosutinib has an acceptable safety profile in patients with CP CML following failure of IM and DAS or NIL, with primarily low-grade and transient gastrointestinal TEAEs. Bosutinib also demonstrated clinical activity as a third-line therapy, with over one-third of patients achieving a MCyR. These results emphasize the therapeutic potential of bosutinib for CP CML patients with resistance or, particularly, intolerance to other second-generation TKI therapies. Table 1: Table. IM failure + DAS resistant IM failure + DAS intolerant IM failure + NIL resistant Total Cytogenetic response at week 24, n (%)     Evaluablea 26 29 15 70     MCyR 5 (19) 9 (31) 4 (27) 18 (26)       CCyR 2 (8) 5 (17) 2 (13) 9 (13) Cytogenetic response(cumulative), n (%)     Evaluableb 32 38 21 91     MCyR 10 (31) 14 (37) 7 (33) 31 (34)       CCyR 3 (9) 13 (34) 4 (19) 20 (22) Patients retaining MCyR at time of latest data snapshot, n (%) 7 (70) 11 (79) 7 (100) 25 (81) Median follow-up time (range), months 12 (3–47) 27 (0.3–43) 7 (1–42) 23 (0.3–47) Median duration of MCyR (range), weeks 24 (6–64) 68 (7–124) 18 (6–185) 37 (6–185) a Evaluable patients had baseline and week 24 cytogenetic assessments. Patients who had experienced early progression or death before having a post-baseline assessment were also evaluable. b Evaluable patients had baseline and post-baseline cytogenetic assessments. Patients who had experienced early progression or death before having a post-baseline assessment were also evaluable. Disclosures: Khoury: BMS, Novartis: Honoraria. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gambacorti-Passerini:Pfizer Inc: Research Funding. Hochhaus:Novartis, BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer Inc: Research Funding. Dorlhiac-Llacer:Novartis: Research Funding; BMS: Research Funding; Pfizer Inc: Research Funding. Kelly:Pfizer Inc: Employment, Equity Ownership. Besson:Pfizer Inc: Employment, Equity Ownership. McMullan:Pfizer Inc: Employment, Equity Ownership. Kantarjian:Pfizer, Novartis, BMS: Research Funding; Novartis: Consultancy. Cortes:Pfizer Inc: Consultancy, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.892.892

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 119, No. 12 ( 2012-03-22), p. 2965-2966

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2012-01-405373

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 121, No. 18 ( 2013-05-02), p. 3703-3708

Abstract: Frontline nilotinib led to fewer, less diverse BCR-ABL mutations than imatinib in patients with chronic myeloid leukemia in chronic phase. Rates of progression to accelerated phase/blast crisis were lower with nilotinib than imatinib in patients with emergent BCR-ABL mutations.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2012-04-423418

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 6 ( 2013-08-08), p. 872-884

Abstract: Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ≤10% at 3 months, 〈 1% at 6 months, and ≤0.1% from 12 months onward define optimal response, whereas 〉 10% at 6 months and 〉 1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome–positive [Ph+] 〉 95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2013-05-501569

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 152-152

Abstract: Background: The randomized, phase 3 DASISION trial demonstrated improved efficacy with dasatinib compared with imatinib in treatment-naïve CML-CP patients (pts). Dasatinib was also well tolerated, and demonstrated a faster response at 3 months. Here, we report the results of the final, 5-year analysis of DASISION. Methods: Pts with newly diagnosed CML-CP were randomized to receive dasatinib 100 mg once daily (n=259) or imatinib 400 mg once daily (n=260) as previously reported. The primary endpoint was confirmed complete cytogenetic response (cCCyR) by 12 months. Long-term efficacy and safety data from pts with the predefined minimum 5 years of study treatment are presented. Results: Sixty-one percent of dasatinib-treated pts and 63% of imatinib-treated pts were still on their initial study therapy at study end. Cytogenetic and molecular response rates continued to be higher for dasatinib compared with imatinib (intent-to-treat population). Specifically, the rate of cCCyR by 5 years was higher with dasatinib versus imatinib (83% vs 78%, P=.187), as were the rates of major molecular response (MMR; BCR-ABL ≤0.1%; 76% vs 64%, P=.002) and MR4.5 (BCR-ABL ≤0.0032% IS; 42% vs 33%, P=.025) by 5 years. Time to cCCyR (hazard ratio [95% confidence interval] =1.46 [1.20–1.77], P=.0001) and MMR (hazard ratio [95% confidence interval] =1.54 [1.25–1.89], P 〈 .0001) in all randomized pts were faster with dasatinib (Figure 1). Transformations to both accelerated (AP) and blast phase (BP) CML were reported on study or after discontinuation with fewer cases overall for dasatinib (n=12/259; 4.6%) compared with imatinib (n=19/260; 7.3%). Five-year progression-free survival (PFS) and overall survival (OS) rates were similar across treatment arms (PFS: 85% [dasatinib], 86% [imatinib] ; OS: 91% [dasatinib], 90% [imatinib] ). A higher proportion of pts on dasatinib achieved BCR-ABL ≤10% at 3 months (84%) compared with those on imatinib (64%). For pts who achieved BCR-ABL ≤10% versus 〉 10% at 3 months, improved PFS, OS, and lower rates of transformation to AP/BP have been previously reported and were maintained at 5 years for dasatinib (PFS: 89% vs 72%, P=.0014; OS: 94% vs 81%, P=.0028; transformation n=6/198 [3%] vs n=5/37 [14%] ) and imatinib (PFS: 93% vs 72%, P 〈 .0001; OS: 95% vs 81%, P=.0003; transformation: n=5/154 [3%] vs n=13/85 [15%] ). Between 4 and 5 years, the number of mutations increased slightly in dasatinib-treated pts (12 pts at 4 years; 15 pts at 5 years), and the spectrum remained the same. No new, unexpected safety events were identified in either treatment arm at 5 years. However, the total incidence of pleural effusion continued to increase each year in dasatinib-treated pts (29% overall). Most cases of pleural effusion were grade 1/2 (n=67/74), and the median time to first grade 1/2 pleural effusion was 114 weeks (range, 4–299 weeks). Discontinuation of dasatinib due to pleural effusion occurred in only 15 pts (6% overall; 20% of pts who experienced a pleural effusion). Arterial ischemic events overall were not common, occurring in 12 pts (5%) on dasatinib and 6 pts (2%) on imatinib. Cardiovascular (CV) ischemic events and transient ischemic attack were reported in 10 and 2 dasatinib-treated pts, respectively. CV ischemic and peripheral arterial occlusive events were reported in 4 and 2 imatinib-treated pts, respectively. Of the pts with overall arterial ischemic events, 8 pts on dasatinib and 3 pts on imatinib had a history and/or risk factors for atherosclerosis. Fourteen dasatinib-treated pts experienced pulmonary hypertension by 2D echocardiogram, with right heart catheterization (RHC) performed in 1; 6 discontinued therapy. No pts were diagnosed with World Health Organization Group 1 pulmonary arterial hypertension (confirmed by RHC). Conclusion: At 5 years, dasatinib 100 mg once daily has demonstrated superior outcome compared to imatinib 400 mg once daily as initial therapy for CML. This is manifested by a faster time to cytogenetic and molecular responses, with more pts achieving BCR-ABL ≤10% at 3 months, sustained higher cumulative rates of response, and a lower rate of transformation. The 5-year rates of PFS and OS were equal in both arms. After 5 years, no new safety signals have been reported. These consistent results suggest that dasatinib offers meaningful advantages for pts with newly diagnosed CML-CP and remains a standard of care in this setting. Figure 1 Figure 1. Disclosures Cortes: ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Saglio:Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; BMS: Consultancy, Fees for occasional speeches Other. Baccarani:Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Kantarjian:ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding. Mayer:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Shah:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding. Chuah:Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Bradley-Garelik:Bristol-Myers Squibb: Employment. Manos:Bristol-Myers Squibb: Employment. Hochhaus:Novartis: Research Funding; BMS: Research Funding; MSD: Research Funding; Ariad: Research Funding; Pfizer: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.152.152

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 4552-4552

Abstract: Background: Resistance to tyrosine kinase inhibitors (TKIs) in patients (pts) with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib is the only approved oral TKI that inhibits the T315I mutant, which is uniformly resistant to other TKIs. Here we report long-term follow-up of the efficacy and safety of ponatinib in pts with the T315I mutation at baseline from the Phase 1 (Ph1) and PACE trials. Methods: The Ph1 trial (NCT01207440) evaluated safety and anti-leukemic activity of ponatinib (2-60 mg qd) in pts with CML or Ph+ ALL (N=81); the PACE trial (NCT00660920) evaluated efficacy and safety of ponatinib (45 mg qd) in CML and Ph+ ALL pts (N=449) resistant/intolerant to dasatinib or nilotinib or with the T315I mutation. Data reported are for pts with the T315I mutation at baseline, detected by Sanger sequencing at a central lab. Results: The Ph1 and PACE trials included 19 (29%) and 128 (29%) pts with the T315I mutation, respectively. Median age and median time since diagnosis were 47 and 2.7 years for Ph1, and 53 and 3.6 years for PACE.Pts were heavily pretreated: 89% in Ph1 and 84% in PACE had received ≥2 prior TKIs. As of Jan 6, 2014, median follow-up was 42 (1-59) months in Ph1, and 20 (0.1-40) months in PACE; 58% Ph1 (92% CP-CML) and 33% PACE (52% CP-CML) pts remained on study. Most-common reasons for discontinuation: administrative decision (16%) and progressive disease (16%) for Ph1, and progressive disease (31%) and adverse events (AEs; 13%) for PACE. Of the pooled chronic phase (CP)-CML pts, 75%, 72%, and 61% achieved MCyR, CCyR, and MMR, respectively, with deeper responses (MR4, MR4.5) observed in over a third of the pts (Table). MaHR was achieved in 58%, 27% and 38% of pooled AP-CML, BP-CML and Ph+ ALL pts, respectively. For Ph 1 CP-CML pts, 3-year CCyR duration estimates were 80%. For PACE CP-CML pts, 2-year MCyR/CCyR duration, PFS and OS estimates were 93%/79%, 72% and 82%, respectively. Only 1 CP-CML pt in PACE lost MCyR and 1 transformed to AP-CML. For AP-CML, BP-CML, and Ph+ ALL, estimated OS/PFS at 2 years was 69%/54%, 14%/10%, and 10%/N/A, respectively. The most frequent treatment-emergent AEs (TEAEs) observed in Ph1 CP-CML pts were dry skin (83%), rash (83%), arthralgia (75%), fatigue (75%), headache (67%), abdominal pain (58%), hypertension (58%), hypertriglyceridemia (58%), myalgia (58%), and nausea (58%). None of the 19 serious TEAEs that occurred in Ph1 CP-CML pts occurred in 〉 1 pt. The most common (≥25%) TEAEs in PACE CP-CML pts were rash (48%), dry skin (42%), headache (41%), abdominal pain (39%), nausea (36%), constipation (33%), fatigue (33%), thrombocytopenia (28%), myalgia (28%), hypertension (27%), arthralgia (25%), and upper respiratory tract infection (25%). Most common (≥5 %) serious TEAEs in PACE CP-CML pts were acute myocardial infarction (8%), pancreatitis (8%), atrial fibrillation (6%), coronary artery disease (6%), congestive cardiac failure (5%), pneumonia (5%), cerebral infarction (5%), pyrexia (5%), increased lipase (5%), and dyspnea (5%). Arterial thrombotic events occurred in 1 (8%) Ph1, and 20 (31%) PACE pts. Venous thromboembolic events occurred in 1 (8%) Ph1, and 3 (5%) PACE pts. Despite the higher median dose intensity for T315I CP-CML pts (38 vs 30.8 mg/day overall CP-CML) in PACE, the safety profiles were similar. For CP-CML pts in PACE, responses achieved by 12 months were generally maintained after dose reduction primarily to manage AEs: 100% maintained MCyR; 100% maintained CCyR, and 79% maintained MMR. Conclusions: In Ph+ leukemia pts with the T315I mutation, where effective treatment options are limited, ponatinib continued to exhibit deep and durable responses with up to 6 years follow-up. Dose reductions to manage AEs did not impact maintenance of cytogenetic responses. The response rates and safety profile of T315I pts were comparable to, if not better than, those observed in the overall population of refractory CML and Ph+ ALL pts in ponatinib clinical trials. Table. Responses at Any Time in Ponatinib Treated Pts with T315I Mutation Phase 1 PACE Phase 1 and PACE Pooled n (%) n (%) n (%) CP-CML N=12 N=64 N=76 MCyR 11 (92) 46 (72) 57 (75) CCyR 10 (83) 45 (70) 55 (72) MMR 9 (75) 37 (58) 46 (61) MR4 7 (58) 25 (39) 32 (42) MR4.5 4 (33) 21 (33) 25 (33) AP-CML N=1 N=18 N=19 MaHR 0 11 (61) 11 (58) BP-CML N=2 N=24 N=26 MaHR 0 7 (29) 7 (27) Ph+ ALL N=4 N=22 N=26 MaHR 2 (50) 8 (36) 10 (38) Disclosures Mauro: ARIAD Pharmaceuticals, Inc.: Consultancy. Cortes:ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Guilhot:ARIAD Pharmaceuticals, Inc.: Honoraria. Deininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Kantarjian:ARIAD Pharmaceuticals, Inc., Pfizer, Amgen: Research Funding. Shah:ARIAD Pharmaceuticals, Inc., BMS: Research Funding. Flinn:ARIAD Pharmaceuticals, Inc.: Research Funding. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.4552.4552

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7