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In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 470-470

Abstract: Dasatinib (SPRYCEL®), a potent inhibitor of BCR-ABL and SRC-family kinases, has been shown to be effective and safe for patients with accelerated-phase chronic myelogenous leukemia (AP-CML) who are resistant or intolerant to imatinib. START-A is a 39-center, international study to which patients with AP-CML who failed prior imatinib therapy were enrolled between December 2004 and July 2005. Here we report an update of the efficacy and safety of dasatinib (70 mg BID) from this open-label study of 174 patients with imatinib-resistant (n=161) or -intolerant (n=13) AP-CML after a median follow-up of 14.1 mo (range 0.1–21.7). Dose escalation (100 mg BID) or reduction (50 or 40 mg BID) were allowed for a lack of response or toxicity, respectively. Median time from original diagnosis of CML was 82 mo (range 4–359). Prior therapy included interferon-α in 72% of patients and stem-cell transplantation (SCT) in 13%; 52% had received prior imatinib doses 〉 600 mg/d and 59% treatment with imatinib for 〉 3 years. Best response to prior imatinib therapy was complete hematologic response (CHR) in 79% of patients, major cytogenetic response (MCyR) in 33%, and complete cytogenetic response (CCyR) in 21%. CHRs were attained by 45% of patients, while MCyRs and CCyRs were seen in 39% and 32%, respectively. Responses were achieved irrespective of imatinib status (with MCyR of 39% for both imatinib-resistant and -intolerant subgroups), prior stem-cell transplantation (26% MCyR), or the presence of prior BCR-ABL mutations (with the exception of T315I) (40% MCyR for both the mutation-positive and -negative subgroups). Twelve-month progression-free survival and overall survival were 66% and 82%, respectively. Dose interruptions were required for 85% of patients and dose reduction for 65%; the average daily dose administered was 126 mg (range 32–196). Grade 3–4 neutropenia and thrombocytopenia were reported in 76% and 82% of patients. Non-hematologic toxicity was generally mild to moderate and consisted primarily of diarrhea (52% all grades, 8% grade 3–4), headache (29%, 〈 1%), nausea (28%, 〈 1%), pleural effusion (27%, 5%), fatigue (26%, 4%), and superficial edema (22%, 1%). Dasatinib is effective in patients with AP-CML following imatinib treatment failure and the overall benefit-risk evaluation is favorable in this poor prognosis population. Updated analyses corresponding to a minimum follow-up of 2 years on all patients will be presented.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V110.11.470.470

Language: English

Publisher: American Society of Hematology

Publication Date: 2007

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2993-2993

Abstract: Abstract 2993 High-dose chemotherapy followed by autologous stem cell transplantation is an approved therapeutic intervention in relapsed Hodgkin-lymphoma (HL) and Non-Hodgkin lymphoma (NHL). In multiple myeloma (MM) it remains standard of care in first remission. Unfortunately, a significant portion of patients fail to mobilize and collect a sufficient amount of hematopoietic stem cells, being considered as “poor-mobilizers”. The effectiveness of the hematopoietic stem cell mobilizing agent plerixafor was evaluated in nationwide compassionate use programs in 13 European countries and reported to the European Consortium of Stem Cell Mobilization (ECOSM). Here we describe the mobilization success of 580 proven poor-mobilizers (304 male, 276 female) with NHL, HL and MM in Europe between May 2008 and August 2009. Furthermore, we analyzed the mobilization of stem cells in major NHL subgroups. All patients received plerixafor plus granulocyte colony-stimulating factor in standard doses with or without chemotherapy. Two-hundred seventy patients with NHL (138 male, 132 female) with a median age of 56 years (range 12 – 75 years) and a median of two prior chemotherapy regimens (range 0 – 10) were enrolled. Median cell yield was 2.56 × 10 ^6 CD34+ cells/kg BW (range 0 – 17.37). The general accepted minimum of 2.0 × 10 ^6 CD34+ cells / kg bodyweight (BW) for transplantation was reached by 175 patients (64.8%) in a median of two apheresis sessions (range 1 – 4). Thirty-four patients (12.6%) yielded more than 5.0 × 10 ^6 CD34+ cells/kg BW. There were no significant differences in in stem cell harvests regarding number of prior mobilization attempts or number of prior chemotherapeutic regimens, as well as in comparing patients with diffuse large B cell lymphoma (n=28), follicular lymphoma (n=15), and mantle cell lymphoma (n=24), respectively. Fifty-four HL patients (24 male, 30 female) with a median age of 36 years (range 19 – 76) and a median of three prior lines of therapy (range 1 – 5) were enrolled. Median cell yield was 3.14 × 10^6 CD34 cells/kg BW (range 0 – 32.6). Forty-four patients (81.5%) collected the minimum of 2.0 × 10^6 CD34+ cells/kg BW in a median of two apheresis sessions (range 1 – 4). Twelve patients (22.2%) collected more than 5.0 × 10 ^6 CD34+ cells/kg BW. A total of 256 patients (148 male, 108 female) with a median age of 60 years (range 28 – 76) diagnosed with MM were enrolled. Patients had received a median of two prior lines of treatment and collected a median of 3.60 × 10 ^6 CD34+ cells/kg BW (range 0 – 15.27) in a median of two apheresis sessions (range 1 – 5). The minimum of 2.0 × 10 ^6 CD34+ cells/kg BW was collected by 209 patients (81.6%). Eighty-two patients (32.0%) yielded more than 5.0 × 10 ^6 CD34+ cells/kg BW allowing tandem transplantation. Overall, the CD34+ cell yield was significantly higher in MM patients than in NHL patients (p 〈 0.0001) and also significantly higher in HL patients than in NHL patients (p =0.013). CD34+ cell yield was not statistically significant between MM patients and HL patients. Furthermore, the number of patients collecting the minimum of 2.0 × 10 ^6 CD34+ cells/kg BW was significantly higher in MM patients compared to NHL patients (p 〈 0.0001) and also significantly higher in HL compared to NHL patients (p =0.017). Analyzing the mobilization strategies and collection success of individual countries demonstrated only minor variations compared to the global results. Chemomobilization and steady state mobilization are used in most countries; however, there is a clear preference for chemotherapy combined with G-CSF/plerixafor in the Czech Republic, Germany, Hungary, Italy and Poland. The data emphasize the role of plerixafor in patients who failed prior mobilization attempts, but the development of improved strategies in poor mobilizers especially with NHL is required. Disclosures: Duarte: Genzyme: Membership on an entity's Board of Directors or advisory committees. Kröger:Genzyme: Membership on an entity's Board of Directors or advisory committees. Mohty:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hübel:Genzyme: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.2993.2993

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 96, No. 8 ( 2000-10-15), p. 2712-2716

Abstract: An analysis was performed of the response to treatment with donor lymphocyte infusions (DLI) and the survival in 66 consecutive patients who relapsed after primary treatment by allogeneic stem cell transplantation for BCR-ABL–positive chronic myeloid leukemia. The transplant donor was an HLA-identical sibling (n = 35) or a “matched” unrelated volunteer (n = 31). Fifty-seven patients were transplanted in chronic phase, eight in accelerated phase, and one in second chronic phase. The recognition of relapse was based on precise molecular, cytogenetic, or hematologic criteria. The median interval from transplant to relapse was 12 months (range 3-85). The median interval from relapse to initiation of DLI was 9.4 months (range 1-70). Patients received DLI from their original transplant donors on a bulk-dose (n = 34) or on an escalating-dose (n = 32) regimen. Patients were monitored serially by hematologic, cytogenetic, and molecular criteria. Molecular remission was defined by the finding of negative results by nested primer reverse transcriptase polymerase chain reaction (RT-PCR) for BCR-ABL transcripts on two consecutive occasions, subject to satisfactory controls. Forty-four patients (67%) achieved molecular remission. Patients who had relapsed to advanced phase disease and patients with short intervals between transplant and relapse had significantly lower probabilities of achieving molecular remission. Of the 44 patients who achieved molecular remission, 4 reverted to a PCR-positive status at 15, 18, 37, and 87 weeks after remission. The probability of survival for patients who achieved molecular remission was significantly better than for those who failed to do so (95% versus 53% at 3 years post-DLI,P = .0001). We conclude that the majority of molecular remissions after DLI are durable, and thus the majority of responding patients may prove to have been cured.

Type of Medium: Online Resource

ISSN: 1528-0020 , 0006-4971

URL: Article

DOI: 10.1182/blood.V96.8.2712

Language: English

Publisher: American Society of Hematology

Publication Date: 2000

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2795-2795

Abstract: Background: Individuals with Gilbert's syndrome present with mild, unconjugated hyperbilirubinaemia, resulting from impaired glucuronidation by reduced uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) expression. The A(TA)7TAA polymorphism responsible for the syndrome has been associated with nilotinib-induced hyperbilirubinaemia in patients with chronic myeloid leukaemia (CML). Our study extends UGT1A1 molecular analysis to a larger cohort of CML patients receiving other tyrosine kinase inhibitors (TKIs) and explores the relationship with other abnormalities of liver function. Methods: We interrogated our database of 832 patients treated with a TKI for CML at our center and identified 467 individuals who presented in first chronic phase, who had received only a TKI (prior interferon, combination experimental therapy, autologous and allogeneic transplant patients were all excluded) and for whom serial liver function results were available. We then performed PCR to identify variations in dinucleotide repeats in the UGT1A1 promoter region. Genotypes were assigned as follows: 6/6 (homozygous for (TA)6 allele; wild-type), 7/7 (homozygous for (TA)7allele) and 6/7 (heterozygous). Because individual patients may have received more than one TKI, we defined the period on treatment with each TKI as an 'episode' in order to be able to attribute abnormalities of liver function to a specific drug. Hyperbilirubinaemia was graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Both ALT and ALP were defined as increased if they were above the upper limit of normal. To date we have completed the analysis for 340 patients comprising a total of 568 episodes of TKI therapy (imatinib 313, dasatinib 125, nilotinib 130). Results: The UGT1A1 genotype analysis showed six variants. The majority of patients displayed one of 6/6 (149 patients), 6/7 (138 patients) or 7/7 (48 patients) genotypes. Small numbers of patients with the 5/6, 5/7 and 6/8 genotypes were excluded from further analysis. Hyperbilirubinaemia was seen in patients with all three genotypes, but was more frequent in patients on nilotinib (44%), compared to imatinib (14%) and dasatinib (8%). The incidence of hyperbilirubinaemia in individuals with the 6/6 genotype was 6%, 0% and 22% for imatinib, dasatinib and nilotinib respectively, and 10%, 6% and 56% for patients with the 6/7 genotype. The frequency of hyperbilirubinaemia in those with the 7/7 genotype was significantly higher compared to the occurrence of such events in any other genotype, irrespective of treatment. However, it occurred more often in patients on nilotinib (80%), followed by imatinib (61%) and dasatinib (44%). A significantly higher number of patients with the 7/7 genotype on nilotinib reported Grade 3 hyperbilirubinaemia (25%), with no grade 3 events on imatinib and only one on dasatinib. Hyperbilirubinaemia on any single drug did not predict for this event on any subsequent drug. Further analysis of liver function tests (LFTs) and bilirubin levels divided episodes into four groups: 1. Episodes with normal bilirubin and normal LFTs (n = 273), 2. Episodes with isolated raised LFTs but normal bilirubin (n = 179), 3. Episodes with isolated hyperbilirubinaemia (n = 27) but normal LFTs and 4. Episodes with raised bilirubin and raised LFTs (n = 84). Abnormal LFTs with or without hyperbilirubinaemia were most commonly seen on nilotinib (65%) compared to imatinib (40%) and dasatinib (46%), confirming previous reports of the frequencies of transaminitis on the various TKIs. Isolated hyperbilirubnaemia was uncommon ( 〈 6%) on any of the drugs, but was more frequent in the 7/7 than the 6/6 or 6/7 genotypes for imatinib or dasatinib. Interestingly it was not seen in patients with the 7/7 genotype on nilotinib, as 80% of the 7/7 patients with hyperblirubinaemia on nilotinib had other abnormalities of liver function. Conclusion. We confirmed the increased risk of hyperbilirubinaemia in individuals with the A(TA)7TAA polymorphism when treated with nilotinib. In contrast to other reports, we found that all patients with the 7/7 genotype are susceptible to increases in bilirubin when treated with any of imatinib, dasatinib or nilotinib. Hyperbilirubinaemia most commonly occurs alongside elevations in LFTs on nilotinib, indicating a nilotinib-induced hepatotoxicity that is compounded by the additional UGT1A1 inhibition. Disclosures Milojkovic: ARIAD Pharmaceuticals Inc.: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Apperley:Pfizer: Honoraria; Bristol Myers Squibb: Honoraria; Ariad: Honoraria; Novartis: Honoraria. Foroni:Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Ariad: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.2795.2795

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3515-3515

Abstract: Abstract 3515 With the advent of tyrosine kinase inhibitors (TKI), allogeneic stem cell transplantation (allo-SCT) is largely reserved for patients with CML who do not achieve durable cytogenetic responses to TKIs or patients with advanced phase (Adv) disease. Data relating to the outcome of transplant in Adv-CML is limited. We have allografted 43 patients (median age 40.8 yrs) for Adv phase disease who had received prior treatment with one or more TKI. The indications for allo-SCT included progression from CP to accelerated phase (AP) (n=16) or blast crisis (BC) (n=11) on TKI and presentation in accelerated phase (AP) (n=9) or blast crisis (BC) (n=7). The median duration of TKI therapy prior to transplantation was 5.5 months (range 1–51 months); 42 patients received imatinib, 9 received dasatinib (8 following imatinib failure), 2 received nilotinib (following imatinib and dasatinib failure). 35 patients were transplanted from HLA-identical siblings and 36 patients received myeloablative conditioning. The status at transplant was CP 〉 1 in 17 patients, AP in 24, and BC in 2. In patients in whom CP was restored prior to transplant (n=17), this had been achieved using a TKI only in 6 and with combination chemotherapy in 11. There was no difference in disease-free survival (DFS) or overall survival (OS) between the TKI only group and the group that received chemotherapy in addition. Among the 43 patients in the TKI-treated cohort, 13 died without relapse, 3 from graft versus host disease (GVHD), 8 from sepsis, pneumonitis and multiorgan failure, and one each from graft failure and VOD. The estimated probabilities of non-relapse mortality (NRM) at 100 days and 1 year were 17.3% and 43.3%, Grade 2–4 acute GVHD was seen in 24% and extensive cGVHD in 54%. The estimated 1- and 3-year DFS rates were 23% and 16%. The 1 year and 3 year estimates of overall survival according to disease stage at allo-SCT were as follows: AP (54.2% and 50%), CP 〉 1 (49.4% and 29.6%) and BC disease 0% and 0%. The impact of maximal disease stage was examined, documented as either AP (23/43 patients) or BP (20/43 patients) at any time prior to allo-SCT. The probability of 3 year OS for patients who were in AP at maximal disease stage was 61% compared to 33% of patients who had at one time been in BC (p=0.04). Post allo-SCT, patients were monitored for relapse by RQ-PCR. Eleven patients received TKIs, 5 for molecular relapse, 1 for cytogenetic relapse, 4 for hematological relapse and 1 for GvHD. Three of the 11 remain alive, 2 of whom received a TKI for molecular relapse.We compared the outcome of these 43 patients with that of 158 patients who were transplanted for Adv-CML but who had been treated before TKI became available. The disease status at time of transplant was AP (n=90), CP 〉 1 (n=41) and BC (n=27). The two groups were matched for type of donor, conditioning regimens and time from diagnosis to transplant but the historical group were younger at allo-SCT with a median age of 33.3 yrs (p=0.001). There were no significant differences in the incidences of acute and chronic GvHD, NRM, DFS or OS between the two groups. The 1 year and 3 year estimates of OS for the historical cohort were 46.4% and 38.5% in AP, 53.7% and 24.3% for CP 〉 1 and 7% and 0% in BC. For the total group of 201 patients the outcome of transplant defined as 3yr OS was 40.9% for AP 25.7% for CP 〉 1 and 0% for BC. In conclusion, we found that patients receiving transplant for advanced phase disease after prior treatment with a TKI have similar outcomes to a historical group of advanced phase patients transplanted prior to the advent of TKI therapy. Our data strongly support the influence of disease stage in prediction of allo-SCT survival. Allo-SCT may be valuable for CML patients who have never progressed to BC. Overt BC is a predictor of poor allo-SCT outcome, so attempts should be made to restore CP prior to allo-SCT. Close monitoring of patients still classifiable as AP who are responding poorly to TKI should permit identification of those who may do well if offered allo-SCT before their disease has progressed further. Disclosures: Marin: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.3515.3515

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 4025-4025

Abstract: Introduction: Ponatinib is a potent oral tyrosine kinase inhibitor (TKI) approved for use in patients with refractory CML and Ph+ ALL, including patients with the resistant BCR-ABLT315I mutation. To evaluate whether patient characteristics and outcomes with ponatinib differed by extent of pretreatment with other TKIs, this post hoc analysis examines results among CP-CML patients enrolled in the phase 2 PACE trial (NCT01207440) according to the number of TKIs received prior to study entry. Updated data with 4 years of follow-up will be presented. Methods: Patients with CML or Ph+ ALL who were resistant or intolerant to dasatinib or nilotinib or who had the T315I mutation were enrolled (N=449). Ponatinib was initiated at 45 mg once daily. CP-CML patients were evaluated based on previous treatment with 1, 2, 3, or 4 prior TKIs approved for use in CP-CML (ie, imatinib, dasatinib, nilotinib, and bosutinib). Data reported in this abstract are as of February 2, 2015. Results: Overall, 270 CP-CML patients were enrolled and treated in PACE. Patient characteristics and disposition varied by number of prior TKIs (Table 1). Both median age and median time from diagnosis increased with number of prior TKIs; median dose intensity was highest in patients who had received only 1 prior TKI. The most common reasons for discontinuation across groups were adverse events (AEs) and withdrawal by patient request. Responses by number of prior TKIs are shown in Table 2. Rates of cytogenetic and molecular response to ponatinib were higher with fewer prior TKIs. While the frequency of individual AEs did not follow a consistent trend, the incidence of grade ≥3 AEs appeared to increase with the number of prior TKIs received (68%, 86%, 89%, and 100%, respectively); grade ≥3 AEs in ≥10% of CP-CML patients overall were thrombocytopenia (35%), neutropenia (17%), hypertension (13%), increased lipase (12%), and abdominal pain (10%). A similar frequency pattern was observed for serious AEs, which occurred in 58%, 53%, 62%, and 92% of patients who had previously received 1, 2, 3, and 4 approved TKIs, respectively. Serious AEs in ≥5% of CP-CML patients overall were pancreatitis (7%), angina pectoris (5%), and pneumonia (5%). The frequency of arterial occlusive events (AOEs) was 32% (6/19), 26% (25/98), 28% (39/141), and 42% (5/12) by increasing number of prior TKIs; exposure-adjusted incidence rates of new AOEs were 11.75, 10.4, 12.6, and 33.3 events per 100 patient-years, respectively. Conclusions: With 4 years of follow-up, ponatinib continues to provide benefit to ongoing CP-CML patients in the PACE trial. Analysis by treatment history indicates that patients who had received fewer TKIs prior to study entry appear to exhibit better efficacy and safety profiles. However, treatment decisions should be primarily guided by individual patient and disease factors, including mutation status, and physicians should weigh both the benefits and risks of prescribing ponatinib. Table 1. Patient Characteristics and Disposition by Number of Prior TKIs 1 TKI (n=19) 2 TKIs (n=98) 3 TKIs (n=141) 4 TKIs (n=12) Median age at baseline, years 52 58 63 67 Median time from diagnosis to first dose, years 2.8 5.2 7.9 12.4 Median dose intensity, mg/d 34.0 28.7 29.9 31.0 Mutations detected at baseline, % 68 51 43 75 T315I mutation detected at baseline, % 63 31 16 0 Prior TKI exposure, %, imatinib/dasatinib/nilotinib/bosutinib 68/21/5/5 97/66/36/1 100/96/96/7 100/100/100/100 Remain on study, % 53 48 40 8 Discontinued, % 47 52 60 92 Primary reason for discontinuation, % AE 16 18 17 33 Withdrawal by patient request 5 11 11 25 Disease progression 16 5 13 0 Lack of efficacy 0 2 9 8 Death 0 2 3 17 Othera 11 13 8 8 Median follow-up, months 42.3 42.9 42.1 28.2 aIncludes noncompliance, physician decision, protocol violation, and other reasons Table 2 Responses to Ponatinib by Number of Prior TKIs 1 TKI (n=16a) 2 TKIs (n=98) 3 TKIs (n=141) 4 TKIs (n=12) MCyR 12 (75) 69 (70) 69 (49) 7 (58) CCyR 12 (75) 63 (64) 63 (45) 4 (33) MMR 10 (63) 41 (42) 51 (36) 1 (8) MR4 6 (38) 30 (31) 38 (27) 1 (8) MR4.5 4 (25) 22 (22) 34 (24) 1 (8) All responses are n (%) a16/19 patients were evaluable for efficacy Disclosures Hochhaus: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Cortes:ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role, Research Funding. Pinilla-Ibarz:Novartis: Consultancy, Other: Consulting & Advisory Role, Research Funding; ARIAD Pharmaceuticals, Inc.: Consultancy, Other: Consulting & Advisory Role, Research Funding; Teva: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: Consulting & Advisory Role, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Other: Consulting & Advisory Role, Speakers Bureau. le Coutre:Novartis: Honoraria; BMS: Honoraria; ARIAD Pharmaceuticals Inc.: Honoraria; Pfizer: Honoraria. Paquette:ARIAD Pharmaceuticals Inc.: Honoraria; BMS: Honoraria; Novartis: Honoraria. Chuah:Children International: Honoraria; Novartis: Honoraria; Bristol Meyers Squibb: Honoraria. Nicolini:Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Apperley:BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Talpaz:Pfizer: Other: CONSULTING OR ADVISORY ROLE; Novartis: Other: CONSULTING OR ADVISORY ROLE; ARIAD Pharmaceutical Inc.: Other: CONSULTING OR ADVISORY ROLE; Pfizer: Other: TRAVEL, ACCOMODATIONS, EXPENSES, Research Funding; Novartis: Other: TRAVEL, ACCOMODATIONS, EXPENSES, Research Funding; ARIAD Pharmaceutical Inc.: Other: TRAVEL, ACCOMODATIONS, EXPENSES, Research Funding; Incyte: Other: TRAVEL, ACCOMODATIONS, EXPENSES, Research Funding; Sanofi: Research Funding. DeAngelo:Incyte: Other: Consulting or Advisory Role; Pfizer: Other: Consulting or Advisory Role; Novartis: Other: Consulting or Advisory Role; BMS: Other: Consulting or Advisory Role; ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role; Amgen: Other: Consulting or Advisory Role. Abruzzese:BMS: Other: Consulting or Advisory Role; ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role; Novartis: Other: Consulting or Advisory Role; Pfizer: Other: Consulting or Advisory Role. Rea:Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Baccarani:Pfizer: Other: Travel, Accommodations, Expenses; BMS: Other: Travel, Accommodations, Expenses; Novartis: Other: Travel, Accommodations, Expenses; ARAID Pharmaceutical Inc.: Other: Consulting or Advisory Role, Speakers Bureau; Pfizer: Honoraria, Other: Consulting or Advisory Role, Speakers Bureau; Novartis: Honoraria, Other: Consulting or Advisory Role, Speakers Bureau; BMS: Honoraria, Speakers Bureau; ARIAD Pharmaceutical Inc.: Other: Travel, Accommodations, Expenses. Muller:ARIAD Pharmaceuticals Inc.: Honoraria, Other: Consulting & Advisory Role, Research Funding; Novartis: Honoraria, Other: Consulting or Advisory Role, Research Funding; BMS: Honoraria, Other: Consulting or Advisory Role, Research Funding. Lustgarten:ARIAD Pharmaceuticals Inc.: Employment, Equity Ownership, Other: Stock. Conlan:ARIAD Pharmaceuticals Inc.: Other: Stock. Rivera:ARIAD Pharmaceuticals Inc.: Employment, Other: Full-time Employee & Shareholder (self-managed). Guilhot:Celgene: Consultancy, Other: CONSULTING OR ADVISORY ROLE; Pfizer: Honoraria; Novartis: Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES. Deininger:Incyte: Consultancy, Honoraria, Other: Consulting or Advisory Role; Pfizer: Consultancy, Honoraria, Other: Consulting or Advisory Role; ARIAD Pharmaceutical Inc.: Consultancy, Honoraria, Other: Consulting or Advisory Role; Gilead: Research Funding; Celgene: Research Funding; Novartis: Consultancy, Honoraria, Other: Consulting or Advisory Role, Research Funding; BMS: Consultancy, Honoraria, Other: Consulting & Advisory Role, Research Funding. Hughes:Bristol-Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Shah:Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Plexxikon Inc.: Research Funding. Kantarjian:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Amgen: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.4025.4025

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 478-478

Abstract: Allogeneic transplantation continues to have a role in the management of high risk CML. However the place of reduced intensity (RIC) versus myeloablative conditioning (MAC) is uncertain in younger patients. A total of 2331 first HSCT’s performed from 1998–2005 were reported to the European Group for Blood and Marrow Transplantation Registry, RIC was used in 276 and MAC in 2055. Overall survivals were similar for the first 9 months. After 9 months the survival curves separated (HR for RIC 1.8, 95% CI 1.2–2.8 p=0.01). All estimates were based on time dependent Cox models and landmark analyses at 9 months. EBMT score was higher in the RIC group (score 0–2, 27% vs 52% p 〈 0.001) and was associated with 5-year survival estimates: EBMT score 0–2, 68% vs 68%, 3–4, 48% vs 56% and 5–7, 27% vs 33% for RIC and MAC respectively. Comparison of RIC and MAC is complicated by differences in patient characteristics. A propensity score was developed to adjust for these differences from a logistic regression model based on the following factors: age, use of PBSC, T cell depletion, disease phase, year, CMV status, sex mismatch, time to transplant and donor type. The propensity score predicts the likelihood of receiving a RIC (high score, RIC more likely). Adjusting for the propensity score compensates for the differences in the underlying covariates. Forty nine percent of RIC allografts were performed in centres reporting ≥5 RIC transplants. There was a significant interaction between propensity score, a centre’s RIC-activity and conditioning intensity on survival. Excluding centres not performing RIC to avoid bias and adjusting for propensity score, survival 〉 9 months was worse in RIC patients with a low propensity score when treated in centres with 〈 5 RICS (HR 2.4 CI 1.3–4.4) whereas survival 〉 9 months was equal in centres treating ≥5 patients with RIC who had a high propensity score (HR 0.8 CI 0.4–1.6). The figures below illustrate this showing the cumulative risk of non-relapse mortality, relapse and death after relapse for these groups estimated in a competing risk setting. Conclusion: Transplant centre experience and patient selection impact on outcome. Survival with RIC HSCT is inferior to MAC except for the subgroup of patients with a high propensity score transplanted at centres with ≥5 RIC HSCT. Low Propensity Score and 〈 5 RIC HSCT Low Propensity Score and 〈 5 RIC HSCT High propensity Score and ≥5 RIC HSCT High propensity Score and ≥5 RIC HSCT

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V110.11.478.478

Language: English

Publisher: American Society of Hematology

Publication Date: 2007

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3753-3753

Abstract: Abstract 3753 The tyrosine kinase inhibitors (TKIs) imatinib (IM), nilotinib (NIL) and dasatinib (DAS) are remarkably effective as single-agent therapy for chronic myeloid leukemia (CML) in chronic phase (CP). However little is known of their potential impact on the immune response. No human in vivo studies to assess how these molecular-targeted drugs affect immune function in patients are available and data from in vitro and animal studies with imatinib have been contradictory, ranging from impaired antigen-specific T-cell response to enhanced stimulation of tolerant T cells. Furthermore, although the immunomodulatory effects of TKIs on T cells, NK cells and dendritic cells have been explored in vitro, little is known of their potential impact on B cells. To characterize the in vivo immunomodulatory effects of TKIs, 51 patients with CP-CML in complete cytogenetic response (CCyR) on standard dose IM (n=26), DAS (n=14) or NIL (n=12) and 28 adult controls were recruited during two influenza seasons (2008 and 2009). Patients and controls were concomitantly immunized with an influenza vaccine (Ph. Eur. 2008/2009 or Ph. Eur. 2009/2010, CSL Biotherapies) and with the 23-valent polysaccharide pneumococcal vaccine (Pneumovax II; Sanofi Pasteur MSD). Peripheral blood mononuclear cells (PBMCs) and serum samples were collected from patients and donors prior to vaccination and T and B responses to vaccination were assessed at 4 weeks and at 2–3 months post-immunization. T-cell responses to influenza vaccine were analyzed quantitatively and qualitatively using flow cytometry and intracellular cytokine assay for TNF-α, IFN-γ, IL-2 and the cytotoxicity marker CD107a. Serum titers of IgM and IgG pneumococcal antibodies were determined by ELISA. Analysis of B cell subsets was performed using flow cytometry and correlated with the pneumococcal IgM and IgG humoral response. Following vaccination, Flu-specific T cells were detected in 24/51 (47.0%) patients on TKI and 15/24 (62.5%) healthy controls (p=0.16). Polyfunctional T-cell responses (defined as the production of 2 or more cytokines or one cytokine and the cytotoxic marker CD107a) were induced in 6/10 evaluable patients and 4/8 normal controls (p=1.0). T-cell independent humoral responses to vaccination were assessed in 45 patients and 12 healthy controls by measuring pneumococcal IgM titers. Four weeks postimmunization, 11/12 (92%) controls achieved IgM pneumococcal Ab titers 〉 80 U/ml compared to only 23/45 (53%) CML patients on TKI (p=0.010). The pneumococcal IgM titers were significantly lower in patients with CML on TKI compared to healthy controls (median, 89.0 U/ml, range 5–200 vs 200 U/ml, range 58–200, p=0.0006), suggesting that CML patients on TKI have impaired IgM responses to vaccination. To further characterize the humoral immune response to Pneumovax, we stratified CML patients based on their pneumococcal IgM titers. We found a significantly lower percentage of IgM memory B cell subset in CML patients who failed to mount a significant pneumococcal IgM response compared to patients who achieved a pneumococcal IgM response (median, 6.25% vs 16.4%, p=0.0059) and healthy controls (median, 6.25% vs 14.3%, p=0.0086). Furthermore, we found a significant correlation between anti-pneumococcal IgM titers and IgM memory B cell percentage (Spearman rank correlation test, r=0.61, p 〈 .0001). To investigate a putative role of TKIs for the loss of IgM memory B cell subsets in CML patients, we determined the frequencies of IgM memory B cells in paired samples collected from 15 CML-CP patients at diagnosis (i.e. prior to initiating IM) and once CCyR was achieved. We found a significant decrease in the percentage of IgM memory B cells in CML-CP patients treated with IM compared to the pre-treatment sample (median 9.4%, vs. 15.2% respectively, p=0.0023). In summary, patients with CML on TKIs can mount effective T-cell immune responses to influenza vaccination. Our data suggest that TKIs (IM, DAS and NIL) impair T-cell independent humoral immune responses, namely IgM responses to vaccination. This is associated with a loss of IgM memory B cell subsets. Further investigations to understand the mechanisms by which TKIs may impact B-cell subsets are underway. These results are of particular interest in terms of the long-term effects of TKI on tumor immune surveillance and susceptibility to infections and may have implication for vaccination strategies in CML patients. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.3753.3753

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 102, No. 7 ( 2003-10-01), p. 2702-2703

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2003-06-2042

Language: English

Publisher: American Society of Hematology

Publication Date: 2003

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