Safety and Efficacy of Dasatinib Treatment Change for Patients Previosly Treated with Imatinib with Late Warning Response. Results from the Phase II, Open, Multicenter Dasapost Study

Abstract Background: Current European LeukemiaNet (ELN) recommendations (ELN 2013) endorse closely monitoring, due to risk of failure, for patients with so called late warning response (patients with complete cytogenetic response without major molecular response after 12 months of treatment). In this situation, for patients initially treated with imatinib, previous studies have shown a benefit of treatment change to nilotinib in terms of the achievement of deeper molecular responses. However, the role of treatment change to dasatinib in this group of patients have not been evaluated. DASAPOST is the first clinical trial evaluating efficacy and safety of dasatinib in patients with late warning responses. Methods: We are presenting results of the 18 patients enrolled in the phase II, open, multicenter DASAPOST study (NCT01802450). Main inclusion criteria were patients previously treated with imatinib with late suboptimal response by ELN2009 (CCyR without MMR after 18 months of treatment). The primary end point was rate of MMR by 6 moths after treatment change to dasatinib. Secondary end points were rate of MMR by 12 months, rate of deep molecular responses, progression free survival and safety of treatment change. Results were expressed as the proportion of patients who achieved molecular responses in the intention-to-treat (ITT) population, considering as failure if the evaluation was not performed in a specific time point. All BCR-ABL/ABL (IS) measurements were centralized in an EUTOS laboratory. Results: From April 2013 to May 2015, 18 patients were enrolled in 12 Spanish centers. Median age was 59 years (39-77). The ratio of men to women was 13/5, and the risk groups according to Sokal Score were 48%, 30% and 22% for low, intermediate and high risk, respectively. Median time from diagnosis to treatment change to dasatinib was 2.6 years (1.6-23) and median time while on imatinib to achieve CCyR 1.4 years (0.2-12). Median exposure to imatinib was 2.4 years (1.6-14). Seventy-two percent of the patients achieved MMR by 6 months (primary endpoint). Rates of MMR and deeper molecular responses at different time points are shown in table 1. Of interest 9/18 patients (50%) achieved MR4 by 12 months. Treatment change to dasatinib was safe, with only 3 study discontinuations (16%), due to adverse events (AE) and 4 serious AE (congestive heart failure, acute gastroenteritis, pyelonephritis and pancreatitis (only congestive heart failure was related to dasatinib). Most commonly reported (>5%) drug-related AEs are shown in table 1. Conclusions: Our study shows, for the first time, that in patients treated with imatinib and with late warning responses, switching to Dasatinib induced MMR in 2 out every 3 patients, and MR4 in half of the patients by 6 months, with a good safety profile. Table 1 Most commonly reported (>5%) drug-related AEs Table 1. Most commonly reported (>5%) drug-related AEs Table Table. Disclosures García-Gutierrez: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Casado:Ariad: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria. Sánchez-Guijo:Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers-Squib: Consultancy, Honoraria. Martinez-Lopez:BMS: Research Funding. Steegmann:Ariad: Honoraria, Other: Research funding for the Spanish CML Group; Pfizer: Honoraria, Other: Research funding for the Spanish CML Group; BMS: Honoraria, Other: Research funding for the Spanish CML Group; Novartis: Honoraria, Other: Research funding for the Spanish CML Group.

Download Full-text

Time-Related Interpretation of Molecular Response Levels According to Long Term Overall and Progression-Free Survival of CML Patients on First-Line Imatinib Treatment

Blood ◽

10.1182/blood.v118.21.1681.1681 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1681-1681

Author(s):

Martin C. Müller ◽

Benjamin Hanfstein ◽

Michael Lauseker ◽

Philipp Erben ◽

Ulrike Proetel ◽

...

Keyword(s):

Disease Progression ◽

Research Funding ◽

Progression Free Survival ◽

Published Data ◽

Molecular Response ◽

Imatinib Treatment ◽

Prognostic Impact ◽

Treatment Change ◽

Free Survival ◽

Time Points

Abstract Abstract 1681 Introduction: The prognostic impact of different levels of molecular remission (BCR-ABL transcript expression according to International Scale, IS) at various time points on survival under imatinib treatment is still unclear. Whereas recently published data from the IRIS trial described relevant milestones at 6, 12, and 18 months for event-free and progression-free survival (PFS; Hughes et al., Blood 2010), little is known about an association of molecular response with overall survival (OS). The aim of this evaluation of the German CML Study IV was to elucidate the risk of disease progression and death as a function of the depth of molecular response in order to provide guidance in the interpretation of BCR-ABL levels in the clinical setting. Methods: 1,340 patients (median age 52 years, range 16–88, 60% male) were recruited into the randomized German CML Study IV and treated with an imatinib-based therapy as follows: imatinib 400 mg/d, n=381; imatinib 800 mg/d, n=399; imatinib 400 mg/d + interferon alpha, n=402; imatinib 400 mg/d + low-dose cytarabine, n=158. A total of 1,262 patients with typical b2a2 and b3a2 BCR-ABL transcripts were evaluable. Molecular responses were assessed in 811, 764, 671, and 619 patients at 6, 12, 18, and 24 months, respectively. Disease progression was defined as accelerated phase or blastic phase, or death from any reason. Landmark analyses and log-rank tests for OS and PFS were performed according to the achievement of different BCR-ABL response levels at different time points. Results: Patients were grouped according to the degree of molecular response (<0.1%, 0.1%-1%, 1%-10%, >10% BCR-ABL IS) at each of the 4 time points and evaluated for 5-year OS and PFS. Estimated 5-year OS for the different molecular response categories was: 97% vs 96% vs 90% vs 88% (6 months, p=0.009); 96% vs 95% vs 89% vs 69% (12 months, p<0.001); 98% vs 97% vs 92% vs 66% (18 months, p<0.001); 97% vs 96% vs 96% vs 68% (24 months, p<0.001). Applying the 4 response categories revealed estimated 5-year PFS of 97% vs 96% vs 91% vs 86% (p=0.004) at 6 months, 97% vs 92% vs 89% vs 72% (p<0.001) at 12 months, 99% vs 95% vs 90% vs 77% (p<0.001) at 18 months, and 97% vs 97% vs 93% vs 65% (p<0.001) at 24 months (s. Table). Conclusions: Faster and deeper response to imatinib-based treatment revealed to be associated with improved overall and progression-free survival. Inferior OS and PFS can be deducted from the synopsis of BCR-ABL expression and treatment duration, e.g. >1% BCR-ABL IS at 6 months or 12 months might be, and >10% BCR-ABL IS should be a trigger for a treatment change. Thereby this analysis might provide decision guidance for alteration or continuation of primary imatinib treatment. Disclosures: Schnittger: Münchner Leukämie Labor: Equity Ownership. German CML Study Group:EU: Research Funding; BMBF: Research Funding; Novartis: Research Funding; Deutsche Krebshilfe: Research Funding; Roche: Research Funding; Essex: Research Funding.

Download Full-text

Combination of Dasatinib and Peg-Interferon Alpha 2b in Chronic Phase Chronic Myeloid Leukemia (CP-CML) First Line: Preliminary Results of a Phase II Trial, from the French Intergroup of CML (Fi-LMC)

Blood ◽

10.1182/blood.v126.23.134.134 ◽

2015 ◽

Vol 126 (23) ◽

pp. 134-134 ◽

Cited By ~ 6

Author(s):

Lydia ROY ◽

Jean-Claude Chomel ◽

Joelle Guilhot ◽

Agnes Guerci-Bresler ◽

Martine Escoffre-Barbe ◽

...

Keyword(s):

Phase Ii ◽

Research Funding ◽

Phase Ii Trial ◽

Molecular Response ◽

First Line ◽

Molecular Responses ◽

Deep Molecular Response ◽

To Receive ◽

Advisory Role

Abstract Background: Combination of Pegylated-Interferon alpha (Peg-IFNa) 2a and imatinib (IM) has been reported to significantly induce higher rates of molecular responses (including undetectable BCR-ABL transcript) over IM alone, as frontline therapy for CP-CML patients (pts) in a randomized phase 3 trial (SPIRIT, Preudhomme et al, NEJM 2010). Second generation TKIs such as dasatinib (DASISION, Kantarjian et al, NEJM 2010) enhance the speed and depth of molecular response (MR) in comparison to IM. Phase II trial using nilotinib and PegIFNa2a has recently reported high rates of deep molecular response (MR4.5) within 24 months (Nicolini FE et al, Lancet Haematology 2015). Aims: To determine the efficacy and safety of the combination of dasatinib and Peg-IFNa2b in CP-CML frontline. (EUDRACT Number: 2012-003389-42, Dasa-PegIFN trial). Methods: Newly diagnosed Ph+ CP-CML pts less than 65-year-old started dasatinib 100 mg/day. At 3 months, they were assigned to receive Peg-IFNa2b associated to dasatinib when platelets (plt) > 100 X 109/L, Neutrophils (ANC) > 1.5 X 109/L) and lymphocytes < 4.0 X 109/L counts were achieved. Otherwise, dasatinib was continued alone in the study according to the current international ELN guidelines. The maximum duration of the combination dasatinib and Peg-IFNa2b is 21 months. The primary endpoint is the cumulative rate of Molecular Response 4.5log (MR4.5 defined as BCR-ABL1/ABL1IS≤0.0032%) at 12 months. Molecular analyses were centralized and expressed according to the international scale (IS). Secondary endpoints included efficacy (cytogenetic and molecular responses at several time-points) and safety endpoints. Preliminary results are reported here. Results: 81 pts were enrolled between October 2013 and July 2014. All pts will have completed the 12 months follow-up time-point in August 2015. 79/81pts were included in the analysis (1 pt died of a CML-related haemorrhage before receiving dasatinib, 1 screening failure (masked Ph)). Median age was 48 (20-65) years. 54% of pts were male. Sokal scores were low, intermediate and high in 51%, 32% and 17% of pts respectively. After the first 3 months of therapy (M3), sixty-one patients (77%) started Peg-IFNa2b at the dose of 30 microg/week in association with dasatinib. For these pts after M3, reported hematologic adverse events (AE) were neutropenia (G3/4 n=11; G1/2 n=17), thrombocytopenia (G3/4 n=0; G1/2 n=7), anemia (G3/4 n=0; G1/2 n=7). Extra-hematologic AE were essentially of low grade (overall, G3/4 n=3; G1/2 n=113). According to NCI CTCAE V4.0, most frequent AE were infections (16%), general symptoms (15%), skin lesions (10%), hepato-biliary abnormalities (7.7%), nervous system/headache (7.7%) musculoskeletal pain (7%), psychiatric (7%), GI (6%) disorders. Eight serious AE (SAE) were reported after Peg-IFNa2b initiation: G4 neutropenia n=2, dysthyroitidis n=1, dyspnea n=1, pleural effusion n=1, lymphoid hyperplasia n=1, hemorrhoids n=1, rectal fistula (SUSAR) n=1. Efficacy was analysed according to the intention-to-treat principle (ITT), and considering missing data as no response to avoid inflated results. Overall at M3, 85% of pts had a BCR-ABL1/ABL1 ratio ≤10%. For eligible patients who received combined therapy (n=61), rates of MMR were 16%, 51%, 70%, and 70% (pending n=5) at M3, M6, M9 and M12, including MR4.5 rates 10%, 20%, 30% at M6, M9 and M12 respectively. Eighteen pts (22.7%) were not eligible to receive Peg-IFNa2b. Reasons, according to protocol criteria, were ANC <1.5 X 109/L (n=10), plt <100.0 X 109/L (n=5), lymphocytes >4.0 X 109/L (n=1), absence of complete hematologic response (n=1), non compliance (n=1). Rates of MMR for these pts were 27% at M6, 50 % at M9 (missing n=2), pending data for n=6 at M12. Conclusion: Peg-IFNa2b combined to dasatinib therapy in first line CP-CML induces a high rate of deep molecular response (ie MR4.5) during the first year of therapy. Despite few pending data, results at 12 months are already in line with previous data combining Peg-IFNa and TKI, expecting a potential for an increased rate in therapy cessation attempt. Preliminary data of this phase II trial indicate a manageable toxicity profile for this combination, despite an increased rate of neutropenia. Updated analyses (ITT and per protocol) will be presented for all the pts with at least 12 months follow-up. Disclosures ROY: BMS: Other: CongressTravels/Accomodations, Research Funding, Speakers Bureau; Novartis: Other: Congress Travels/Accomodations, Research Funding, Speakers Bureau; Merck: Other: Peg-Interferon provided in the trial. Guerci-Bresler:Novartis: Speakers Bureau; BMS: Speakers Bureau; ARIAD: Speakers Bureau; PFIZER: Speakers Bureau. Giraudier:BMS: Speakers Bureau; Novartis: Other: Congress Travel/Accomodation, Speakers Bureau. Johnson-Ansah:Hybrigenics SA: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; BMS: Speakers Bureau. Amé:Novartis: Speakers Bureau; BMS: Speakers Bureau. Etienne:BMS: Consultancy, Honoraria, Speakers Bureau; ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau. Nicolini:BMS: Other: Travel/Accommodations/Expenses; Novartis: Other: Travel, Accommodations, Expenses; ARIAD: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting or Advisory Role, Speakers Bureau; Novartis: Honoraria, Other: Consulting & Advisory Role, Research Funding, Speakers Bureau. Rea:Novartis: Honoraria; BMS: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Cony-Makhoul:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Ianotto:Novartis: Other: Congress Travel/ Accomodations. Legros:ARIAD: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Coiteux:BMS: Speakers Bureau. Hermet:BMS: Speakers Bureau; Novartis: Speakers Bureau. Mahon:BMS: Speakers Bureau; Novartis: Speakers Bureau. Rousselot:ARIAD: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Speakers Bureau.

Download Full-text

Early Prediction of Stable MR4.5 By Achievement of 2.8 Log Reduction in BCR-ABL1 qPCR Levels at 6 Months in Patients with Chronic Myeloid Leukemia Treated with Frontline Imatinib

Blood ◽

10.1182/blood-2018-99-110135 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3022-3022

Author(s):

Aisling Nee ◽

Jeffrey H. Lipton ◽

Dennis Dong Hwan Kim

Keyword(s):

Median Time ◽

Research Funding ◽

Multivariable Analysis ◽

Imatinib Therapy ◽

Molecular Response ◽

Molecular Responses ◽

Log Reduction ◽

Disease Characteristics ◽

Univariate Analyses ◽

Tki Discontinuation

Abstract Introduction Tyrosine kinase inhibitor (TKI) therapy has dramatically improved the prognosis of CML, with life expectancy now approaching that of the general population. TKIs are, however, associated with impaired quality of life, toxicity and financial burden to the patient and economy. Treatment free remission (TFR) is achievable in approximately half of patients who attain a sustained deep molecular response (DMR), however, it is not yet fully elucidated how best to predict candidates for successful TFR attempt. It is even harder to predict which patients will achieve a sustained DMR for 2 years or longer, which is a pre-requisite for TKI discontinuation. If it were possible to identify the patients who will not achieve a sustained DMR with Imatinib, a TKI switch could be considered earlier in order to make them a candidate for TFR attempt. Aims We aimed to identify disease characteristics and molecular responses that can predict future achievement of Stable MR4.5 (defined as a reduction in BCR/ABL1 transcripts of 4.5 logs or deeper on repeated testing for 2 consecutive years) with frontline Imatinib. Patients and Methods We collected data on pre-TKI variables (baseline disease characteristics), post-TKI variables (molecular response at various timepoints) and outcomes in patients commencing frontline Imatinib in our institution from 1999 to 2014 (n=593). Statistical analysis was performed using EZR software. Univariate analysis was performed by cumulative incidence method considering competing events and Gray test. Cut-offs for continuous variables were determined by recursive partitioning (rpart). Multivariable analysis was performed using Fine-Gray model. Results With 8.9 years of median follow-up duration, the overall survival was 96.9% at 8 years. The median time to MR4.5 was 8.8 years. The rate of MR4.5 was 39.7% at 5 years and 48.3% at 8 years. The rate of Stable MR4.5 was 25.6% at 8 years. In the subset of patients achieving MR4.5, over 80% subsequently achieved Stable MR4.5 (82.4% at 8 years) (Fig. 1). The median time from achievement of first MR4.5 to Stable MR4.5 was 3.5 years. Univariate analyses of baseline variables (age, gender, disease phase, additional cytogenetic abnormalities and baseline blood counts) were performed, using rpart method to determine cut-offs for blood counts as follows: white cell count (WBC) ≥218x109/L, blast percentage ≥4%, hemoglobin (Hb) ≥88.5g/L and platelets ≥176x109/L. The only statistically significant pre-TKI variables on these analyses were WBC, blast percentage, Hb and platelet count. Univariate analyses of the following post-TKI variables were also performed: molecular response at 3, 6 and 12 months, time to complete cytogenetic response, major molecular response and MR4.5.Early molecular responses of ≥1 log reduction in transcripts at 3 months, ≥2 logs at 6 months and ≥3 logs at 12 months were tested. The following cut-offs for molecular response, as determined by rpart method, were also tested: ≥2.2 log reduction at 3 months, ≥2.8 logs at 6 months and ≥3 logs at 12 months.Univariate analysis showed statistical significance (p<0.0001) for all the post-TKI variables tested. Multivariable analyses of baseline blood counts and molecular response at 3 and 6 months were performed. The only variable that remained statistically significant was molecular response at 6 months using a cut-off of ≥2.8 log reduction in transcripts (HR 3.1, p<0.001) (Table 1). 44.4% of patients achieved ≥2.8 log reduction in transcripts at 6 months, with a rate of Stable MR4.5 at 8 years of 65.8%, compared to 17.2% for those with <2.8 log reduction at 6 months (Fig. 2). Conclusions In patients who achieved MR4.5, over 80% subsequently achieved Stable MR4.5, making them eligible for TKI discontinuation. In multivariable analysis, molecular response at 6 months was the only predictor for subsequent achievement of Stable MR4.5. Based on this data, a patient at high-risk of failing to attain Stable MR4.5 with Imatinib therapy can be identified if they fail to achieve a 2.8 log reduction or deeper within 6 months of Imatinib therapy. If a patient interested in TFR has a molecular response at 6 months of less than a 2.8 log reduction, then a switch in therapy to a second generation TKI may be considered. The optimal 6 month response to predict future Stable MR4.5 remains unclear, but our data suggest that a cut-off in transcripts of ≥ 2.8 log reduction may be a better predictor of future Stable MR4.5. Disclosures Lipton: ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kim:BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Paladin: Consultancy.

Download Full-text

Switching to a Second Generation TKI in Chronic Myeloid Leukemia Patients with Late Suboptimal Response with Imatinib Obtained Better Molecular Responses That the “Watch and Wait” Approach. an Experience of a Multicenter Registry in Patients Outside Clinical Trials

Blood ◽

10.1182/blood.v120.21.3768.3768 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3768-3768

Author(s):

J Valentin Garcia-Gutierrez ◽

Begoña Maestro ◽

Luis Felipe Casado ◽

Manuel Perez-Encinas ◽

Isabel Massague ◽

...

Keyword(s):

Clinical Trials ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Second Generation ◽

Molecular Response ◽

Treatment Change ◽

Molecular Responses ◽

Group 2 ◽

Group 1

Abstract Abstract 3768 Introduction: Tyrosine kinase inhibitors (TKIs) have dramatically changed chronic myeloid leukemia prognostic. The European Leukemia Net guidelines are widely used for patients treated with TKIs. While strategies for patients with optimal response and failure after imatinib are clear, there are doubts about the best treatment option for patients with suboptimal response (SubR), specially for late SubR (patients with complete cytogenetic response (CCyR) but not mayor molecular response (MMR) after 18 months of treatment). Patients with MMR seem to have better outcomes than patients with CCyR but not MMR, but at this time, there are few data showing the benefits of treatment change in this group of patients. Aims: To identify the benefits of treatment change in patients with late SubR, outside clinical trials, in the setting of a multicenter hospital-based registry. Patients and methods: We have studied retrospectively a group of 488 CML chronic phase patients treated with imatinib as first TKI, identifying 96 patients (19%) with SubR criteria (following the ELN recommendations) after 18 months of treatment. These patients have been classified according to the strategy followed by their physician after SubR identification. Group 1 includes 65 patients (67%) continuing with imatinib (either initial dose or higher dose) and group 2 includes 31patients (33%) that were changed to second generation TKI (2GTKI: dasatinib or nilotinib). Sokal risk index was high in 17% and 9%; intermediate 44 % and 41%; and low in 39% and 50 % for group 1 and 2, respectively. 31% and 30% of patients had received interferon prior to imatinib. Molecular response was analyzed after 12 months of identifying late SubR (for group 1) or after switching to 2GTKI, for group 2. Results: The use of 2G TKIs resulted in significant benefit to patients in terms of improving molecular responses. Complete molecular responses (CMR) and MMR rates were 3.8% vs 27% and 41.5% vs 69% for group 1 and 2 respectively (p=0.006). Time for the achievements the best molecular responses was significantly lower for patients receiving second generation TKI (4.1 vs 20.2 months, p=0.004). Probabilities of treatment failure, defined as loss of CCR, were also higher in patients remaining with imatinib (15.4% vs 5.7% (p=0.12). Progression free survival was 93.8% vs 97.2% (p=0.18) for group 1 and 2 respectively. Changing treatment for late SubR patients was also safe, and only 17% of patients needed to switch to another TKI due to intolerance. Conclusions: In CML patients treated with Imatinib with late SubR, and outside clinical trials, switching to second generation TKI increased probabilities of achievement a deeper molecular response, with a good safety profile. Disclosures: Casado: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Steegmann:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau.

Download Full-text

Impact of Age in the Outcome of Patients with Chronic Myeloid Leukemia in Late Chronic Phase: Clinical and Molecular Results of a Phase II Study of the GIMEMA CML Working Party.

Blood ◽

10.1182/blood.v108.11.4805.4805 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4805-4805

Author(s):

Giovanni Martinelli ◽

Francesca Palandri ◽

Ilaria Iacobucci ◽

Simona Bassi ◽

Fausto Castagnetti ◽

...

Keyword(s):

Phase Ii ◽

Older Patients ◽

Age Groups ◽

Chronic Phase ◽

Working Party ◽

Progression Free Survival ◽

Observation Time ◽

Molecular Response ◽

Term Outcome ◽

Long Term Outcome

Abstract To assess the effect of age on response and compliance we performed a sub-analysis within a phase II trial of the GIMEMA CMLWorking Party (CML/002/STI571). Since the WHO cut-off age to define an older patient is 65 years, we identified: 226/284 (80%) younger patients (below 65 years) and 58/284 (20%) older patients (above 65 years) before starting imatinib. Responses (hematologic and cytogenetic) were lower in older age group but progression free survival and overall survival probabilities (median observation time 3 years) were the same. Moreover, among complete cytogenetic responders, no differences were found in the level of molecular response between the 2 age groups. As probably expected, older patients experienced more adverse events (AEs), both hematologic and non-hematologic: this worsen compliance, however, did not prevent a long term outcome similar to younger ones. CML

Download Full-text

Response and Outcomes to Nilotinib at 24 Months in Imatinib-Resistant Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) and Accelerated Phase (CML-AP) with and without BCR-ABL Mutations.

Blood ◽

10.1182/blood.v114.22.1130.1130 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1130-1130 ◽

Cited By ~ 1

Author(s):

Jerald P. Radich ◽

Giovanni Martinelli ◽

Andreas Hochhaus ◽

Enrico Gottardi ◽

Simona Soverini ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Advisory Committees ◽

Imatinib Resistant

Abstract Abstract 1130 Poster Board I-152 Background Nilotinib is a selective and potent BCR-ABL inhibitor, with in vitro activity against most BCR-ABL mutants (excluding T315I) indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) CML in CPor AP resistant or -intolerant to prior therapy, including imatinib. In a previous analysis of nilotinib in patients with BCR-ABL mutations, mutations occurring at three specific amino acid residues (E255K/V, Y253H, and F359C/V) were shown to be associated with less favorable response to nilotinib. The current analysis is based on mature data with a minimum follow-up of 24-months for all patients. Outcomes of patients at 24 months were analyzed by mutation type. Methods Imatinib-resistant CML-CP (n = 200) and CML-AP (n = 93) patients were subdivided into the following mutational subsets: no mutation, sensitive mutations (including mutations with unknown in vitro IC50). or E255K/V, Y253H, or F359C/V mutations at baseline. Patients with mutations of unknown in vitro sensitivity were classified as sensitive in this analysis based on a previous finding that patients with these mutations responded similarly to nilotinib as patients with sensitive mutation. Patients with baseline T315I mutations were excluded from this analysis. Patient groups were analyzed for kinetics and durability of cytogenetic and molecular response to nilotinib, as well as event-free survival (EFS), defined as loss of hematologic or cytogenetic response, progression to AP/BC, discontinuation due to disease progression, or death, and overall survival (OS). Results In CML-CP and -AP patients with no mutation, sensitive mutations, or E255K/V, Y253H, or F359C/V mutations, hematologic, cytogenetic and molecular responses are provided in the Table. Overall, patients with no mutations responded similarly to patients with sensitive mutations, whereas patients with E255K/V, Y253H, or F359C/V mutations had less favorable responses. This correlation was observed in both CML-CP and CML-AP patients, respectively. Median time to CCyR was 3.3 months (range, 1.0–26.7) for CML-CP patients with no mutations, and 5.6 months (range, 0.9–22.1) for patients with sensitive mutations. At 24 months, CCyR was maintained in 74% of CML-CP patients with no mutation and in 84% of patients with sensitive mutations. One patient with CML-CP and an E255K mutation achieved CCyR at 25 months and maintained until last assessment at 30 months. Median time to MMR was similar at 5.6 months (range, 0.9–25.8) for CML-CP patients with no mutations and 5.6 months (range, 2.7–22.1) for patients with sensitive mutations. No patient with a less sensitive mutation achieved MMR. Median EFS and 24-month estimated OS rate are provided in the Table. Conclusions Imatinib-resistant CML-CP and CML-AP patients treated with nilotinib therapy with BCR-ABL mutations (excluding E255K/V, Y253H, or F359C/V) achieved rapid and durable cytogenetic responses, and estimated EFS and OS at 24 months similar to that of patients with no mutations, respectively. Patients with E255K/V, Y253H, or F359C/V mutations had lower and less-durable responses and shorter EFS than patients with sensitive mutations. Alternative therapies may be considered for patients with these uncommon mutations (E255K/V, Y253H, and F359C/V). Disclosures Radich: Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Branford:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Shou:Novartis: Employment. Haque:Novartis: Employment. Woodman:Novartis: Employment. Kantarjian:Novartis: Research Funding. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Kim:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau.

Download Full-text

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

Blood ◽

10.1182/blood.v114.22.3290.3290 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3290-3290 ◽

Cited By ~ 6

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>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 >90%) and the 6-year probability of major molecular response (MMR) (28.4% vs 94.5%, p<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.

Download Full-text

Eculizumab Is An Effective Long-Term Treatment In Patients with Atypical Hemolytic Uremic Syndrome (aHUS) Previously Receiving Chronic Plasma Exchange/Infusion (PE/PI): Extension Study Results,

Blood ◽

10.1182/blood.v118.21.3303.3303 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3303-3303 ◽

Cited By ~ 2

Author(s):

Christoph Licht ◽

Petra Muus ◽

Christophe Legendre ◽

Kenneth W Douglas ◽

Maryvonne Hourmant ◽

...

Keyword(s):

Renal Function ◽

Median Time ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Trial ◽

Time Dependent ◽

Significant Time ◽

Extension Trial ◽

Free Status

Abstract Abstract 3303 INTRODUCTION: Chronic uncontrolled complement activation drives systemic thrombotic microangiopathy (TMA) and life-threatening complications in aHUS. In the initial 26-wk, phase II trial of eculizumab, (ECU) a terminal complement inhibitor, in pts with aHUS requiring chronic PE/PI for an extended period of time, a statistically significant and sustained suppression of TMA was observed. In addition, no pt required PE/PI, no new dialysis was required and all pts either maintained/improved renal function in the absence of PE/PI (Licht ASN 2011). We report longer follow-up data from this trial. METHODS: Pts ≥12 yrs with aHUS, receiving chronic PE/PI on an unchanged regimen were enrolled in a controlled, open-label, single-arm, phase II trial. After an 8-week observation period, pts discontinued PE/PI and started ECU (900mg/week for 4 wks, 1200mg at wk 5, then 1200mg q2 wks). Pts received a meningococcal vaccine. Primary endpoint: TMA event-free status defined as ≥12 consecutive wks of stable platelet count, no PE/PI and no new dialysis. Secondary endpoints included TMA intervention rate (no. of PE/PI and new dialysis events/pt/day), renal function, and safety. Pts continued into an extension trial. RESULTS: Of 20 pts (median age=28 yrs) who received ECU through Wk 26 of the initial trial, 19 pts continued ECU treatment into the extension trial. Mean (SD) duration of ECU treatment was 60 (12) wks at data cut-off. Median time from diagnosis to screening=48 mo (0.66–286). Median time from overt clinical symptoms of aHUS to screening=8.6 mo (1.2–45). Median no. of PE/PI sessions per pt during current clinical presentation=62 (20–230). Median duration of eGFR ≤60 mL/min/1.73m2=180 days (23–485). Six pts had no complement regulatory factor mutation (CRFM) identified. Ongoing treatment with long-term ECU was associated with continued improvements in TMA intervention rate and TMA event-free status and further improvement in renal function (Table). Long-term ECU treatment showed a highly significant time-dependent improvement in eGFR (p<0.0001) with a significant improvement from baseline of 8 mL/min/1.73m2 at 1 yr (p<0.0001). PE/PI or new dialysis was not required with chronic ECU treatment in any pt through Wk 26 or during ongoing long-term ECU therapy (through data cut-off). ECU was similarly effective in pts with/without identified CRFMs. ECU was well tolerated; only 7 pts had adverse events deemed possibly or probably related to drug (mild to moderate in severity). The extension trial continues. CONCLUSIONS: Despite PE/PI, >50% of pts with aHUS are expected to die, require dialysis or have permanent renal damage within the first year of diagnosis. In this trial, all pts treated with ECU for a mean duration of >1 year are still alive and none progressed to ESRD or required new dialysis with sustained ECU treatment. Importantly, compared with historical outcomes with chronic PE/PI, initiation of sustained, long-term ECU therapy, without PE/PI, was associated with a highly significant time-dependent improvement in eGFR. Switching to chronic ECU therapy significantly changed the course of the disease in severe and prolonged renal insufficiency pts, resulting in sustained suppression of TMA. These data further demonstrate ECU to be the new standard of care for aHUS. Disclosures: Licht: Alexion: Honoraria, Research Funding. Off Label Use: Eculizumab but as part of clinical controlled trials. Muus:Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding. Legendre:Alexion: Research Funding. Douglas:Alexion: Genzyme, but not relevant to current submission, Research Funding. Hourmant:Alexion: Research Funding. Delmas:Alexion: Research Funding. Herthelius:Alexion: Research Funding. Trivelli:Alexion: Research Funding. Goodship:Alexion: Honoraria, Research Funding. Bedrosian:Alexion: Employment. Loirat:Alexion: Honoraria, Research Funding.

Download Full-text

Cyclophosphamide, Adriamycin, Vincristine and Prednisone Plus Rituximab (CHOP-R) in Fludarabine (F) Refractory Chronic Lymphocytic Leukemia (CLL) or CLL with Autoimmune Cytopenia (AIC) or Richter's Transformation (RT): Final Analysis of a Phase II Study of the German CLL Study Group

Blood ◽

10.1182/blood.v118.21.2860.2860 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2860-2860

Author(s):

Petra Jenke ◽

Barbara Eichhorst ◽

Raymonde Busch ◽

Nadine Anheier ◽

Ulrich Duehrsen ◽

...

Keyword(s):

Overall Survival ◽

Phase Ii ◽

Research Funding ◽

Progression Free Survival ◽

Response Rates ◽

Median Number ◽

Response Evaluation ◽

Free Survival ◽

Richter's Transformation ◽

Grade 3

Abstract Abstract 2860 Introduction: In the last decade, important progress has been achieved in the treatment of CLL through the use of purine analog-based chemoimmunotherapies. Several conditions remain a challenge, often with a poor outcome. Amongst these therapeutic problems are Richter's transformation (RT), refractoriness to F-based therapies (Fref), and the occurrence of AIC, which are sometimes induced by F. Fref and RT pts have a very poor prognosis with an estimated overall survival (OS) of only 10 and 8 months (mos), respectively. Therefore, therapeutic alternatives are urgently warranted. CHOP-R has improved the outcome of pts with aggressive non-Hodgkin's lymphoma. To test the efficacy and tolerability of the CHOP-R regimen in CLL patients with RT, Fref, or AIC, the GCLLSG initiated a prospective phase II trial. Material and Methods: 62 patients were included in the study. Due to protocol violations, 2 patients were excluded. Within the group of Fref pts, the medical review detected 11 patients who had received pre-treatment with F (Fpret), but were not refractory according to the updated guidelines (Hallek et al., Blood 2008). Thus, 26 pts were classified as Fref/pret, 19 pts as AIC and 15 pts as RT. All patients received CHOP every 3 weeks (cyclophosphamide 750mg/m2, adriamycin 50mg/m2 and vincristine 1, 4mg/m2 d1; prednisone 100mg/m2 d1–5). Rituximab was added starting with the 2nd cycle (375mg/m2 on each d0, and 21 days after the last CHOP-R). RT pts received up to 8, Fref/pret and AIC up to 6 courses of CHOP-R. In case of PD after 3 cycles, pts went off-study. The primary endpoints were remission rate, quality and duration of response. Results: 79%, 73%, and 40% of AIC, Fref/pret, and RT pts were male, respectively. The median age was 65 years (y) for Fref/pret-pts, 66y in the AIC and 69y in the RT group. Binet stages for Fref/pret pts were: A: 8%; B: 27% C: 65 %. All but 3 AIC pts were at Binet stage C. Initial RT stages according to Ann Arbor were: II: 13%, III: 13%, IV 73%. The median number of previous therapies were 3 for Fref/pret, 2 for AIC and 2 for RT. A total of 314 cycles were administered, with a median number of 3 cycles for AIC and Fref pts and a median number of 4 cycles for the RT group. Due to toxicity 73% of cycles in the Fref/pret group, 66% in the AIC and 87% in the RT group were dose-reduced. 69% of Fref/pret-pts and 58% of AIC-pts received full 6 cycles of therapy and only 40% of RT-pts completed 8 cycles of therapy. Treatment was stopped in 6 pts because of PD. Due to treatment related toxicity treatment was stopped in 16 pts (27%). Treatment related mortality was 3% (2 pts). Treatment toxicity was reported according to NCI common toxicity criteria (CTC) version 2.0. Adverse events grade 3 or 4 for anemia, neutropenia and thrombocytopenia were documented in 75%, 55% and 65% of patients, respectively. Infections were the most common non-hematologic toxicity and occurred in 67%; severe infections CTC grade 3 or 4 occurred in 28%. All 26 Fref/pret-pts were available for response evaluation. CHOP-R achieved 54% PR, 35% SD and 12% PD. The median progression-free survival (PFS) and median treatment-free survival (TFS) were 11 and 14 mos. OS was 27 mos with a significant difference concerning F-ref (n=15) and F-pret (n=11) pts (17 vs. 35m; p=0.05). We evaluated the response of all 15 RT-pts with 60% PR, 7% CR, 13% SD and 20% PD. The PFS was 15 mos, TFS was 17 mos and OS 27 mos. 17 AIC pts were available for response evaluation with 82% PR, 6% SD and 12% PD. The PFS and TFS were only 14 and 16 mos. The OS was 50 mos. The population had a high incidence of unfavourable genetic markers: deletion of chromosome 17p [del(17p)] was detected in 24%, del(11q) in 34% and unmutated IGHV in 70%. 85% had high levels of serum thymidine kinase (sTK > 10 U/l), and 49% had high levels of ß2-microglobulin (ß2M > 3.5 mg/l). Patients with del(17p) had an unfavourable response rate and achieved significant less a PR or CR (36% vs. 76%; p=0.03). Multivariate analyses showed that del(17p) and ECOG performance status had a negative prognostic impact on OS (p<0.0001). Moreover the presence of a del(17p) predicted a short PFS (6 vs. 16.9 mos; p=0.001). Conclusion: CHOP-R achieves promising response rates in CLL patients with Fref and RT and very good response rates in patients with AIC. However, the progression-free survival and overall survival remain unsatisfactory. Therefore, CHOP-R might be used as induction therapy prior to allogeneic stem cell transplantation in physically fit patients. Disclosures: Eichhorst: Hoffmann La Roche: Honoraria, Research Funding, Travel Grants; Mundipharma: Research Funding, Travel Grants; Gilead: Consultancy. Dreyling:Roche: Research Funding, Scientific advisory board, Speakers Bureau. Bergmann:Celgene: Honoraria. Stilgenbauer:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Fink:Hoffmann La Roche: travel grants. Fischer:Hoffmann La Roche:. Wendtner:Hofmann-La Roche: Consultancy, Honoraria, Research Funding. Hallek:Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Honoraria.

Download Full-text

Kinetics of Molecular Response with Different Tyrosine Kinase Inhibitors (TKI) Used As Frontline Therapy in Chronic Myeloid Leukemia-Chronic Phase (CML CP),

Blood ◽

10.1182/blood.v118.21.3784.3784 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3784-3784 ◽

Cited By ~ 1

Author(s):

Kiran Naqvi ◽

Hagop M Kantarjian ◽

Rajyalakshmi Luthra ◽

Elias Jabbour ◽

Susan O'Brien ◽

...

Keyword(s):

Research Funding ◽

Transcript Level ◽

Initial Therapy ◽

Molecular Response ◽

Term Outcome ◽

Long Term Outcome ◽

Molecular Responses ◽

Transcript Levels ◽

Frontline Therapy

Abstract Abstract 3784 Background: TKI are standard therapy for patients with CML CP. Imatinib was first established as frontline therapy and more recently dasatinib and nilotinib have shown improved rates and speed of response. Early molecular response has been associated with improved long-term outcome (Blood 2009; 113: 6315), thus the kinetics and rates of molecular response are important predictors of long-term outcome. Aim: To determine the kinetics and rates of molecular response with different TKIs used as initial therapy for patients with CML CP. Methods: We evaluated all pts treated with frontline TKIs (imatinib standard dose or high dose, dasatinib and nilotinib) in consecutive or parallel trials. Cytogenetic and molecular responses were assessed at least every 3 months for the first 12 months, then every 6 months, and were defined using the recommendations of European LeukemiaNet. Molecular responses were defined using international scale. Survival was calculated by the Kaplan-Meier method. Results: Of the 485 pts treated, 73 received imatinib 400mg; 208 imatinib 800mg; 99 dasatinib, and 105 nilotinib. Median age was 48 years (15–86) and median time from diagnosis to TKI therapy was 1 mo (1–13). The median follow-up for each group were 109 months (mo) with imatinib 400, 69 mo with imatinib 800, 30 with dasatinib and 25 mo with nilotinib. Nineteen pts with clonal evolution, but otherwise in CP, were included. Sokal risk score was high in 7%, intermediate in 24% and low in 69%. Cumulative rates of complete cytogenetic response (CCyR) were: imatinib 400mg 87%; imatinib 800mg 91%; dasatinib 96%; and nilotinib 94%. The rate of MMR with imatinib 400mg was 73%, with imatinib 800mg 87%, dasatinib 86%, and nilotinib 88%. Rates of CMR (BCR-ABL/ABL ≤0.0032% IS) were 51%, 71%, 61% and 62%. Median time to achieve MMR and CMR were: imatinib 400mg, 12 mo (3–60) and 18 mo (3–60); imatinib 800mg, 6 mo (3–60) and 9 mo (3–60); dasatinib, 6 mo (3–36) and 12 mo (3–54), and nilotinib 6 mo (3–48) and 6 mo (3–42). The median transcript levels at 3, 6, 12, 18, 24 and 36 mo by treatment arm are shown in table 1. The rates of MMR and CMR at 36 mo for imatinib 400mg were 58% and 34%. Corresponding rates for imatinib 800mg were 87% and 59%; for dasatinib 87% and 54%; and for nilotinib 90% and 63%. We then assessed the probability of achieving MMR and CMR at 12 mo according to the BCR-ABL/ABL levels at earlier timepoints. Two of 9 (22%) evaluable pts with transcript level >10 at 3 mo achieved a MMR at 12 mo but none achieved a CMR. In contrast, 31/52 (60%) evaluable pts with transcript level >1–10 at 3 mo, achieved a MMR at 12 mo and 4 (8%) achieved a CMR. Similarly, pts with level >0.1–1 at 3 mo, 72/129 (56%) evaluable pts achieved a MMR and 29 pts (22%) a CMR at 12 months. For each individual TKI, a similar trend was noted where a higher transcript level (>10; >1–10; >0.1–1) at 3 mo was associated with a decline in achieving a MMR and CMR at 12 mo (MMR- imatinib 400mg: 0%; 50%; 67%, imatinib 800mg: 0%; 62%; 80%, dasatinib: 33%; 67%; 71%, nilotinib: 100%; 50%, 88%, CMR-imatinib 400mg: 0%, imatinib 800mg: 0%; 8%; 10%, dasatinib:0%; 17%; 29%, nilotinib: 0%; 0%; 32%). The probability of transformation to AP/BP by transcript levels at 3 mo (>10; >1–10; >0.1–1, ≤0.1) was 0%, 3%, 2% and 1% for the overall population, with similar trends for the different therapies. Conclusion: New TKI provide a faster improvement in molecular response among pts with CML CP receiving TKI as initial therapy. Early responses are equally predictive of long-term outcome across all treatment options. Disclosures: Kantarjian: Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Cortes:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; ChemGenex: ChemGenex is now Cephalon, Inc., Consultancy, Research Funding; Deciphera: Research Funding.

Download Full-text