The Role of Peg-Interferon (P-IFN) in Salvaging Patients with Chronic Myeloid Leukemia Chronic Phase (LMC-CP) in Molecular Resistant (MolRes) to Second- Generation Tyrosine Kinase Inhibitors (TKIs)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5461-5461
Author(s):  
Manuel Ayala ◽  
Antonieta Chavez ◽  
Jacqueline Domínguez
Keyword(s):  
Second Generation ◽  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Age At Onset ◽  
Chronic Phase ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
First Line ◽  
Change Behavior ◽  
Third Line

Abstract Introduction.- Interferón for two decades was the gold standard in the treatment of CML, with the beginning of the era of ICTs, their role was secondary or even abandoned its use, combination with ICTs in the first line, has controversial and had toxic effects that limit their use results, however some clinical trials have shown advantages in the molecular response, even less explored yet, this use in molecular resistance (MolRes) to second-generation TKIs. Objective.-Get as molecular response major (MMR) in CML-CP patients with MolRes to nilotinib or dasatinib management. Material and methods.-A total of 146 CML-CP patients treated with nilotinib or dasatinib in second or third-line, twenty six patients with MolRes included a minimum of 18 months of treatment, to receive P-IFN 90 or 180 mcg SC weekly and evaluated quarterly by q-PCR to reach the MMR. Results.-26 CML patients (13 male and 13 female) were included, the median age at diagnosis was 34.5 years (19-60), 8 patients received first-line treatment as P-IFN and 12 patients (60%) imatinib by a median of 30 months (18-52), presented half resistance cytogenetic and half MolRes, being treated with second-generation TKIs (17 nilotinib and 9 dasatinib), wherein MolRes over 18 months of treatment (19-62), they synergize with P-IFN at a dose 90 to 180 mcg weekly, with a median age at onset of the P-IFN synergizers 42 years (18-67), reaching RMM to a median of 3 months (range 3-9), including 5 patients with undetectable molecular response (uMR), achieving the goal of MMR 62% of patients (65 and 56% for nilotinib and dasatinib respectively). La toxicidad hematológica y no hematológica fue evaluada, no siendo significativa, ni una limitante para su uso. Hematologic and non-hematologic toxicity was assessed not to be significant, or limit its use. El 100% de los pacientes sigue vivo y mantienen respuesta molecular mayor 13 pacientes (65%) a una mediana de 8.5 meses (4-20). Conclusiones.-El manejo con nilotinib en 2da línea, ofrece en nuestra experiencia en pacientes con LMC-FC en 2da (90%) o 3ª línea (10%), respuestas citogenéticas en resistentes citogenéticos en un 77% y un 50% alcanzan la RMM, en los casos con fracaso a ese objetivo, la conducta es cambiar de ICT o realizar un trasplante alogénico cuando se dispone de un donador histocompatible, a la sinergizacion 10 pacientes (71%) de 14, lograron la RMM, para un global de RMM del 60% (22% en RMi), los resultados actuales demuestran que es posible retrasar un cambio en la mayoría de los pacientes combinando con P-IFN, recuperando con esta estrategia la RMM en 2/3 de esos pacientes. All patients still alive (except for one patient with dasatinib/P-IFN who died of a heart attack) and remain major molecular response in 15 patients (58%) at a median of 18 months (4-20). Conclusions.- management with nilotinib in 2nd line offers our experience in patients with CML-CP in second-line (90%) or 3rd line (10%), they are achieved complete cytogenetic cytogenetic responses in 77% and 50% reach the RMM, in cases of failure to this goal is to change behavior TKIs or make an allogeneic transplant, when you have a histocompatible donor, the synergizers 11 patients of 17, achieved the MMR, for a global MMR 62% (22% in uMR), the current results show that it is possible to delay a change in the majority of patients with P-IFN combining, recovering with this strategy the MMR in 2/3 of these patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Expert Opinion on the Treatment of Refractory Chronic Phase Chronic Myeloid Leukaemia

2017 ◽  
Vol 13 (01) ◽  
pp. 17
Author(s):  
Tim Hughes ◽  
Giuseppe Saglio ◽  
◽  
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Second Generation ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Response ◽  
Line Treatment ◽  
T315i Mutation ◽  
Third Line ◽  
Third Line Treatment

The development and clinical availability of second-generation tyrosine kinase inhibitors (TKIs) for the treatment of patients who discontinue imatinib therapy has further improved the outlook for patients with chronic phase chronic myeloid leukaemia (CP-CML). There is, however, uncertainty surrounding how best to treat patients after failing second-generation TKIs. A three-section questionnaire was devised by chronic myeloid leukaemia experts to address questions surrounding this issue. Responses were received from 14 out of 34 experts (41.2%). Generally, a reasonable consensus was found among the responses for most issues. There was a complete consensus that ponatinib was suitable for all patients carrying the T315I mutation regardless of the molecular response to prior treatment. There was also complete consensus that allografting is appropriate in any patient who has had blast crises and is back in a second chronic phase. More recommendations for third-line treatment of CP-CML patients are necessary.

scholarly journals Incidences of Deep Molecular Responses and Treatment-Free Remission in de Novo CP-CML Patients

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2521
Author(s):  
Gabriel Etienne ◽  
Stéphanie Dulucq ◽  
Fréderic Bauduer ◽  
Didier Adiko ◽  
François Lifermann ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
De Novo ◽  
Chronic Phase ◽  
Risk Scores ◽  
Prolonged Treatment ◽  
Molecular Response ◽  
First Line ◽  
Treatment Free Remission ◽  
Tki Discontinuation

Background: Tyrosine Kinase Inhibitors (TKIs) discontinuation in patients who had achieved a deep molecular response (DMR) offer now the opportunity of prolonged treatment-free remission (TFR). Patients and Methods: Aims of this study were to evaluate the proportion of de novo chronic-phase chronic myeloid leukemia (CP-CML) patients who achieved a sustained DMR and to identify predictive factors of DMR and molecular recurrence-free survival (MRFS) after TKI discontinuation. Results: Over a period of 10 years, 398 CP-CML patients treated with first-line TKIs were included. Median age at diagnosis was 61 years, 291 (73%) and 107 (27%) patients were treated with frontline imatinib (IMA) or second- or third-generation TKIs (2–3G TKI), respectively. With a median follow-up of seven years (range, 0.6 to 13.8 years), 182 (46%) patients achieved a sustained DMR at least 24 months. Gender, BCR-ABL1 transcript type, and Sokal and ELTS risk scores were significantly associated with a higher probability of sustained DMR while TKI first-line (IMA vs. 2–3G TKI) was not. We estimate that 28% of CML-CP would have been an optimal candidate for TKI discontinuation according to recent recommendations. Finally, 95 (24%) patients have entered in a TFR program. MRFS rates at 12 and 48 months were 55.1% (95% CI, 44.3% to 65.9%) and 46.9% (95% CI, 34.9% to 58.9%), respectively. In multivariate analyses, first-line 2–3G TKIs compared to IMA and TKI duration were the most significant factors of MRFS. Conclusions: Our results suggest that frontline TKIs have a significant impact on TFR in patients who fulfill the selection criteria for TKI discontinuation.

Efficacy and Clinical Outcome of Philadelphia (Ph) Positive Acute Lymphoblastic Leukemia (ALL) Patients Treated with Second Generation Tyrosine Kinase Inhibitors (TKIs): The Bologna Experience.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2027-2027
Author(s):  
Cristina Papayannidis ◽  
Ilaria Iacobucci ◽  
Simona Soverini ◽  
Sabrina Colarossi ◽  
Alessandra Gnani ◽  
...  
Keyword(s):  
Second Generation ◽  
Kinase Inhibitors ◽  
Mutational Analysis ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Progression Free Survival ◽  
Molecular Response ◽  
Third Generation ◽  
Wild Type ◽  
Subsequent Relapse

Abstract Abstract 2027 Poster Board II-4 Background. The prognosis of Ph+ adult ALL patients treated with standard therapies, including multi-agent chemotherapy, Imatinib, and allogeneic stem cell transplantation, is still dismal, due to a high risk of relapse. Dasatinib and Nilotinb are second generation TKIs developed to overcome the problem of resistance to Imatinib in relapsed Ph+ leukemias. Design and Methods. We retrospectively evaluated the single center experience on therapy efficacy of Dasatinib, Nilotinib, and experimental third generation TKIs, administered as second or subsequent line of therapy on 25 relapsed Ph+ adult ALL patients. All patients were previously treated with Imatinib. The median age at time of diagnosis was 50 years (range 18-74), 17 patients were male and 8 female. Ten patients presented a BCR-ABL P190 fusion protein and corresponding fusion transcript, the remaining a BCR-ABL P210. Nineteen patients received Dasatinib, 2 patients Nilotinib and the remaining 4 patients were treated with third generation TKIs. Fourteen patients (56%) were in first relapse, and 7 (28%), 3 (12%) and 1 (4%) were in second, third and fourth relapse, respectively. A mutational analysis was performed in all the patients before TKIs (9 wild type, 16 mutated, including T315I) and at the time of subsequent relapse; gene expression profiling, SNPArray (6.0 Affymetrix chip), and Ikaros deletions were also analyzed. Results. 13 out of 25 patients (52%) obtained a haematological response (HR) (11 patients treated with Dasatinib, 1 patient with Nilotinib and 1 patient with a third generation experimental TKI). 10 patients obtained also a cytogenetic response (CyR) and 6 patients a molecular response (MolR). With a median follow up of 10.8 months (range 2-29 months), median duration of HR, CyR and MolR were 117 days (range 14-385 days); progression free survival were 162 days with Dasatinib and 91 days with Nilotinib. Overall survival was 25.8 months. Interestingly, in 6 out of 9 wild-type patients, treated with Dasatinib, the mutational analysis showed the emergence of T315I or F317I mutation at the time of relapse. Conclusion. Second and third generation TKIs represent a valid approach in relapsed Ph+ adult ALL patients; the subsequent relapse is often associated to the emergence of mutation, conferring resistance to TKIs. Since TKIs are different and have different efficacy, pharmacokinetic, pharmacodynamic and toxicity profiles, and since are all effective, an alternative experimental option for the treatment of Ph+ ALL could be a combination or a rotation of two or more than two TKIs. Moreover, the addition of new promising targeted molecules, such as Aurora kinase or T315I inhibitors may contribute to overcome the problem of resistance to TKIs. Acknowledgments. Work supported by European LeukemiaNet, FIRB 2006, AIRC, AIL, COFIN, University of Bologna and BolognAIL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Early Molecular Response with Generic Imatinib Therapy in Sokal/Hasford Intermediate- & High-Risk Chronic Phase Chronic Myeloid Leukemia Patients: A Single Institution Experience from India

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4276-4276
Author(s):  
Uttam Kumar Nath ◽  
Rituparna Chetia ◽  
Avriti Baveja
Keyword(s):  
High Risk ◽  
Second Generation ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Molecular Response ◽  
Intermediate Risk ◽  
First Line ◽  
High Risk Patients ◽  
2Nd Generation ◽  
Risk Patients

Abstract Introduction: Chronic myeloid leukemia (CML) is the commonest adult leukemia in India. Prognostication of newly diagnosed patients of chronic phase CML (CML-CP) is done by calculating pre-treatment risk scores as per Sokal and Hasford scoring systems, and patients are categorized into low-, intermediate- & high-risk groups. According to the latest NCCN guidelines, CML-CP patients with intermediate- or high-risk Sokal or Hasford score may preferentially benefit from second generation tyrosine kinase inhibitor (TKI) treatment. The two second generation TKI drugs available in India are dasatinib & nilotinib. Unfortunately, majority of CML-CP patients in India cannot afford upfront second generation TKI therapy, and generic imatinib is the mainstay of treatment even for intermediate-risk & high-risk patients. Achievement of early molecular response (EMR), defined as BCR-ABL1 (international scale, IS) ≤ 10% after 3 months of first-line TKI therapy, has emerged as one of the most important predictors of favourable long-term outcomes in CML-CP. The present study describes the rate of EMR achievement with first-line generic imatinib therapy in Sokal & Hasford intermediate- & high-risk patients. Objectives: To study the early molecular response rates with generic imatinib therapy at 400 mg/day dose in CML-CP patients with intermediate-risk & high-risk Sokal or Hasford scores. Methods: Our study enrolled 73 newly diagnosed CML-CP patients with intermediate- or high-risk Sokal/Hasford scores between March 2016 and March 2018. All the patients hailed from poor socio-economic background with severe financial constraint, and none of them had any medical insurance. All the patients were treated with generic imatinib mesylate 400 mg/day which was available free of cost at the hospital. None of the patients could afford dasatinib or nilotinib, despite adequate counseling & information regarding the efficacy of 2nd generation TKIs. Treatment response was monitored and defined as per European LeukemiaNet 2013 recommendations. Hematological response was assessed at 3 months for achievement of complete hematologic response (CHR). Molecular response was assessed at 3 months of first-line treatment by quantitative real-time PCR for BCR-ABL1 (IS). Complete data of 65 patients who were compliant to imatinib treatment for at least 3 months were available for analysis. Eight patients were lost to follow up. Results: The median age of patients was 35 years (age range 17 - 72 years; 40 male). CHR was achieved in 92% patients (60 out of 65 patients). Early molecular response at 3 months (BCR-ABL1, IS) ≤ 10%) was documented in 68% (44 out of 65) patients. The range of BCR-ABL1 transcript level at 3 months was 0.01% - 10% in patients who achieved EMR. EMR was not achieved in about 60% of Sokal high-risk patients and 30% of Hasford high-risk patients. Conclusion: The real scenario of CML treatment in developing countries with resource-constrained settings is very much different from that in the developed countries. The response rates to generic Imatinib therapy in Sokal/Hasford intermediate-risk & high-risk CML-CP patients are not impressive. There is scope for significant improvement in treatment response with upfront 2nd generation TKI therapy in intermediate- & high-risk CML-CP patients, if the drugs can be made available at affordable costs in developing countries. Disclosures No relevant conflicts of interest to declare.

scholarly journals Correlations between Mutations in Cancer-Related Genes, Therapy Responses and Outcomes of the 3 rd Generation Tyrosine Kinase-Inhibitor (TKI) in Persons with Chronic Myeloid Leukemia Failing Prior TKI-Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 308-308
Author(s):  
Xiaoshuai Zhang ◽  
Zongru Li ◽  
Yazhen Qin ◽  
Robert Peter Gale ◽  
Xiaojun Huang ◽  
...  
Keyword(s):  
High Risk ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Functional Enrichment ◽  
Molecular Response

Abstract Background Most, but not everyone with chronic myeloid leukaemia (CML) responds to imatinib or 2 nd-generation tyrosine kinase-inhibitors (TKIs). Mutations in cancer-related genes and in other than ABL1 may explain variable responses and outcomes to the 3 rd-generation TKIs including ponatinib and olverembatinib. Aim Interrogate correlations between mutations in cancer-related genes and therapy responses and outcomes to 3 rd-generation TKIs. Methods We used deep targeted sequencing for cancer-related mutations and Sanger sequencing for BCR::ABL1 on DNA samples from 167 subjects with CML failing to the prior imatinib and/or 2 nd-generation TKI-therapy and just before receiving a 3 rd-generation TKI. Gene ontology (GO) analysis was used to evaluate functional enrichment in GO terms among mutated genes. Optimal cut-offs for variant allele frequencies (VAFs) of the common mutations were determined by analyzing receiver-operator characteristic (ROC) curves. A Cox multi-variable regression model was used to identify correlations between mutations in cancer-related genes and therapy responses and outcomes of 3 rd-generation TKI-therapy. Results 167 subjects in chronic phase (n = 125) and accelerated phase (n = 42) received ponatinib (n = 28) or olverembatinib (n = 139) therapy. 27 subjects were exposed to imatinib; 79, a 2 nd-generation TKI; 61, imatinib and a 2 nd generation TKI. 142 (85%) subjects had ABL1 mutations including ABL1T315I (n = 116) or others (n = 26). 163 subjects had other cancer-related mutations which were evaluated in epigenetic regulators (n = 150), transcription factors (n = 84), cell signaling (n = 42), tumor suppressors (n = 39), protein kinases (n = 27), chromatin modification (n = 9) and DNA damage repair (n = 3) related-genes according to functional enrichment. The top 10 mutations were ASXL1 (n = 115), RUNX1 (n = 12), KMT2D (n = 12), PHF6 (n = 8), KMT2C (n = 8), IKZF1 (n = 8), STAT5A (n = 8), DNMT3A (n = 7), TET2 (n = 6) and BCOR (n = 6). 20 subjects had high-risk additional chromosomal abnormalities (ACAs). Frequency of BCR::ABL1 mutations was inversely- (p < 0.001) and of cancer-related mutations directly-related (p = 0.009) to increasing exposure to prior TKI therapies. These relationships were especially so for mutations in KMT2C (p = 0.06), DNMT3A (p = 0.09), KDM6A (p = 0.06) and TNFAIP3 (p = 0.08). BCR::ABL1 (82% vs. 95%, p = 0.03), RUNX1 (5% vs. 14%, p = 0.04), KMT2C (3% vs. 10%, p = 0.08) and IKZF1 (3% vs. 10%, p = 0.10) were more common in accelerated phase. With a median follow-up of 34 months (interquartile range [IQR], 12-40 months), 95 and 71 subjects achieved a complete cytogenetic response (CCyR) and major molecular response (MMR). 18 subjects transformed to accelerated (n = 8) or blast (n = 10) phases, 16 died of disease progression (n = 12) or other causes (n = 4). 3-year cumulative incidences of CCyR and MMRwere 65% (95% Confidence Interval [CI], 58, 71%) and 52% (43, 61%). 3-year probabilities of progression-free survival (PFS) and survival were 88% (81, 92%) and 91% (85, 95%). Mutations in tumor suppressor genes were more common in subjects not achieving a CCyR (27% vs. 19%, p = 0.01). In multi-variable analyses ASXL1 mutation with a VAF ≥ 17% and a PHF6 mutation were significantly associated with lower cumulative incidences of CCyR (p < 0.001 and p = 0.032) and MMR (p < 0.001 and p = 0.04). Moreover, subjects with BCR-ABL1T315I mutation had significantly higher cumulative incidences of CCyR (p = 0.07) and MMR (p = 0.04) than those with no BCR-ABL1 mutation and other BCR-ABL1 non-T315I mutation. Increasing age, more Ph 1-chromosome-positive cells, the best prior therapy-response < partial cytogenetic response (PCyR) and more TKI-therapies were associated with poor responses. STAT5A mutation was significantly associated with worse PFS (p = 0.002) and survival (p < 0.001), RUNX1 mutation (p = 0.006), high-risk ACAs (p = 0.07) and accelerated phase (p = 0.002) with worse PFS and increasing age (p = 0.05) and comorbidity(ies) (p = 0.05) with wosre survival. Conclusions ASXL1 mutations with a VAF ≥ 17% and PHF6 mutations were associated with poor responses of the 3 rd-generation TKI-therapy. STAT5A and RUNX1 mutations and high-risk ACAs were also associated with worse outcomes in persons receiving a 3 rd-generation TKI. These data should help physicians select people to receive 3 rd-generation TKIs. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Outcomes of Chronic Phase Chronic Myeloid Leukemia after Treatment with Multiple Tyrosine Kinase Inhibitors

2020 ◽  
Vol 9 (5) ◽  
pp. 1542
Author(s):  
Jee Hyun Kong ◽  
Elliott F. Winton ◽  
Leonard T. Heffner ◽  
Manila Gaddh ◽  
Brittany Hill ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Response ◽  
Line Treatment ◽  
First Line ◽  
Blastic Phase

We sought to evaluate the outcomes of chronic phase (CP) chronic myeloid leukemia (CML) in an era where five tyrosine kinase inhibitors (TKIs) are commercially available for the treatment of CML. Records of patients diagnosed with CP CML, treated with TKIs and referred to our center were reviewed. Between January 2005 and April 2016, 206 patients were followed for a median of 48.8 (1.4–190.1) months. A total of 76 (37%) patients received one TKI, 73 (35%) received two TKIs and 57 (28%) were exposed to >3 TKIs (3 TKIs, n = 33; 4 TKIs, n = 17; 5 TKIs, n = 7). Nineteen (9.2%) patients progressed to advanced phases of CML (accelerated phase, n = 6; myeloid blastic phase, n = 4; lymphoid blastic phase, n = 9). One third (n = 69) achieved complete molecular response (CMR) at first-line treatment. An additional 55 patients achieved CMR after second-line treatment. Twenty-five patients (12.1%) attempted TKI discontinuation and 14 (6.8%) stopped TKIs for a median of 6.3 months (range 1–53.4). The 10-year progression-free survival and overall survival (OS) rates were 81% and 87%, respectively. OS after 10-years, based on TKI exposure, was 100% (1 TKI), 82% (2 TKIs), 87% (3 TKIs), 75% (4 TKIs) and 55% (5 TKIs). The best OS was observed in patients tolerating and responding to first line TKI, but multiple TKIs led patients to gain treatment-free remission.

Efficacy of Nilotinib in EARLY Chronic PHASE CML Patients WHO Have Suboptimal Cytogenetic or Molecular Response to Imatinib. A Multicentric Retrospective Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4454-4454
Author(s):  
Luigia Luciano ◽  
Elisa Seneca ◽  
Mario Annunziata ◽  
Luca Pezzullo ◽  
Paolo Danise ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Second Generation ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Treatment Resistance ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Free Survival

Abstract Abstract 4454 The CML-CP suboptimal responders rappresent an eterogenous group of patients in which it is possible either to obtain an optimal renponse or to experiment a failure. The Clinical data of MDACC, Hammersmith Hospital and GIMEMA group showed that patients with suboptimal response at 6 and 12 months have worse long term outcomes than patients with optimal responses, particularly if the suboptimal response occurs early in the treatment, suggesting an advantage for pts with early major molecular response, expecially for event free survival and progression free survival. Moreover, recently, the German group has shown the benefit of early major molecular response on overall survival too. So earlier use of nilotinib or dasatinib in suboptimal CP CML may be beneficial in two potential ways: by promoting an early response, thereby potentially improving prognosis; by avoiding the development of treatment resistance. The clinical challenge in this setting would be to accurately identify patients who are likely to fail treatment with TKIs. This retrospective analysis was designed to explore the efficacy of the early switch to Nilotinib in patients with suboptimal responses to imatinib (IM) according to ELN raccomandations. In this multicentric retrospective study, 15 CML-CP patients with suboptimal response to IM within 24 months from diagnosis were evaluated: 4pts with a low, 3 with intermedied and 5 with high Sokal score. The best response to IM was CCyR for 6 pts, PCyR for one pt and Complete Hematological Response for 5 pts. As for suboptimal responses, 5 pts were defined in suboptimal cytogenetic response: 2 pts at 12 months and 2 pts at 6 months; 6pts were 18 months suboptimal molecular responders and 1 pt had a loss of CCyR at 12 months. All patients were switched to Nilotinib 400 mg twice daily. Bone marrow was done at baseline in all pts and at 3,6,12 and 18 months in cytogenetic suboptimal pts, while the molecular analysis was performed on peripheral blood every three months in all other pts. 12 pts have been treated with Nilotinib for a median of 17,5 months (range 3–37), 9 patients for ≥ 12 months. Before switching to Nilotinib, pts were treated with IM 400 mg once daily apart for 2 patients who needed an adjustment dose to 300 mg and 600 mg for toxicity and suboptimal response, respectively. Among 6 pts with suboptimal CyR, 4 obtained CCyR, 3 at 3 months and one at 6 months; 2 pts had any response at the milestones timepoints and they switched to another therapy. All pts with molecular suboptimal response obtained MMR at 3 months apart for one, who showed MMR at 12 months. Nilotinib was well tolerated in all 12 pts; only one developed a moderate transaminase elevation. A brief drug intrerruption was sufficient to manage this adverse event. Our data confirm that second generation TKIs give deeper and earlier responses also in second line treatment, garantendo optimal PFS and OS. In our serie infact, Nilotinib treatment results in high and relatively quick cytogenetic and molecular response rate in CML –CP-pts with suboptimal response to IM. These results demonstrate that the early switch to Nilotinib could be raccomanded in suboptimal responders in order to improve the outcome of this kind of pts and strongly suggest the second generation TKI as first line therapy in CML patients. A larger patient population and a longer period of observation could allow to confirm these preliminary data. Disclosures: No relevant conflicts of interest to declare.

Evaluation Of hOCT1expression In Patients With Chronic Myeloid Leukemia (CML) Treated With Imatinib In First Line

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4041-4041
Author(s):  
Cintia Do Couto Mascarenhas ◽  
Maria Helena Almeida ◽  
Eliana C M Miranda ◽  
Bruna Virgilio ◽  
Marcia Torresan Delamain ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Taqman Probe ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
First Line ◽  
Transcript Levels

Abstract Introduction The majority of chronic myeloid leukemia (CML) patients (pts) in chronic phase (CP), present satisfactory response to imatinib treatment. However, 25-30% of these pts exhibit suboptimal response or treatment failure. The probability of achieving optimal response may be related with several factors. The human organic cation transporter 1 (hOCT1, SLC22A1), an influx transporter, is responsible for the uptake of imatinib into chronic myeloid leukemia (CML) cells The aim of this study was to analyze hOCT-1 levels at diagnosis of CML patients and correlate with cytogenetics and molecular responses. Methods hOCT-1 expression was evaluated in 58 newly diagnosed CML pts. Pts were treated with imatinib 400-600mg in first line. Samples were collected from peripheral blood at diagnosis and RNA was obtained from total leucocytes. For cDNA synthesis, 3 ug of RNA was used. hOCT-1 expression was evaluated by real-time PCR with TaqMan probe SLC22A1 (Applied Biosystems) and endogenous GAPDH control. The results were analyzed using 2-ΔΔCT. Cytogenetic analysis was performed at diagnosis, 3, 6, 12 and 18 months after starting therapy and then every 12-24 months thereafter if CCR was achieved. BCR-ABL transcripts were measured in peripheral blood at 3-month intervals using quantitative RT-PCR (RQ-PCR). Results were expressed as BCR-ABL/ABL ratio, with conversion to the international scale (IS). Major molecular response (MMR) was defined as a transcript level ≤ 0.1%. Results 58 CML pts, 60% male, median age of 46 years (19-87) were evaluated, 71% in chronic phase (CP), 21% in accelerated phase (AP) and 5% in blast crisis (BC). The mean and median of hOCT-1 transcript levels in the total group was 2.03 and 0.961 respectively (0.008–19.039) and CP pts was 1.86 and 1.00 (0.008-10.34).The median duration of imatinib treatment was 27 months (1-109) and 96.6% achieved complete hematological response, 79.3% complete cytogenetic response and 69% major or complete molecular response. The regression analysis showed correlation between higher transcript levels of hOCT-1 and BCR-ABL transcripts<10%) at 3 months analysis (p<0.0001). Albeit, there was no influence of the hOCT-1 transcript levels at diagnosis in the achievement of cytogenetic and molecular response at 24 months of treatment. Conclusions In this report, we found that high hOCT-1 expression was predictive of BCR-ABL transcripts<10% at 3 months, although we did not find correlation between hOCT-1 levels at diagnosis and the achievement of molecular response at 24 months, studies show that there is correlation between BCR-ABL log reduction in the first months of treatment and the achievement of molecular response. Disclosures: No relevant conflicts of interest to declare.

Deep Molecular Response Achieved By Second-Generation Tyrosine Kinase Inhibitors (TKIs) Can Lead to Stopping TKIs

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1594-1594
Author(s):  
Tetsuro Ochi ◽  
Taiichi Kyo ◽  
Kayo Toishigawa ◽  
Takeshi Okatani ◽  
Ryota Imanaka ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Relapse Rate ◽  
Median Duration ◽  
Second Generation ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Chronic Phase ◽  
Molecular Response ◽  
Molecular Monitoring ◽  
Tki Treatment

Abstract Background: Imatinib (IMA), a first-generation tyrosine kinase inhibitor (TKI), has enabled safer, more successful treatment of chronic myeloid leukemia (CML). Moreover, second-generation TKIs such as nilotinib (NIL) and dasatinib (DAS) have enabled achievement of deeper molecular responses than IM. TKIs have improved prognosis for CML patients, but lifelong continuation of TKIs lowers quality of life and places an economic burden on patients. Whether administration of TKIs can be stopped is thus an important question. Trials including the STIM trial have suggested that IMA can be stopped in CML patients who maintain complete molecular response (CMR) for >24 months, but little data is available regarding second-generation TKIs. Methods: Among adult CML patients in the chronic phase diagnosed at Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital from May 1995 to September 2010, we analyzed patients who achieved and maintained CMR for >1 year on TKIs, and then stopped TKIs. We started TKI treatment with IMA in all patients and changed to NIL or DAS after March 2009, when second-generation TKIs became available in Japan. We continued each TKI for ³6 months, and for >12 months in most cases. Molecular monitoring was performed with BCR-ABL1 real-time quantitative PCR (RQ-PCR) using bone marrow or peripheral blood samples. Sensitivity of this RQ-PCR was 0.004%, corresponding to MR4.4. Relapse was defined as a loss of CMR. We provided TKI therapy for relapsed patients. RQ-PCR was performed every three months after relapse. Results: Stopping TKI was possible in 51 patients (32 males, 19 females). Observations were continued until June 2015, and the median duration of observation was 147 months (range, 59-257 months). Interferon (IFN)-α was administered to 18 patients. Median age at diagnosis was 44 years (range, 22-83 years). Two deaths were observed, with neither due to CML. Median duration of TKI treatment was 91 months (range, 29-160 months). Median interval from starting TKIs until achieving CMR was 41 months (range, 6-144 months), and that from achieving CMR to stopping TKIs was 20 months (range, 10-91 months). Median duration of observation from stopping TKIs was 42 months (range, 4-135 months). TKI treatment comprised IMA alone in 10 patients, IMA → NIL in 8, and IMA →NIL → DAS in 33. Relapse after stopping TKIs was observed in 14 cases. The period from stopping TKIs to relapse was 3 months in 12 patients, and 6 months and 18 months in 1 patient each. We treated all relapse patients with TKIs as patients chose, and all achieved 2nd CMR. Median period from relapse to 2nd CMR was 20.5 months (range, 6-40 months). In univariate analysis by Fisher's exact test, no correlation was seen between relapse rate and sex (male, n=32 vs. female, n=19; p=0.106), history of IFN-α therapy (yes, n=18 vs. no, n=33; p=0.525), duration from achieving CMR to stopping TKI (³24 months, n=34 vs, <24 months, n=17; p=0.183), and use of second-generation TKI (yes, n=34 vs. no, n=10; p=0.25). However, relapse rate was significantly lower in patients who received second-generation TKIs for ³24 months (n=23 vs. <24 months, n=10; p=0.0425). Conclusions: In our cohort, the rate of relapse after stopping TKIs was lower among patients who received second-generation TKIs for a longer period. This suggests that achieving deeper molecular response may be more important than maintaining CMR for a long time when trying to stop TKIs. The fact that most relapses after stopping TKIs occurred 3 months after stopping TKIs implies a need for careful molecular monitoring, particularly just after stopping TKIs. Disclosures No relevant conflicts of interest to declare.

Outcomes of Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia (CML) Who Switch to Imatinib Following Optimal Response to Second Generation Tyrosine Kinase Inhibitors

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1592-1592
Author(s):  
Vamsi K Kota ◽  
Elliott F. Winton ◽  
Martha Arellano ◽  
Anand Jillella ◽  
Morgan L. McLemore ◽  
...  
Keyword(s):  
Second Generation ◽  
Kinase Inhibitors ◽  
Prospective Trial ◽  
Chronic Phase ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Optimal Response ◽  
Log Reduction ◽  
Is Value

Abstract The second-generation TKIs (2G-TKIs) Dasatinib (DAS) and Nilotinib (NIL) yield faster responses in newly diagnosed chronic phase (CP) CML as compared to Imatinib (IM) however, long-term safety of these agents is a growing concern. We identified 10 patients with CP CML diagnosed between 08/2013 and 06/2015 who initiated 2G-TKIs and were then switched after optimal response at 3 months to IM. DAS was administered to 8 patients at 100 mg/d and NIL in two patients at 300 mg twice a day. Response to TKI was assessed by quantitative reverse transcriptase polymerase chain reaction (qPCR) for BCR-ABL1. Response to 2G-TKIs after 3 months was as follows: CHR (n=10), 1 log (<10%, n=10), 2 log (<1%, n=7), and 3 log (<0.1%, n=2) reduction of BCR-ABL1 transcripts. Median qPCR at 3 months was 0.77% by IS (range 0-7%). NIL was discontinued due to grades 2-3 non-hematological toxicities in both patients. DAS was discontinued due to patient or physicians' preference or drug availability. Median time to discontinuation of 2G-TKIs and initiation of IM was 103 days (range, 92 - 120) from diagnosis. IM was started at 400 mg/d and was well tolerated except in 2 patients who required dose-reduction and discontinuation due to grade 2 skin rash (1) and grade 2 anxiety (1). Both patients switched back to DAS at 54 and 228 days after initiation of IM respectively. 9/10 patients that switched to IM were evaluable with a follow up of at least 3 months. These patients have shown a continuous response with 9/9(100%) achieving a 2 log reduction at 6 months. With a median follow-up from initiation of IM of 8 months (range 2-20 months), 5/9 (55.5%) evaluable patients achieved MMR at 6 months and 3/6 MR5 at 9 months from diagnosis. In conclusion, this retrospective analysis shows that IM can be safely and effectively administered following optimal response to 2G-TKIs. Longer follow-up is needed, but with up to 20 months follow-up, all patients showed continuous decrease in their transcripts (Figure 1) and no losses of major molecular response or progression to blast phase were observed. A strategy of induction with 2G-TKIs followed by maintenance with IM is worth evaluating in a prospective trial. Figure 1. BCR-ABL1 qPCR (IS value) at diagnosis and follow-up after a switch to IM at 3 months from 2G-TKIs. Figure 1. BCR-ABL1 qPCR (IS value) at diagnosis and follow-up after a switch to IM at 3 months from 2G-TKIs. Disclosures Kota: Leukemia Lymphoma Society: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees.

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