CD117 (c-kit) Expression On CD34+ Cells Participates In The Cytogenetic Response To Imatinib In CML Patients In First Chronic Phase

Abstract Background Chronic myeloid leukemia (CML) biology seemed to be perfectly explored especially at the beginning of tyrosine kinase inhibitors era (TKI). Later years with imatinib and second generation TKI showed variety of resistance mechanisms and it became obvious bcr-abl chimeric gene is not the only enemy to fight. Some studies assumed the decreased rate of programmed cell death (apoptotic) to be the primary mechanism by which BCR-ABL effects expansion of the leukemic clone in CML. Other studies showed the important role of patients adherence in achieving best possible response for imatinib. Imatinib plasma level was recognized as a useful tool for adherence evaluation. In this study we evaluate the expression of apoptotic marker, Annexin V in CD34+CD117+ cells of CML patients in first chronic phase treated with imatinib and try to find the correlation between this expression and cytogenetic response or imatinib plasma level. Patients The group of 54 CML patients (F/M = 30/24, median age, 50.5) in first chronic phase treated with imatinib (400 mg daily) was analyzed. The median time of treatment was 17 months (min. 12 months, max. 24 months. Only patients with the conventional translocation (Philadelphia chromosome) without additional chromosomal aberrations or clonal evolution during the treatment period were included in the study. Patients were categorized according to ELN criteria for cytogenetic response: complete cytogenetic response (CCyR) vs. no cytogenetic response (NCyR, defined as everything less than CCyR), and for molecular response: major molecular response (MMR) vs. no molecular response (NMR). Results In the cohort of 54 patients, 39 achieved CCyR in a median time of 12 months. Among these patients, 30 achieved MMR within the same time. Bone marrow CD34 positive cells were assessed for expression of CD117 and Annexin V in all groups of patients (CCyR with MMR, CCyR with NMR, and NCyR). The mean percentage of CD34+CD117+ cells was significantly higher in the NCyR group (7.67±5.62) in comparison with the CCyR group (2.27±1,78; p=0.002). The difference between MMR and NMR subgroups was not significant. While analyzing the CD34+CD117+ population, we found a significantly higher percentage of apoptotic cells (Annexin V positive) in the CCyR group (4.65±4.55) than in the NCyR group (1.67±1.22; p=0.004). Once again this difference was not significant between MMR and NMR subgroups. Serum imatinib levels were quantified in both CCyR and NCyR groups. We found higher values in the CCyR group (1244 μg/l±599) than in the NCyR group (1192 μg/l±593) but this difference was insignificant. Conclusions It was recently reported that c-kit must be inhibited to allow apoptosis of CML cells. Our results also correspond with these data. Not only was a lower percentage of CD34+CD117+ cells found in the CCyR group, but the fraction of these cells that were apoptotic was significantly greater compared with the NCyR group. Although other studies have indicated that trough plasma concentration of imatinib reflects clinical response in chronic phase of CML, we did not observe this. Our results showed higher imatinib levels in CCyR, but these data were insignificant. In conclusion, our results indicate that to achieve optimal treatment response in CML patients, c-kit kinase inhibition may be a requirement for successful proapoptotic activity of imatinib. Disclosures: No relevant conflicts of interest to declare.

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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.

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Impact of Imatinib Dose Escalation in Chronic Myeloid Leukemia Patients in Chronic Phase with Sub-Optimal Response or Failure with Imatinib 400 Mg.

Blood ◽

10.1182/blood.v114.22.3289.3289 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3289-3289

Author(s):

Katia BB Pagnano ◽

Marcia T Delamain ◽

Eliana C.M. Miranda ◽

Vagner O Duarte ◽

Brunna Eulálio Alves ◽

...

Keyword(s):

Median Time ◽

Dose Escalation ◽

Conflicts Of Interest ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Dose Increase ◽

Free Survival ◽

Optimal Response ◽

Hematological Response

Abstract Abstract 3289 Poster Board III-1 Imatinib dose escalation has been used in sub-optimal response and therapeutic failure to imatinib in conventional doses. The aim of this study was to evaluate the efficacy of imatinib dose increase in CML patients in CP who did not achieve the best response to imatinib 400 mg QID. Patients and methods: All CML patients in CP treated in our institution with imatinib 400mg between March 2002 and December 2008 were evaluated. Imatinib was escalated to 600–800mg in cases with sub-optimal response or failure, according to Leukemia Net or IRIS Trial criteria. All survival curves were calculated from date of dose increase: overall survival (OS) until death or last follow-up, event free survival (EFS) until loss of complete hematological response (CHR) or major cytogenetic response (MCyR), progression to accelerated phase (AP) or blast crisis (BC) or death from any cause. Transformation free survival (TFS) was calculated from dose increase until progression to AP, BC or death. Results: 137 patients in CP were treated with imatinib 400 mg. Dose was escalated in 55 (40%) patients due to loss or failure to achieve CRH (13 = 24%); progression to BC (2 = 3.5%); no CCR (11 = 20%); loss of RCC (5 = 9%); CCR without major molecular response (MMR) after 18 months of imatinib (24 = 43.5%). Males: 37, females 18 cases. Median age: 44 (16–74) years. Twenty-eight patients (49%) were treated with imatinib as first line therapy and 51% had used IFN previously. Median time between diagnosis and imatinib start was 4.5 (0–94) months. Responses: 94% achieved CHR; 58% CCR and 34% MMR. After dose increase, 31 (56%) responded: 58% of the patients with previous sub-optimal molecular response achieved MMR. Among those who benefited from dose increase, only 3 cases lost the response: one with hematological resistance and two with cytogenetic resistance (2 lost CCR and one CHR). Seven out of 16 patients who increased dose due to cytogenetic failure (loss of response, failure and sub-optimal response) achieved response: one had partial cytogenetic response (PCyR) and 6 CCR. Five patients with hematological failure presented response: CHR (2), CCR (1), PCyR (1) and MMR (1). Patients with BC (2 cases) did not respond to dose escalation. TFS was 89% and 67% in 2 and 5 years, respectively. EFS was 71% and 64% in 2 and 5 years respectively. When stratified by the type of failure, EFS was 100%, 49% and 34% in the group with molecular sub-optimal response with median time of 22 (4–41) months, cytogenetic 17 (1.2–42) and hematological failure 7.7 (0.2–57), respectively (P<0.03). Conclusions: imatinib dose escalation was successful in molecular sub-optimal response. However, the patients who do not achieve MMR might be candidates to second line treatment. Patients who did not achieve cytogenetic or hematological response did worse with imatinib dose escalation. Disclosures: No relevant conflicts of interest to declare.

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Clinical Outcome of CML Patients with Philadelphia Chromosome Complex Variants.

Blood ◽

10.1182/blood.v116.21.4499.4499 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4499-4499

Author(s):

Santiago del Castillo ◽

Regina Garcia Delgado ◽

Laura Entrena ◽

Agustin M Hernandez ◽

Arturo Campos ◽

...

Keyword(s):

Conflicts Of Interest ◽

Philadelphia Chromosome ◽

Genetic Material ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Imatinib Treatment ◽

Current State ◽

Worse Prognosis

Abstract Abstract 4499 INTRODUCTION: The presence of translocation between chromosomes 9 and 22 that characterizes the chronic myeloid leukemia (CML) is occasionally accompanied by more complex variations involving additional exchange of genetic material with other chromosomes. This variants of Philadelphia chromosome have no worse prognosis than those others with the common translocation. MATERIAL: Since 1997 we have diagnosed in our hospital 5 CML patients who didn't show any of these variants. Three women 17, 23 and 76 years old and two men of 36 and 65. All of them diagnosed in chronic phase. Risk stage at diagnosis by Sokal were 1 high, 1 intermediate and 3 low. By Hasford 2 were intermediate end 3 low. Philadelphia chromosome variants involve a third chromosome in 4 cases (translocations 2;9;22, 9;22;12, 9;22;9 and 6;9;22) and in one case involving four chromosomes (translocation 1;2;9;22). Three patients diagnosed before the imatinib approval started treatment with IFN and Ara-C and subsequently changed to Imatinib treatment. Two others started treatment with imatinib directly. RESULTS: All patients had a good outcome with treatment being the current state of 2 patients in complete molecular response (105 and 60 months of follow-up) and 2 patients in Major Molecular Response (146 and 143 months). The 5th patient, a 17 years old woman, has been treated for three months with Imatinib and showed complete haematological response at first month and major cytogenetic response at third month. It is striking in this last patient the fact that two years earlier had been referred for study of myeloid moderate leukocytosis (20,000 leukocytes with circulating myeloid progenitors without anemia, thrombocytosis, or splenomegaly). The patient didn't come to clinic when Bone Marrow Test was cited and two years later resumes the visit continuing with the same leukocytosis in peripheral blood and without splenomegaly unchanged despite not having received any treatment. CONCLUSION: Our experience confirm that this type of patients with complex translocation variants have no worse prognosis than normal translocation under imatinib treatment and suggests that may have a more benign clinical behavior. Disclosures: No relevant conflicts of interest to declare.

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Prognostic Significance of the Lost of a Major Molecular Response In Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia (Ph+CML).

Blood ◽

10.1182/blood.v116.21.3435.3435 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3435-3435

Author(s):

J. Valentin García-Gutiérrez ◽

Pilar Herrera ◽

Marta Jimenez-Rolando ◽

María Tenorio ◽

María Calbacho ◽

...

Keyword(s):

Kinase Inhibitors ◽

Conflicts Of Interest ◽

Residual Disease ◽

Prognostic Significance ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Cytogenetic Response ◽

Myelogenous Leukemia ◽

Molecular Response ◽

Major Molecular Response

Abstract Abstract 3435 Background: Albeit of well-known, dramatic improvements, there remain some questions to be solved around Ph+CML in treatment with tyrosine kinase inhibitors (TKI). Among these, the significance of the amount of minimal residual disease (MRD) measured by RT-PCR. For instance, loss of a so-called major molecular response (MMR) is claimed to be a Òsuboptimal responseÓ and following the ELN recommendations, a change in treatment should be considered in these patients. Aims: To evaluate the relevance of a loss of MMR in patients with complete cytogenetic response (CCR). Study Group and Methods: We have analized 81 patients treated with imatinib for CML in chronic phase with a median follow up of 66 months. 36 patients started imatinib after interferon failure and 45 as front line therapy. Major Molecular Response (MMR; BCR-ABL/ABL ratio<0.1% IS) at any time was achieved by 63 patients. Results: 22 patients (34%) lost MMR (documented al least twice). The risk of losing MMR was higher in late MMR (>18 months) compared with those cases whose MMR came much earlier (<18 months): 70% vs 18% (p=. 000). We have found no correlation among the lost of MMR and classical prognostic factors (Sokal-Index, mutations at the TK domain or imatinib plasma levels). Of these 22 patients, 7 (32 %) recovered MMR later with no therapy changes, 8 (36%) experienced fluctuations in the BCR-ABL transcript-levels without losing CCR, 4 (19%) did not attain a MMR but remained in stable CRR, and 3 (13%) lost CCR. These regained MMR after being treated on second generation TKI. The results show how the stability of the early MMR is greater than late MMR (table1). Conclusions: In our experience, one third of the patients who lost MMR recovered it later on the same treatment. And only 13% went on to treatment failure. Perhaps some similar cases (after first losing MMR) should be closely monitored before a change in treatment. Also of note is, of course regarding only our experience, that the risk of a loss of MMR seems to be maximal in patients who achieve a late MMR. Disclosures: No relevant conflicts of interest to declare.

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Safety and Efficacy of Nilotinib (NIL) in Patients (Pts) with Chronic Phase (CP) or Accelerated Phase (AP) Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia (CML) with Resistance or Intolerance to Imatinib Mesylate (IM): Results from the Multicenter, Observational NOVEL Study in Taiwan

Blood ◽

10.1182/blood.v126.23.1593.1593 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1593-1593

Author(s):

Ching-Yuan Kuo ◽

Po-Nan Wang ◽

Wen Li Hwang ◽

Cheng-Hwai Tzeng ◽

Li-Yuan Bai ◽

...

Keyword(s):

Median Time ◽

Chronic Myelogenous Leukemia ◽

Philadelphia Chromosome ◽

Safety Data ◽

Chronic Phase ◽

Cytogenetic Response ◽

Myelogenous Leukemia ◽

Molecular Response ◽

Safety And Efficacy ◽

Philadelphia Chromosome Positive

Abstract Background: The selective tyrosine kinase inhibitor (TKI) NIL is approved for the treatment of IM resistant CML-CP or CML-AP pts globally, including Taiwan. A non-interventional, multi-center observational study of N ilotinib in pts with CP or AP Philadelphia chrOmosome positiVe (Ph+) chronic myElogenous Leukemia (NOVEL) was conducted to assess the safety and efficacy of NIL in Taiwanese patients with IM intolerance or resistance. Methods: NOVEL was an open-label, single arm, study conducted across 12 centers in Taiwan for a period of up to 2 years (y). Adult CML-CP or CML-AP pts with confirmed Ph+ chromosome (or BCR-ABL) and resistant or intolerant to ≥1 prior CML therapy were enrolled. Also, IM resistant or intolerant pts with prior second-generation TKI therapy could be included. The primary objective was to collect long-term safety data in pts treated with NIL 400 mg twice daily. Efficacy data were collected as secondary objectives. Results: A total of 85 pts including CML-CP (n = 76) pts and CML-AP (n = 9) were enrolled. Median age was 47 y (range, 21-85); 56.5% were males. At baseline, median duration of CML diagnosis was 20.3 (range: 1.4-287.7) months (mo). In 7 pts, confirmed BCR-ABL mutations (E450G, E543A, F317L, F486S, G250E, M244V, M351T) were found, 26 (30.6%) did not have mutations, and 52 (61.2%) did not perform BCR-ABL mutation analysis. All pts (100%) had been treated with prior IM, while 19 pts (22.4%) pts had also received dasatinib; 61 (71.8%) pts had complete hematologic response (CHR) prior to NIL initiation. Of the 85 pts, 54 (63.5%) completed the study while 31 (36.5%) discontinued due to unsatisfactory therapeutic effect (n = 14), consent withdrawal (n = 5), adverse events (n = 4), deaths (n = 3), pregnancy (n = 1), administrative problems (n = 1), unknown (n = 1), and other reasons (n = 2). A total of 1166 AEs were reported by 80 (94.1%) pts, of which 70 (6%) AEs in 28 (32.9%) pts were serious. Of the total AEs, 336 (28.8%) drug-related AEs were reported in 60 (70.6%) pts with the majority (87.5%) being Grade 1 or 2. Of the total drug-related AEs, 85 (25.3%) were hematological and 251 (74.7%) were non-hematological. Common hematological AEs (≥5 % of pts) were thrombocytopenia (n=18; 21.18%) and anemia (n=12; 14.1%). Frequent non-hematological AEs (≥5 % of pts) were increased alanine amino-transferase ([ALT], n = 18; 21.2%), pruritus (n = 15; 17.7%), increased bilirubin (n=12; 14.1%), rash (n = 10; 11.8%), increased aspartate transaminase ([AST], n = 7; 8.2%, and increased lipase (n = 5; 5.9%). Seven deaths were reported during the study and follow-up period, respectively due to cardiopulmonary failure (suspected to be related to study-drug), acute myelogenous leukemia, accident, exacerbation of chronic obstructive pulmonary disease, subarachnoid hemorrhage, pneumonia, and sepsis. Of the 19 pts, who switched to NIL due to known AEs with IM, AEs resolved in 16 (84.2%) pts (Table). Cumulative CHR, major cytogenetic response (MCyR), complete cytogenetic response (CCyR), major molecular response (MMR), MR4.0 (BCR-ABLIS <0.01%) and MR4.5 (BCR-ABLIS <0.0032%) rates are presented in figure. Almost 50% of pts achieved MMR by 18 mo. In pts with confirmed BCR-ABL mutations, the median time to CHR and MMR were 11.9 mo and 37.0 mo compared to 2.3 mo and 16.9 mo in other pts, respectively. In pts without CHR at baseline, median time to CHR and MMR was 3.1 mo and 15.4 mo, respectively. Statistically significant benefit on overall survival (OS) and progression-free survival (PFS) was seen in pts with CML-CP versus pts with CML-AP at screening. Median OS and PFS were not reached for CML-CP pts. In CML-AP pts, median OS was 42.3 mo (95% Confidence interval [CI], 4.4-42.3), and median PFS was 42.3 mo (95% CI, 3.3-42.3). Conclusions: The NOVEL study demonstrates that treatment with NIL was effective in achieving cytogenetic and molecular responses in pts resistant or intolerant to IM in the real world setting. The response outcomes appeared to be influenced by BCR-ABL mutation status and CHR status at baseline, while OS and PFS were influenced by disease status (CML-CP or CML-AP) at screening. Safety profile of NIL was consistent with earlier reports. A number of AEs had lower incidences, with no incidence of peripheral arterial occlusive disorder (PAOD) reported, reflecting appropriate disease management among clinicians in Taiwan. More than 80% of AEs due to IM were resolved after switching to NIL. Disclosures Tang: Novartis: Consultancy, Honoraria. Chang:Novartis: Honoraria. Hseih:Novartis: Employment. Lin:Novartis: Employment. Darko:Novartis: Employment. Cheng-Shyong:Novartis: Honoraria, Speakers Bureau.

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Second-line bosutinib (BOS) for patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML): Final 10-year results of a phase 1/2 study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.7009 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 7009-7009

Author(s):

Carlo Gambacorti-Passerini ◽

Tim H. Brümmendorf ◽

Dong-Wook Kim ◽

Yeow Tee Goh ◽

Irina S Dyagil ◽

...

Keyword(s):

Phase 1 ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Dose Intensity ◽

Cytogenetic Response ◽

Molecular Response ◽

Second Line ◽

Prior Therapy ◽

Kaplan Meier ◽

Imatinib Resistant

7009 Background: BOS is approved for Philadelphia chromosome (Ph)+ CML resistant/intolerant to prior therapy and newly diagnosed Ph+ CP CML. In a phase 1/2 study, second-line BOS showed durable efficacy and manageable toxicity in pts with imatinib-resistant (IM-R) or -intolerant (IM-I) Ph+ CP CML. Methods: This final efficacy and safety analysis of the phase 1/2 study and extension study was based on ≥10 y of follow-up (FU). Ph+ CP CML pts who received BOS starting at 500 mg/d after prior treatment (Tx) with imatinib only were included. Results: 19% of pts were on BOS at y 10, and 13% were still on BOS at study completion after ≥10 y; 19% completed ≥10 y of FU. Median duration of Tx and FU were 26 and 54 mo, respectively. Median (range) dose intensity was 436 (87–599) mg/d. The most common primary reasons for permanent Tx discontinuation were lack of efficacy (unsatisfactory response or disease progression; 27%) and adverse events (AEs; 26%). In pts with a valid baseline assessment, cumulative complete cytogenetic response (CCyR), major molecular response (MMR) and MR4 rates (95% CI), respectively, were 50% (43–56), 42% (35–49) and 37% (30–44) (IM-R: 48% [41–56], 46% [37–55] and 39% [31–48]; IM-I: 53% [41–64], 36% [25–48] and 33% [22–45]). Responses were durable, with estimated probabilities of maintaining CCyR, MMR and MR4 > 50% after ≥10 y (Table). At 10 y, cumulative incidence of on-Tx progression/death was 24% and Kaplan-Meier (K-M) overall survival 72% (Table); 55 deaths (IM-R: n = 41; IM-I: n = 14) occurred on study, none BOS-related. Any grade Tx-emergent AEs (TEAEs) in ≥40% of pts were diarrhea (86%), nausea (46%) and thrombocytopenia (42%). Pleural effusion, cardiac and vascular TEAEs occurred in 13%, 12% and 11% of pts, respectively. 28% of pts had AEs leading to permanent Tx discontinuation; most common (≥2% of pts) were thrombocytopenia (6%), neutropenia (2%) and alanine aminotransferase increased (2%). Conclusions: These 10-y data are consistent with prior results of durable efficacy and manageable toxicity with second-line BOS and support long-term BOS use in CP CML pts after imatinib failure. Clinical trial information: NCT00261846 and NCT01903733. [Table: see text]

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Dasatinib Efficacy in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and Pre-Existing BCR-ABL Mutations

Blood ◽

10.1182/blood.v112.11.449.449 ◽

2008 ◽

Vol 112 (11) ◽

pp. 449-449 ◽

Cited By ~ 5

Author(s):

Martin C Müller ◽

Jorge Cortes ◽

Dong-Wook Kim ◽

Brian J. Druker ◽

Philipp Erben ◽

...

Keyword(s):

Amino Acids ◽

Median Time ◽

Chronic Phase ◽

Response Rates ◽

Cytogenetic Response ◽

Molecular Response ◽

Imatinib Treatment ◽

Imatinib Resistant ◽

Dasatinib Treatment

Abstract Dasatinib (SPRYCEL®) is an effective BCR-ABL inhibitor that is 325-fold more potent than imatinib and 16-fold more potent than nilotinib in vitro against unmutated BCR-ABL. Across a series of phase II and III trials, dasatinib has demonstrated durable efficacy in patients with CML following resistance, suboptimal response, or intolerance to imatinib. BCR-ABL mutations are an important cause of imatinib failure and suboptimal response. Here, the efficacy of dasatinib in patients with CML-CP who had baseline BCR-ABL mutations following imatinib treatment was analyzed using data from three trials (CA180-013, -017, and -034). Mutational assessment of the BCR-ABL kinase domain was performed using RT-PCR and direct sequencing of peripheral blood cell mRNA. Hematologic, cytogenetic, and molecular response rates were reported after ≥24 mos of follow-up. Duration of response, progression-free survival (PFS), and overall survival (OS; in 013/034) were calculated using Kaplan-Meier analysis, and rates were estimated at the 24-mo time point. Of 1,150 patients with CML-CP who received dasatinib, 1,043 had a baseline mutational assessment and were analyzed further. Of these, 402 patients (39%) had a BCR-ABL mutation, including 8% of 238 imatinib-intolerant and 48% of 805 imatinib-resistant patients. Excluding known polymorphisms, 64 different BCR-ABL mutations were detected affecting 49 amino acids, with G250 (n=61), M351 (n=54), M244 (n=46), F359 (n=42), H396 (n=37), Y253 (n=26), and E255 (n=25) most frequently affected. Dasatinib treatment in patients with or without a baseline BCR-ABL mutation, respectively, resulted in high rates of major cytogenetic response (MCyR; 56% vs 65%), complete cytogenetic response (CCyR; 44% vs 56%), major molecular response (MMR; 33% vs 45%); PFS (70% vs 83%), and OS (89% vs 94%) (Table). After 24 mos, CCyRs in patients with or without a BCR-ABL mutation had been maintained by 84% vs 85%, respectively, of those achieving this response. Among patients with mutations who received dasatinib 100 mg once daily, which has a more favorable clinical safety profile, efficacy and durability were similar (MCyR: 55%; CCyR: 41%; MMR: 36%; PFS: 73%; OS: 90%). In general, high response rates and durable responses were observed in patients with different mutation types, including highly imatinib-resistant mutations in amino acids L248, Y253, E255, F359, and H396. When responses were analyzed according to dasatinib cellular IC50 for individual BCR-ABL mutations, dasatinib efficacy was observed in 44 patients who had any of 5 imatinib-resistant mutations with a dasatinib cellular IC50 >3 nM (Q252H, E255K/V, V299L, and F317L, excluding T315I), including MCyR in 34%, CCyR in 25%, MMR in 18%, PFS in 48%, and OS in 81%. Among patients whose mutations had a dasatinib IC50 ≤3 nM (n=254) or unknown IC50 (n=83), responses and durability were comparable to patients with no BCR-ABL mutation. As expected, few patients with a T315I mutation (IC50 >200 nM; n=21) achieved a response. Among 70 patients with >1 mutation, a MCyR was achieved in 53% and a CCyR in 37%. Among patients with mutational analysis at last follow-up (n=162), 42 (26%) retained a BCR-ABL mutation (20 retained a mutation with IC50 >3 nM), 42 (26%) lost a mutation (5 lost a mutation with IC50 >3 nM), and 44 (27%) developed a new mutation (39 developed a mutation with IC50 >3 nM), with some patients counted in more than one category. Overall, this analysis demonstrates that dasatinib has broad efficacy against all BCR-ABL mutations except for T315l. For patients with BCR-ABL mutations, dasatinib treatment is associated with durable responses and favorable long-term outcomes. Table Analysis by dasatinib IC50 No BCR-ABL mutation BCR-ABL mutation BCR-ABL mutation treated with 100 mg QD >3 nM (excl. T315I) 3 nM* Unknown IC50** Some patients had >1 mutation. *Excluding patients with a concurrent mutation with dasatinib IC50 >3 nM. **Excluding patients with a concurrent mutation with known dasatinib IC50. Patients, n 641 402 49 44 254 83 Response rates (≥24 mos of follow-up), % CHR 93 90 90 82 94 96 MCyR 65 56 55 34 58 73 CCyR 56 44 41 25 47 54 MMR 45 33 36 18 34 43 Median time to MCyR, mos 2.8 2.9 2.8 5.7 2.9 2.8 Median time to CcyR, mos 3.0 5.3 3.0 5.7 5.4 3.4 24-mo PFS (95% CI), % 83 (79.8–86.5) 70 (65.3–75.2) 73 (60.1–86.3) 48 (31.2–64.7) 73 (66.6–78.9) 89 (82.3–96.3) 24-mo OS (95% CI), % 94 (91.4– 95.7) 89 (85.1– 92.1) 90 (81.2– 98.3) 81 (68.8– 93.8) 90 (85.8– 94.2) 96 (91.2–100)

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Results of Imatinib Dose Escalation After 36 Months of Follow-up in Chronic Myeloid Leukemia Patients with Failure or Sub-Optimal Response According to 2006 EuropeanLeukemia Net (ELN) Criteria.

Blood ◽

10.1182/blood.v114.22.3302.3302 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3302-3302

Author(s):

Massimo Breccia ◽

Fabio Stagno ◽

Roberto Latagliata ◽

Paolo Vigneri ◽

Laura Cannella ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Dose Escalation ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Standard Dose ◽

Acquired Resistance ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response

Abstract Abstract 3302 Poster Board III-190 Introduction Imatinib mesylate (IM) given at a daily dose of 400 mg currently represents the gold standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CP). European LeukemiaNet (ELN) guidelines propose IM dose escalation to rescue those CML patients with either suboptimal response or drug resistance. We report on the long-term efficacy of IM dose escalation in 74 patients with CP-CML after suboptimal response or failure to IM conventional dose. Patients and methods Median age was 50 years (range 19-85), there were 52 males and 22 females. Thirteen patients were classified as hematologic failure (10 primary and 3 secondary), 57 patients as cytogenetic resistance (24 primary and 33 acquired). Three patients escalated the dose for cytogenetic suboptimal response and one patient for molecular suboptimal response at 18 months. Fifty-four received IM dose escalation from 400 to 600 mg and 20 patients from 400 to 800 mg. Results Overall, after a median follow-up of 36 months, 68/74 (91.8%) patients maintained or achieved a complete haematologic response (CHR); this was maintained in all patients who escalated the dose for cytogenetic failure or suboptimal response. A major cytogenetic response (MCyR) was achieved in 41 patients (72%) who escalated the dose for cytogenetic failure and in 6/13 (46%) patients who escalated imatinib for hematologic failure (p=0.002). Overall, complete cytogenetic responses (CCR) were achieved in 27 (37%) out of 74 CML patients: of the 13 hematologic failure patients, only 5 achieved CCyR: all patients had prior acquired resistance to imatinib. Of the 57 cytogenetic failure, 22 reached CCR: this response was obtained in 27% of the primary cytogenetic resistant, and in 50% of the acquired cytogenetic resistant patients (p=0.02). Three patients who escalated the dose for cytogenetic suboptimal response obtained CCR and complete molecular response (CMR), whereas one patient who escalated the dose for molecular suboptimal response at 18 months did not obtain CMR. Median time to cytogenetic response was 3.5 months. Cytogenetic responses occurred in 37/50 patients who escalated the dose to 600 mg and in 10/20 patients who escalated to 800 mg daily (p=0.234). CMR was obtained in 10 patients: in 7 patients who escalated the dose for cytogenetic failure and in 3 patients who escalated imatinib for suboptimal cytogenetic response. Estimated 2 year-progression free survival (PFS) and overall survival (OS) is 87% and 85% respectively. Sixteen patients (21.6%) experienced toxicities and had temporarily IM interruption. Conclusions Imatinib dose escalation can induce sustained responses in a subset of patients with cytogenetic resistance and a prior suboptimal cytogenetic response to standard-dose imatinib, whereas it appears less effective in haematologic failure patients or in molecular sub-optimal responders. The availability of second generation TKI should be taken into account in these letter categories of patients. Disclosures No relevant conflicts of interest to declare.

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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 ◽

10.1182/blood-2021-150020 ◽

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.

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Switching patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with residual disease on long-term imatinib (IM) to nilotinib (NIL): ENESTcmr 24-mo follow-up.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.7053 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 7053-7053

Author(s):

Nelson Spector ◽

Brian Leber ◽

Jeffrey Howard Lipton ◽

Carmino De Souza ◽

Beatriz Moiraghi ◽

...

Keyword(s):

Residual Disease ◽

Blast Crisis ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Molecular Responses ◽

The Difference ◽

Treatment Free Remission

7053^ Background: The 12-mo results of ENESTcmr demonstrated that switching pts on IM with sustained BCR-ABL positivity to NIL leads to faster, deeper molecular responses (MRs)vs remaining on IM. These deeper molecular responses (MR4.5 [BCR-ABL ≤ 0.0032%IS] or greater) are a prerequisite to enter most treatment-free remission studies. Here, we report 24-mo f/u of ENESTcmr. Methods: Philadelphia chromosome–positive CML-CP pts (N = 207) who achieved a complete cytogenetic response, but had detectable BCR-ABL transcripts after ≥ 2 y on IM, were randomized to receive NIL 400 mg twice daily (BID; n = 104) or continue their IM dose (400/600 mg once daily [QD]; n = 103). Results: By 24 mo, significantly more pts achieved confirmed undetectable BCR-ABL (by RQ-PCR with ≥ 4.5 log sensitivity in 2 consecutive samples) with a switch to NIL vs continuing IM (22.1% vs 8.7%; P = .0087). The increase in the rate of undetectable BCR-ABL from mo 12 to 24 was higher for pts on NIL vs IM (9.6 vs 2.9 percentage points). In pts without MR4.5 at baseline (BL), MR4.5 was achieved by 24 mo in 42.9% vs 20.8% of pts (NIL vs IM; P = .0006). In pts without major molecular response (MMR; ≤ 0.1%IS) at BL, MR4.5 was achieved by 24 mo in 29.2% vs 3.6% of pts (P = .016). No progressions to accelerated phase/blast crisis or deaths occurred on study since the 12-mo f/u. Event-free survival at 24 mo was 96.6% vs 92.8% in the NIL and IM arms, respectively. Discontinuations due to adverse events occurred in 11.5% and 2.9% of pts in the NIL and IM arms. The NIL safety profile was consistent with prior switch studies. Conclusions: By 24 mo, significantly more pts achieved deeper responses (MR4.5and undetectable BCR-ABL) with switch to NIL vs remaining on IM, and the difference between arms in these endpoints increased between 12 and 24 mo. Clinical trial information: NCT00760877. [Table: see text]

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