Outcomes of Chronic Phase Chronic Myeloid Leukemia Patients Following Tyrosine Kinase Inhibitors Dose-Reductions

Abstract Introduction: Tyrosine kinase inhibitors (TKI) are overall well tolerated in chronic myeloid leukemia (CML) s, but more than 30% require dose reduction or change to another TKIs due to intolerance. Impact of TKI dose-reduction on outcomes in a "real world" setting is unknown, thus, we evaluated the characteristics and outcomes of chronic phase (CP)-CML patients who received doses of TKI lower than the label/FDA recommendation. Method: CP-CML with at least 12 months of follow-up, with ISBCR/ABL1 available after dose reduction were selected. Last TKI was defined as TKI which were taken at the last follow up visit or before disease progression to accelerated (AP) or blast phase (BP). FDA approved doses of imatinib (IM), dasatinib (DAS), nilotinib (NIL), bosutinib (BOS), and ponatinib (PON) were 400mg, 100mg, 600mg (300mg BID), 500mg, and 45mg, respectively . Results: Between January 2005 and April 2016, 173 CP-CML patients, started IM (75%), DAS (18%) NIL (5%) and PON, BOS on clinical trial in 2%. Overall Fifty-eight (33.5%) patients had TKI dose reduction. IM (n=15) dose was reduced to 75% (range, 25-75), DAS (n=15) to 50% (range, 20-80), NIL (n=15) to 50% (range, 13-67), BOS (n=15) to 80% (range, 40-80) and PON (n=15) to 33% (range, 33-67). Median age for patients that received dose-reduced TKI was 55 (range, 18-88), and 27% received > 3 prior TKIs. With a median follow up of 53.6 (range 13.4-183.7) months, only 1 progressed to AP, and none to BP. Overall 60% achieved MMR. Among 35 patients who achieved MMR before dose reduction, MMR was maintained in 25 (71.4%) for a median of 17.2 (2-97.9) months from dose-reduction. CMR was achieved in patients on a maintenance dose of IM, 100mg QD (n=8); DAS, 20mg QD (n=4); NIL 300mg QD (n=3) and BOS, 200mg QD (n=3). Conclusion: Similar to data reported from clinical trials, TKI dose reduction appears to be safe and associated with high response rates. This data confirms that the minimal effective dose for each TKI remains to be defined. Disclosures Heffner: Pharmacyclics: Research Funding; AbbVie: Research Funding; Millennium: Research Funding; Celgene: Research Funding. Jillella:Leukemia Lymphoma Society: Research Funding. Kota:Ariad Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

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Second Treatment Free Remission after Combination Therapy with Ruxolitinib Plus Tyrosine Kinase Inhibitors in Chronic Phase Chronic Myeloid Leukemia (CML)

Blood ◽

10.1182/blood-2021-147954 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2555-2555

Author(s):

Kendra Sweet ◽

Ehab L. Atallah ◽

Jerry P. Radich ◽

Mei-Jie Zhang ◽

Eva Sahakian ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Molecular Response ◽

Advisory Committees ◽

Treatment Free Remission ◽

One Year

Abstract Background: Discontinuation of tyrosine kinase inhibitors (TKIs) is feasible in a subset of CML patients who have maintained a deep molecular response for at least two years. Numerous discontinuation trials have been performed and consistently show approximately 50% of patients relapse after stopping TKIs. A recent study examining rates of treatment free remission (TFR) after a second attempt at stopping TKIs found, with a median follow up time of 38.3 months, 64.3% of patients had a molecular relapse (defined as a loss of major molecular response (MMR)). At 12, 24 and 36 months, TFR rates were 48%, 42% and 35%, respectively. These data suggest some patients with a history of molecular relapse upon TKI cessation could successfully stop treatment on a subsequent attempt, yet the majority will relapse a second time. 'Complete eradication' of CML remains elusive in most patients likely as a result of minimal residual disease (MRD), which is the result of BCR-ABL independent drug resistance. More specifically, CML cells that reside in sanctuary sites such as the bone marrow adhere to fibronectin and demonstrate cell adhesion mediated drug resistance (CAM-DR). The bone marrow microenvironment contains many cytokines and growth factors capable of inducing STAT3-Y705 phosphorylation via the JAK-STAT pathway leading to protection against TKI-induced cell death. Inhibiting JAK2 and TYK2 leads to complete inhibition of pSTAT3-Y705, thereby implicating the role of activation of JAK2 and TYK2 in STAT3-Y705 phosphorylation and resistance towards BCR-ABL TKI-induced cell death. A phase I clinical trial combined ruxolitinib, which inhibits JAK2 and TYK2, plus nilotinib in chronic phase (CP) CML patients and found that ruxolitinib 15mg PO BID was safe and well tolerated with 4/10 patients achieving undetectable BCR-ABL1 transcripts by PCR. Study Design and Methods: This single arm phase II study (NCT03610971) will enroll 41 subjects from the H Jean Khoury Cure CML Consortium. Eligible subjects must have a confirmed diagnosis of CP-CML and have previously attempted to discontinue TKI therapy per NCCN guidelines and had molecular recurrence, defined as loss of MMR, and were restarted on TKI. This trial combines ruxolitinib 15mg BID plus BCR-ABL TKI (imatinib, dasatinib, nilotinib or bosutinib) for 12 28-day cycles in the combination treatment phase (CTP). RQ-PCR to measure BCR-ABL transcripts will be checked at screening and every three months during the CTP. In the event that a subject experiences intolerance to a TKI, has confirmed loss of MMR, or loss of MR4.5 (>0.0032% IS) on two central PCR results, or discontinues ruxolitinib, the subject will be removed from CTP and enter into long term follow-up (LTFU). CTP phase will be followed by further RQ-PCR screening for the concurrent TFR phase. At this time ruxolitinib will be discontinued and any subject who has met the criteria for the TFR phase will be enrolled. During the TFR phase, subjects will discontinue their TKI and be monitored off treatment with RQ-PCR checked monthly for the first year, every six weeks for year two, and every 12 weeks during year three. Upon molecular recurrence, defined as loss of MMR, TKIs will be restarted. The primary endpoint is the 12-month TFR rate subsequent to completion of 12 cycles of combination therapy; however, subjects will remain in the TFR phase for three years. Therefore, the total duration of the trial will be approximately five years (one year on CTP + three years in the TFR phase + one-year LTFU). Study statistical design was calculated to yield a one-sided type I error rate of 0.025 and power of 65% when the true one-year relapse rate is 35%. This study will additionally assess patient-reported outcomes in conjunction with RQ-PCR testing. PROMIS and other measures will be self-administered through REDCap. Correlative studies will include comparing changes in pSTAT3 in K562 and KU812 cell lines using plasma from CML patients being treated with TKIs plus ruxolitinib, using the plasma inhibitory assay technique. Changes in pSTAT3 and pSTAT5 will be correlated with clinical response and rate of TFR. Additional correlatives include multiparameter flow-based assessment of the T-cell compartment (activity/polarization) as well as natural killer cell fractions in CML patients at various time points (TKIs alone, TKIs plus ruxolitinib and during TFR). Thus far, 14 patients have been enrolled. Disclosures Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Atallah: Amgen: Consultancy; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Abbvie: Consultancy, Speakers Bureau. Radich: Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Thompson: Novartis/ Bristol-Myers Squibb: Research Funding. Mauro: Pfizer: Consultancy; Takeda: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sun Pharma / SPARC: Research Funding. Pinilla Ibarz: AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory; Sellas: Other: ), patents/royalties/other intellectual property; MEI, Sunesis: Research Funding; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau. OffLabel Disclosure: Ruxolitinib is being used off-label in chronic myeloid leukemia

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Myeloid Blast Crisis of Philadelphia Positive Chronic Myeloid Leukemia and Philadelphia Positive Acute Myeloid Leukemia Treated at the AP-HP in Paris: A Retrospective Analysis

Blood ◽

10.1182/blood-2020-140998 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 35-36

Author(s):

Matteo Dragani ◽

Rathana Kim ◽

Clémence Loiseau ◽

Madalina Uzunov ◽

Felipe Suarez ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Advisory Committees ◽

Lost To Follow Up ◽

Acute Myeloid

Introduction :Since the introduction of tyrosine kinase inhibitors (TKIs) the prognosis of Philadelphia positive (Ph+) diseases like chronic myeloid leukemia (CML) dramatically improved (Sasaki K, Lancet Haematol 2015). Nonetheless, myeloid blastic crisis of CML (MBC-CML) and Ph+ acute myeloid leukemia (AML) represent a clinical challenge due to their rarity, the absence of a standard therapy and mutations. Methods :We collected clinical data of patients treated in Paris in 5 different hospitals with confirmed diagnosis in patients with CML successively transformed in MBC-CML, and in patients with MBC-CML straight away or Ph+ AML. We performed descriptive analysis as well as analysis on overall survival (OS) and event-free survival (EFS). Results :We found 64 patients (24 F/40 M) treated since 2001 to present days. 35/64 patients had an history of CML before MBC of which 30 were diagnosed in chronic phase (Sokal risk: low 3 pts, intermediate 8 pts, high 4 pts, NA 15 pts) and 5 in accelerated phase according to ELN classification. Lines of treatment before MBC for these 35 patients were principally TKIs, IFN, hydroxyurea and homoarringtonine: 11 pts experienced only 1 line of treatment, 15 pts 2 lines, 5 pts 3 lines, 1 pt 4 lines and 3 pts 5 lines. Best response before MBC was complete hematological remission (CHR) for 14 pts, complete cytogenetic remission (CCyR) for 7 pts, molecular remission for 6 pts (4 pts MR3, 1 pt MR4, 1 pt CMR TKI free), whereas 8 pts never gained any response. 21/64 pts were in MBC at diagnosis and 8/64 pts were classified as Ph+ AML. At diagnosis of MBC/AML median age was 49 years old (11-73). 12/64 pts had an extramedullary/central nervous system (CNS) involvement of which 2 pts presented a solitary CNS disease and 3 patients had lesions compatible with myeloid sarcomas without marrow blasts. 46/64 pts (72%) received a classical induction therapy (mostly cytarabine + anthracycline combination) combined in 40 pts with a TKI (15 pts Imatinib, 13 pts Dasatinib, 2 Nilotinib and 10 Ponatinib). 11/64 pts (17%) started Azacytidine (1 pt in combination with Imatinib, 2 pts with Nilotinib, 6 pts with Dasatinib, 1 pt with Ponatinib and 1 pt with Venetoclax). 2/64 pts (3%) received Dasatinib monotherapy. 1/64 pt (2%) received ATRA+ATO+Dasatinib combination. 4/64 pts (6%) received only best supportive care. At first revaluation after therapy 47 pts (78%) were in CR/CRi, 9 pts (15%) were refractory, 2 pts (3%) died during induction, 1 pt (2%) induction therapy is ongoing, in 1 pt (2%) lost to follow up. Most patients who obtained CR/CRi after induction continued with consolidations, mostly high-dose Cytarabine associated with a TKI. 41 pts (68%) were transplanted (40 alloHSCT, 1 autoHSCT), 38 pts in first CR (CR1), 1 pt in second CR (CR2) and 2 pts in progressive disease. Notably, 1 pt who had only Dasatinib monotherapy without any form of chemotherapy nor allotransplant is still alive and in second chronic phase after more than two years of follow up. Median follow up for patients who received an active treatment was 23 months. Median OS was 44 months and median EFS was 29 months (figure 1). The only factor whose impact was significant for both OS and EFS in our cohort was transplant (p<0.0001, median OS not reached and median EFS was 93 months for transplanted patients). At last follow up, 30 pts (47%) are still alive (29 in CR, 1 pt with active refractory disease), 30 pts (47%) died, 4 pts (6%) are lost to follow up. Causes of death were progression of disease for 18 pts, sepsis for 7 pts, GVHD for 3 pts, ischemic stroke for 1 pt, cardiovascular complications for 1 pt. Conclusion :We showed here a multicentric experience about an unselected cohort of patients with MBC CML and Ph+ AML who received different treatments according to age, comorbidities, performance status, TKI availability. Survival of this cohort was mostly linked to the possibility to achieve CR and to perform an allotransplant. Already published experiences showed a generical dismal prognosis with median OS which doesn't exceed 1-2 years (16 months, Deau B, Leukemia Research 2011 ; 12 months, Palandri F, Haematologica 2008 ; 6.4 months, Fruehauf S, Cancer 2007) whereas in our real life cohort median OS was longer. For fit and potentially « transplantable » patients, combination with classic chemotherapy plus a TKI seems reasonable and associated with good outcomes in terms of OS and EFS. Disclosures Rousselot: Incyte:Consultancy, Research Funding;Pfizer:Consultancy, Research Funding;Bristol-Myers Squibb:Consultancy;Novartis:Consultancy;Takeda:Consultancy.Itzykson:Jazz Pharmaceuticals:Honoraria, Membership on an entity's Board of Directors or advisory committees;Daiichi Sankyo:Honoraria;BMS (Celgene):Honoraria;Sanofi:Honoraria;Astellas:Honoraria;Oncoethix (now Merck):Research Funding;Novartis:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen:Research Funding;Stemline:Membership on an entity's Board of Directors or advisory committees;Karyopharm:Membership on an entity's Board of Directors or advisory committees;Otsuka Pharma:Membership on an entity's Board of Directors or advisory committees;Amgen:Membership on an entity's Board of Directors or advisory committees;Abbvie:Honoraria.Cayuela:Incyte:Speakers Bureau;Novartis:Speakers Bureau.Rea:BMS:Membership on an entity's Board of Directors or advisory committees;Novartis:Honoraria, Membership on an entity's Board of Directors or advisory committees;Pfizer:Honoraria, Membership on an entity's Board of Directors or advisory committees;Incyte:Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Comparative Efficacy Among 3rd Line Post-Imatinib Chronic Phase-Chronic Myeloid Leukemia (CP-CML) Patients after Failure of Dasatinib or Nilotinib Tyrosine Kinase Inhibitors

Blood ◽

10.1182/blood.v124.21.4551.4551 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4551-4551 ◽

Cited By ~ 2

Author(s):

Jeffrey H. Lipton ◽

Dhvani Shah ◽

Vanita Tongbram ◽

Manpreet K Sidhu ◽

Hui Huang ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Kinase Inhibitors ◽

Cytogenetic Response ◽

Comparative Efficacy ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract INTRODUCTION Patients with chronic myeloid leukemia (CP-CML) failing 1st line imatinib are most commonly treated with the second-generation (2G) tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib. However, for patients who experience resistance or intolerance (R/I) to 2G-TKIs in 2nd line, there currently is no consensus on the optimal therapy sequence for 3rd line treatment. The comparative efficacy of using ponatinib in the 3rd line after 2G TKI failure was examined in a previous study (Lipton et al., ASH 2013). This study assesses the comparative efficacy of ponatinib versus sequential treatment of alternate 2G TKIs in 3rdline setting in two separate patient populations, post-imatinib and dasatinib patients and post-imatinib and nilotinib patients. METHODS A systematic review was conducted in MEDLINE, EMBASE and the Cochrane Libraries (2002-2014), as well as 3 conferences (ASH (2008-2014), ASCO (2008-2014), and EHA (2008-2013)). Studies evaluating any TKI were included if they enrolled 10 or more post-imatinib adult patients with CP-CML who were also R/I to dasatinib or nilotinib. All study designs were considered and no restriction was applied with respect to therapy dose, due to incomplete reporting of doses in the available studies. Analyses was run on two groups of patients, those failing imatinib and dasatinib (Group Ima/Das) and those failing imatinib and nilotinib (Group Ima/Nil). Bayesian methods were used to synthesize major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) from individual studies and estimate the overall response probability with 95% credible interval (CrI) for each treatment. Bayesian analysis also was used to estimate the likelihood that each treatment offers the highest probability of CCyR/MCyR based on available evidence. RESULTS Six studies evaluating bosutinib, nilotinib and ponatinib for Group Ima/Das (n= 419) and five studies evaluating bosutinib, dasatinib and ponatinib for Group Ima/Nil (n=83) were included in the analysis. All studies reported CCyR in both groups. Five studies evaluating bosutinib, nilotinib and ponatinib reported MCyR in Group Ima/Das and three studies evaluating bosutinib and ponatinib reported MCyR in Group Ima/Nil. Synthesized treatment-specific probabilities and 95% CrI for CCyR are presented in Figure 1. Synthesized treatment-specific probabilities of CCyR for Group Ima/Das were 27% for nilotinib, 20% for bosutinib and 54% (95% CrI 43%% to 66%) for ponatinib. Treatment-specific probabilities of MCyR for Group Ima/Das were 41% for nilotinib, 28% for bosutinib and 66% (95% CrI 55%% to 77%) for ponatinib. The probability of ponatinib providing superior response to all other included treatments for group Ima/Das was estimated to be >99% for both CCyR and MCyR. Synthesized treatment-specific probabilities of CCyR for Group Ima/Nil were 25% for dasatinib, 26% for bosutinib and 67% (95% CrI 51%% to 81%) for ponatinib. Treatment-specific probabilities of MCyR for Group Ima/Nil were 33% for bosutinib and 75% (95% CrI 60%% to 87%) for ponatinib. The probability of ponatinib providing superior response to all other included treatments for group Ima/Nil was estimated to be >99% for both CCyR and MCyR. CONCLUSIONS The post imatinib and dasatinib group included more studies with larger sample sizes compared with the post imatinib and nilotinib group. Overall, response rates appear higher for TKIs in the post imatinib and nilotinib group compared with the post imatinib and dasatinib group. For both groups, patients on ponatinib had higher CCyR and MCyR rates compared with the sequential 2G TKIs included in this analysis. Based on available data, ponatinib appears to provide a higher probability of treatment response for patients failing imatinib and dasatinib/ nilotinib compared with sequential 2G TKI therapy commonly used in this indication. Figure 1 Figure 1. Disclosures Lipton: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Shah:Ariad Pharmaceuticals: Research Funding. Tongbram:Ariad Pharmaceuticals: Research Funding. Sidhu:Ariad Pharmaceuticals Inc.: Research Funding. Huang:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. McGarry:ARIAD Pharmaceutical, Inc.: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals Inc: Employment, Equity Ownership. Hawkins:Ariad Pharmaceuticals Inc.: Research Funding.

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Survey of the Frontline Treatment and Management of Chronic Myeloid Leukemia (CML) in a Real-Word Setting: The 3rd Annual Update of the Worldwide Observational Registry Collecting Longitudinal Data on Management of Chronic Myeloid Leukemia Patients (The WORLD CML Registry)

Blood ◽

10.1182/blood.v118.21.1695.1695 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1695-1695

Author(s):

Ricardo Pasquini ◽

Jorge E. Cortes ◽

Hagop M. Kantarjian ◽

David Joske ◽

Luis A Meillon ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Disease Status ◽

Asia Pacific ◽

Primary Therapy ◽

Molecular Monitoring ◽

Advisory Committees

Abstract Abstract 1695 Background: A global, prospective registry was established to document the frequency of diagnostic testing, management (mgmt) strategies, and outcomes of patients (pts) with CML. Here, we summarize the reported deviations from published disease mgmt recommendations and the overall efficacy achieved by pts. Methods: 1853 pts (≥ 16 years of age) within 6 months (mo) + 2 weeks of CML diagnosis were enrolled from Latin America (LA; n = 497), United States (US; n = 379), Asia Pacific (AP; n = 465), Middle East and Africa (MEA; n = 209), and Russia and Turkey (RT; n = 303). Baseline demographics and medical history were collected at enrollment; current disease status and mgmt information were collected at approximately 6-mo intervals or with a change in disease status or mgmt. Results: From February 2008 to June 2011, data were available for 1831 (99%) pts. Across all regions, nearly all (93.8%) screened pts were in chronic phase CML. Regardless of the time of evaluation (eval), disease burden was mostly assessed through the use of hematologic counts (Table 1). Cytogenetic testing and molecular monitoring were used in a minority of pts at any timepoint. Hydroxyurea (HU) and imatinib were the first agents used in 61.9% and 29.5% of pts, respectively (Table 2). Overall, 81.1% of pts received imatinib therapy at some time and it was the most common second agent (48.1%) pts received. Among the 49% of pts who had response assessments, subsequent treatment changes occurred most frequently (23.9% of pts) at the 3-mo timepoint (Table 1). The median time from disease eval to dose/regimen modification was 3 days. Of those who received imatinib, 32% had dose modifications primarily for: lack of efficacy (20%), physician request (20%), and adverse events (19%). Of the pts with a corresponding eval at 12 mo after diagnosis, 88% had a CHR, 65.4% had a CCyR, and 42.5% had a MMR (BCR-ABLIS ≤.1%). These data are preliminary; response assessments by treatment, as well as further efficacy analyses, are ongoing. Conclusions: Overall, the majority of pts did not have cytogenetic or BCR-ABL transcript level testing performed per the European LeukemiaNet recommendations. Furthermore, despite availability of more effective therapies for the treatment of CML, HU is still used as a primary therapy in a substantial proportion of pts. Based on this analysis, pts outside the US primarily receive HU as initial therapy rather than tyrosine kinase inhibitors (TKIs). Overall, second-generation TKIs, such as nilotinib and dasatinib, are infrequently used. These results illustrate the need for continuing education on the mgmt of CML in order to improve outcomes for all pts. Disclosures: Pasquini: Bristol Myers Squibb: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cortes:Bristol Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuitcals: Consultancy, Research Funding. Kantarjian:Pfizer: Research Funding; Novartis: Research Funding; Novartis: Consultancy; BMS: Research Funding. Zernovak:Novartis: Employment, Equity Ownership. Sivarathinasami:Novartis: Employment. Collins:Novartis: Employment. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Nilotinib Shows Safety and Efficacy in Older Patients (≥ 65 years) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase Comparable with That in Younger Patients with Chronic Myeloid Leukemia in Chronic Phase: Results From ENESTnd,

Blood ◽

10.1182/blood.v118.21.3768.3768 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3768-3768 ◽

Cited By ~ 5

Author(s):

Richard A. Larson ◽

Udomsak Bunworasate ◽

Anna G. Turkina ◽

Stuart L. Goldberg ◽

Pedro Dorlhiac-Llacer ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 3768 Background: Data from the phase 3, randomized multicenter ENESTnd trial have demonstrated the superiority of nilotinib over imatinib after 24 months (mo) of follow-up, with significantly higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR), and significantly lower rates of progression to accelerated phase/blast crisis (AP/BC). The current subanalysis evaluated the efficacy and safety of nilotinib 300 mg twice daily (Nil300) and nilotinib 400 mg twice daily (Nil400) in older (≥ 65 years [yrs] at study entry) patients (pts) with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) with a minimum follow-up of 24 mo. Methods: In ENESTnd, 846 pts stratified by Sokal risk score were randomized 1:1:1 to Nil300 (n = 282), Nil400 (n = 281), or imatinib 400 mg once daily (n = 283). Pts with impaired cardiac function or ECOG performance status > 2 were excluded. Rates of CCyR and MMR by 24 mo, progression to AP/BC on treatment, and safety were evaluated according to age group (< 65 vs ≥ 65 yrs) in the 2 nilotinib arms. Safety data are reported for any pt who received ≥ 1 dose of nilotinib (n = 279, Nil300; n = 277, Nil400). Results: 36 pts (13%) and 28 pts (10%) were ≥ 65 yrs old in the Nil300 and Nil400 arms, respectively. Of the pts aged ≥ 65 yrs, 51/64 (80%) had an ECOG performance status of 0 at baseline and 60/64 (94%) had intermediate or high Sokal risk scores. Of the older pts, 8 (22%) on Nil300 and 6 (21%) on Nil400 had type 2 diabetes at baseline. CCyR rates by 24 mo were 83% and 68% among older pts treated with Nil300 and Nil400, respectively, and 87% for pts aged < 65 yrs in each nilotinib arm. By 24 mo, MMR was achieved by 72% and 61% of older pts on Nil300 and Nil400, respectively; in pts aged < 65 yrs, the respective rates were 71% and 67%. All 5 pts who progressed to AP/BC on treatment (2 on Nil300 and 3 on Nil400) were aged < 65 yrs. The frequency of grade 3/4 hematologic adverse events (AEs) was low in older pts; no pts had grade 3/4 neutropenia and only 1 older pt reported grade 3/4 thrombocytopenia in each nilotinib arm (Table). Transient, asymptomatic lipase elevations were reported in 11% and 16% of older pts treated with Nil300 and Nil400, and 7% of younger pts in each arm. Hyperglycemia occurred in 23% and 16% of older pts on Nil300 and Nil400, respectively, and 4% of younger pts in each arm; regardless of age, no pt discontinued study due to hyperglycemia. Among the 12 older pts with grade 3/4 hyperglycemia (8 on Nil300; 4 on Nil400), 9 pts had type 2 diabetes at baseline. There were no QTcF increases of > 60 msec from baseline in older pts and 3 in nilotinib-treated pts < 65 yrs old (1 on Nil300; 2 on Nil400). QTcF prolongation of > 500 msec did not occur in any pt treated with nilotinib on study. Periodic echocardiograms were done, and there were no decreases of > 15% in left ventricular ejection fraction from baseline in any pt treated with nilotinib on study. There were 4 cases of ischemic heart disease reported in older pts (1/35 [3%] on Nil300; 3/25 [12%] on Nil400) and 7 cases in pts < 65 yrs of age (4/244 [2%] on Nil300; 3/252 [1%] on Nil400). No sudden deaths occurred on study. Discontinuation occurred in approximately 25% of older and younger pts with Nil300, of which, 6% and 9%, respectively, were due to AEs/lab abnormalities. Discontinuation from study with Nil400 was 46% in older pts and 19% in younger pts; of which, 36% and 10% were due to AEs/lab abnormalities. Conclusions: Older pts treated with nilotinib demonstrated high rates of cytogenetic and molecular responses and low rates of progression. Nilotinib was generally well tolerated by older pts. In older pts, Nil300 had numerically higher rates of CCyR and MMR and was generally better tolerated (as evidenced by fewer AEs and discontinuations) vs Nil400. These data support the use of Nil300 in older pts with newly diagnosed CML-CP. Disclosures: Larson: Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Bunworasate:Novartis Pharmaceutical: Research Funding. Turkina:Novartis: Consultancy, Honoraria; BMS: Honoraria. Goldberg:Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding. Dorlhiac-Llacer:Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding. Saglio:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy. Hochhaus:Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Yu:Novartis: Employment, Equity Ownership. Gallagher:Novartis: Employment, Equity Ownership. Clark:Bristol Myers Squibb: Honoraria, Research Funding; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Proteomic Signature of CD34+ Cells From Chronic Myeloid Leukemia Patients

Blood ◽

10.1182/blood.v120.21.3733.3733 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3733-3733

Author(s):

Maria Rosaria Ricciardi ◽

Valentina Salvestrini ◽

Roberto Licchetta ◽

Simone Mirabilii ◽

Maria Teresa Petrucci ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Molecular Therapy ◽

Antibody Array ◽

Proteomic Profile ◽

Advisory Committees ◽

Cd34 Cells

Abstract Abstract 3733 The tyrosine kinase inhibitors (TKIs) represent the successful molecular therapy for patients with chronic myeloid leukemia (CML), targeting the Bcr-Abl oncogenic product. However, this disease may remain not curable for the presence of residual refractory cells, persisting during the history of the disease treatment. Several mechanisms have been associated with resistance to TKIs, including the presence of rare quiescent leukemic stem cells, less susceptible to TKIs. Moreover, Bcr-Abl activates additional downstream pathways involved in the apoptotic and proliferation control of CML cells, such as RAS/MEK/ERK, PI3K/Akt, Wnt and STAT5 pathways, potentially contributing to CML TKIs drug resistance. Therefore, in this study we aimed to investigate, at the protein level, proliferative and apoptotic signal transduction pathways (STP) in CML CD34+ cells, as compared to normal CD34+ cells, in order to identify additional aberrant signals, potentially therapeutic targetable. CD34+ cells were purified from peripheral blood (PB) of five newly diagnosed, chronic phase (CP) CML patients, three normal cord blood (CB) and one leukapheretic product of a normal volunteer (PBSC). The phosphorylation status of 46 proteins from various STP and the expression of 32 proteins of the apoptotic machinery were assessed by using a customized direct phase proteome profiler antibody array. The resulting dots were visualised using ECL and quantified by densitometric analysis. CML samples were collected from patient in CP, with a WBC count ranging between 41900–135400 per microliter. The Sokal risk category was low (1/5) and intermediate (4/5). The comparison between normal CD34+ cells obtained from CB and PBSC showed that the first cells were characterized by a lower expression of STAT, Tyrosine-protein kinase and MAPK protein families. The phospho-proteomic profile of CD34+ cells from CML samples showed remarkably similarity when compared to normal CB CD34+ cells, while only two proteins resulted differently expressed in CP CD34+ cell vs. PBSC: CREB-S133, involved in the pro-survival/anti-apoptotic gene control (p=0.025) and p70S6K-T389, along the PI3k/Atk pathway and involved in the cell proliferation (p=0.049). The analysis of the 32 apoptotic proteins revealed that 10 of them were statistically significant lower in CML CD34+ cells compared to PBSC. Most of them were related to the Bcl-2 family and caspase inhibitors family, such as cIAP-1 (p=0.025), cIAP-2 (p=0.0003) and livin (p=0.016). The expression of the cyclin-dependent kinase inhibitors (CKI) was found significantly lower in CML CD34+ (p=0.05 and p=0.02 for p21/CIP1 and p27/Kip1, respectively). In conclusion, we have reported in this study that proteins and/or phosphoproteins controlling apoptosis and proliferation STP, such as Bcl-2, IAP, MAPK, PI3K/Akt, STATs and CKI families, are differentially expressed in CD34+ from CML CP, compared to PBSC. The understanding of these differences in the proteomic profile may confirm that additional multiple aberrant STP are involved in the CML and therefore must be taken into account for targeted therapies, especially of resistant cases. Disclosures: Petrucci: Jansse-Cilag, Celgene: Honoraria. Castagnetti:Novartis Pharma: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Rosti:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau.

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Interim Analysis of a Pan European Stop Tyrosine Kinase Inhibitor Trial in Chronic Myeloid Leukemia : The EURO-SKI study

Blood ◽

10.1182/blood.v124.21.151.151 ◽

2014 ◽

Vol 124 (21) ◽

pp. 151-151 ◽

Cited By ~ 16

Author(s):

Francois-Xavier Mahon ◽

Johan Richter ◽

Joelle Guilhot ◽

Martin C Muller ◽

Christian Dietz ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Interim Analysis ◽

Null Hypothesis ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Molecular Response ◽

Advisory Committees ◽

Tki Treatment

Abstract Background: The tyrosine kinase inhibitors (TKIs) have dramatically changed the natural history of chronic myeloid leukemia (CML) leading to significant improvement in clinical outcome and survival rates. The option of treatment cessation has recently become of utmost importance. Indeed, prospective trials suggest that imatinib therapy may be safely and successfully discontinued in CML pts with deep and sustained molecular responses (Mahon Lancet Oncol 2010, Ross Blood 2013). The major aim of the EURO-SKI study (European Leukemia Net Stop TKI study) was to define prognostic markers to increase the rate of patients in durable deep MR after stopping TKI. Further aims were the evaluation of harmonized methods of molecular monitoring, assessment of quality of life, and calculation of saved treatment costs per country. Methods: Adult CML patients in chronic phase CML on TKI treatment in confirmed deep molecular response (MR4, BCR-ABL <0.01%) for at least one year (>4 log reduction on TKI therapy for >12 months confirmed by three consecutive PCR tests) and under TKI treatment for at least 3 years were eligible. MR4confirmation was performed in a standardized laboratory (n=6). Primary endpoint was the assessment of the duration of MR (defined by continuous MMR) after stopping TKI. Patients (pts) after a prior TKI failure were excluded. According to protocol, an interim analysis was planned after 200 patients with eligible molecular results at month (mo) 6 were available to test the null hypothesis that relapse-free survival at 6 mo is less or equal 40%. Results: From June 2012 to June 2014, 498 CML pts in chronic phase from 10 countries were enrolled and included in the trial. From June 2012 to July 2013, 254 pts from 8 countries were registered; 54 were excluded (consent withdrawal n=1, protocol violation n=1, not eligible n=34, restart of TKI without relapse n=4, atypical or unknown transcript n=6, missing data n=8). Of the eligible 200 pts, 41.5% were female. Median age at diagnosis was 53.3 years (range, 13.8 to 85.5). In assessable pts 8.7% and 18.2 % were high-risk according to EUTOS and Sokal Scores. 103 pts were treated prior to the start TKI therapy, mostly with hydroxyurea or interferon. 1st-line TKI was imatinib in 97%, dasatinib in 1.5%, and nilotinib in 1.5% of pts. Twenty-four pts switched to second-line TKI therapy due to intolerance, 16 to dasatinib, 2 to imatinib, and 6 to nilotinib. The median time from diagnosis of CML to TKI cessation was 8 years (range, 3-19 years). TKI treatment duration was less than 5 years in 16%, 5-8 years in 36% and > 8 years in 48% of pts. Median duration of TKI treatment was 8 years (range, 3-12.6 years) and median duration of MR4 before TKI cessation was 5.4 years (range, 1-11.7 years). MR4duration was less than 2 years in 8%, 2-5 years in 37%, 5-8 years in 39% and >8 years in 16% of pts. For all eligible pts, a standardized European laboratory confirmed MR4 assessment. Since 123 of the 200 pts (61.5%, 95% CI: [54.4%; 68.3%]) remained without relapse the first 6 mo, the null hypothesis could be discarded (p<0.0001). Recurrence of CML, defined as loss of MMR, was observed in 43/92 pts (47%) treated <8 years, as compared to 23/87 pts (26%) treated for >8 years (p= 0.005). So far, there was a trend for prognostic significance of MR4 duration: 33/71 pts with MR4 <5 years (46%) lost MMR within 6 mo as compared to 28/87 pts (32%) with MR4duration >5 years (p=0.07). No significant difference was observed for relapse within 6 mo according to depth of molecular response at discontinuation (MR4 vs MR4.5 vs MR5). TKI cessation was a safe procedure but a substantial proportion of pts reported transitory musculoskeletal pain starting within weeks after imatinib discontinuation. The phenomenon was described in 30% of Swedish patients as a “TKI withdrawal syndrome” (Richter JCO 2014). Taking into account the cost of imatinib in Europe and time without treatment in the total study population at the most recent analysis, total savings for the community within the EURO-SKI trial were estimated at 7 million Euros. Conclusion: Employing a standardized molecular testing for patient selection within a TKI cessation trial in CML the chance to stay in treatment-free remission could be higher than previously reported. The EURO-SKI trial will further elucidate the prognostic factors but the preliminary results confirm (as reported in the STIM Study) the prognostic impact of the duration of TKI therapy before stopping. Disclosures Mahon: NOVARTIS PHARMA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BRISTOL MYERS SQUIBB: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ARIAD: Honoraria; PFIZER: Honoraria. Porkka:BMS: Honoraria; BMS: Research Funding; Novartis: Honoraria; Novartis: Research Funding; Pfizer: Research Funding. Hjorth-Hansen:Novartis: Honoraria; Bristol-myers Squibb: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Mayer:Janssen Research & Development: Research Funding; Roche: Research Funding; GlaxoSmithKline: Research Funding; Celgene: Research Funding. Almeida:Celgene: Consultancy; Novartis: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyer Squibb: Membership on an entity's Board of Directors or advisory committees. Berger:Genzyme/Sanofi and Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Saussele:Novartis: Honoraria, Research Funding, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria, Travel, Travel Other.

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The TKI-Free Duration after a First Discontinuation Attempt That Failed in CP CML Patients Is a Predictive Factor of TKI-Free Remission after a Second Attempt

Blood ◽

10.1182/blood-2019-123719 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 28-28 ◽

Cited By ~ 3

Author(s):

Laurence Legros ◽

Franck E Nicolini ◽

Gabriel Etienne ◽

Philippe Rousselot ◽

Delphine Rea ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Kinase Inhibitors ◽

Blast Crisis ◽

Univariate Analysis ◽

Chronic Phase ◽

Molecular Response ◽

Advisory Committees ◽

Tki Discontinuation

Background: Tyrosine kinase inhibitors (TKIs) are able to induce, in some chronic myeloid leukemia (CML) patients in chronic phase (CP), long-term molecular response 4.5 (MR4.5) and several studies have now demonstrated that TKIs could be safely discontinued in those patients with a Treatment-Free Remission (TFR) rate reaching ~50%. The French CML group had recently demonstrated that a failure of the first TKI discontinuation attempt does not preclude a 2nd successful attempt (RE-STIM study, Legros et al. Cancer 2017). Methods: The RE-STIM study is a national observational multicentre study collecting all cases of 2nd TKI discontinuation attempt of regardless the type, the duration of TKI, the duration of MR4.5 and the reason of discontinuation. CP-CML Patients in failure of a 1st attempt, had to recover a 2nd sustained MR4.5 on TKI to be eligible for this new analysis of the enlarged database (n=106). Loss of MMR loss was the trigger for therapy re-introduction. Results: At the time of analysis (1st June 2019), 106 patients (median age: 55 years (range: 25-81 years)) were included with 41 months (2-131) of follow-up after 2nd discontinuation. Fifty males and 56 females were enrolled. The Sokal risk score was low in 45%, intermediate in 26.5%, high in 20% and unknown in 8.5% of patients. The majority of patients (95%) were treated with imatinib as first-line, and the others with a 2nd generation TKI. The median total time on TKI prior to a 2nd discontinuation was 104 months (range: 38-235) and the median duration of a 2nd MR4.5 prior to a 2nd discontinuation was 68 months (range: 20-176). After a 1st discontinuation attempt, the reason for TKI re-challenge was in majority a loss of MMR (66%), a loss of MR4.5 in 33% of patients (missing data in 1%). The TFR rates after a 2nd discontinuation attempt were 44.3% [95% CI 35.48-55.41] at 24 months, 38.5% [95% CI 29.65- 50.09] at 36 months and 33.2% [95% CI 24.31- 45.39] at 48 months. In univariate analysis, we failed to find any association between TFR and: age, gender, Sokal score, prior exposure to IFN, TKI in combination versus monotherapy, TKI type, TKI treatment duration and uMR4.5 duration before the 1st and 2nd discontinuation attempts, and type of molecular relapse after the 1st discontinuation attempt (MR4.5 versus MMR loss). However, the speed of molecular relapse after the 1st TKI discontinuation remains a factor significantly associated with outcome. In patients who remained in uMR4.5 at 3 months after the 1st discontinuation, the TFR rate at 48 months was 53% [95% CI: 35.32-79.31] and 26% [95% CI: 16.88-40.28] for others. Another factor significantly associated with outcome is the TKI-free duration after the 1st attempt (Figure). The TFR rate at 48 months was 45 % [95% CI: 28.64- 69.62] in patients who remained without treatment more than 6 months after their 1st attempt and 27% [95% CI: 17.57- 41.34] for others. All patients are alive at last follow-up except 2 who died from CML-unrelated reasons. One patient developed a sudden blast crisis at 4 years from 2nd discontinuation. The last previous molecular biology 3 months before transformation was MR4. In patients in TKI re-challenge (n=63), median TKI-free duration was 6 months (2-64), 55% of patients regained their MMR within 3 months (0-35) and 41% regained MR4.5 within 5 months (2-53). Conclusions: This larger cohort confirms that TKIs could safely and successfully be discontinued a 2nd time in CP CML patients despite a 1st failure. The speed of molecular relapse after the 1st TKI discontinuation and TKI-free duration remain major factors significantly associated with TFR outcome. Figure: TFR according TKI-free duration after the 1st attempt of discontinuation Figure Disclosures Legros: Incyte Biosciences: Honoraria, Research Funding; BMS: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria. Nicolini:Sun Pharma Ltd: Consultancy; Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Etienne:BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Rea:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Incyte Biosciences: Honoraria. Guerci:INCYTE: Consultancy, Honoraria. Huguet:Incyte Biosciences: Honoraria; Novartis: Honoraria; Servier: Honoraria; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Coiteux:Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Mahon:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau.

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A Retrospective Analysis about Frequency of Monitoring in Italian Chronic Myeloid Leukemia Patients after Discontinuation

Blood ◽

10.1182/blood-2019-129335 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4153-4153

Author(s):

Matteo Emidio Dragani ◽

Giovanna Rege Cambrin ◽

Paola Berchialla ◽

Irene Dogliotti ◽

Gianantonio Rosti ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Molecular Response ◽

Major Molecular Response ◽

Molecular Monitoring ◽

Advisory Committees ◽

Tki Discontinuation

Background: Successful tyrosine-kinase inhibitors (TKIs) discontinuation has been obtained in some patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML). Careful molecular monitoring after discontinuation is the key to guarantee the safety, in terms of prompt resumption of therapy according to retreatment threshold criteria. It was observed that the majority of relapses usually occur during the first 6 months after TKI discontinuation [Saussele S, Lancet Oncol 2018; Etienne G, JCO 2017], accounting for the monthly quantitative PCR (qPCR) that all prospective protocols included in the trial design at least during the first half-year. Two studies [Kong HJ, Cancer 2017; Shanmuganathan N, Blood 2019] investigated if performing molecular analysis with a different and less "cautious" timeframe yields comparable efficacy with logistical issues reduction. Here we retrospectively evaluated how molecular monitoring has been conducted in Italy on a cohort of patients not included in any prospective trial with follow-up visits. Methods: The outcome of Italian patients with CP-CML who discontinued TKIs per clinical practice has recently been reported [Fava C, Haematologica 2019]. For the purpose of the present study, all the 32 participating centers were required to provide dates and molecular results available for each enrolled patient in the first 24 months after TKI stop. Descriptive analysis was carried out. The average time to the loss of major molecular response (MMR), the frequency of the visits (monitoring) and the occurrence of loss of MMR within the first 6 months, between 6-12 months, and 13-24 months were computed. When appropriate non-parametric tests were used to test for differences. Results: 227 chronic phase CML pts were included in this sub-analysis. Median age at TKI discontinuation was 58.73 years and median follow up since TFR was 2.03 years. In this timeframe every patient had a mean of 7.95 appointments for molecular evaluation. Overall, 1804 analysis were performed, of which 18.2% happened in the first three months and 38.2% in the first six months. During the first three months of TKI discontinuation, 40 pts (17.6%) didn't have any molecular assessment; 78 pts (34.4%) had only 1 qPCR performed, 77 pts (33.9%) 2 qPCR, 31 pts (13.7%) 3 qPCR and 1 pt (0.4%) 4 qPCR. For the first six months after TKI stop, 7 pts (3.1%) didn't undergo any BCR-ABL1 evaluation; 37 pts (16.3%) had only 1 analysis, 60 pts (26.4%) 2 analysis, 37 pts (16.3%) 3 analysis, 28 pts (12.3%) were evaluated 4 times, 40 pts (17.6%) 5 times, 17 pts (7.5%) 6 times and only 1 pt (0.4%) 7 times. The majority of visits fell between the 3rd and the 7th month after TKI interruption (Figure 1) with 84 pts (52.2%) being evaluated at month 3, 96 pts (59.6%) at month 4, 80 pts (49.7%) at month 5, 89 pts (55.3%) at month 6, 101 pts (62.7%) at month 7. In the first six months the visits occurred with a mean interval of 1.44 months; between months 7-12 molecular evaluations were performed every 1.94 months; during the second year of discontinuation (months 13-24) every 2.89 months (p<0.001). Seventy-one pts lost major molecular response (MMR) in a mean time of 5.56 months. As expected, 55 pts (77.5%) lost MMR during the first six months whereas 16 pts (22.6%) relapsed later on: 3 pts (4.2) relapsed during the first month, 7 pts (9.9%) after two months, 13 pts (18.3%) after three, 19 pts (26.8%) after four, 8 pts (11.3%) after five months and 5 pts (7%) at six months. Only 6 patients lost MMR after 12 months of follow-up in TFR. All patients regained at least MMR after TKI resumption, and no progression occurred. Finally, we evaluated the number of patients who would experience a delay in the diagnosis of MMR loss if a three-months monitoring schedule was adopted. In the first 6 months, 15 pts (27.3%) would have a one month delay, 22 (40%) a 2 months delay; 18 pts (32.7%) would have a right timing. Very few patients would experience a delay in the following months (Figure 2). Discussion: The safety of TFR relies consistently on the management of patients off-therapy especially during the first 6 months, when molecular relapses more often occur. Our retrospective analysis showed that a less intense frequency of monitoring did not affect the success of TFR nor put pts at risk of progression. However, these data confirm that the first 6 months off-treatment require a more stringent follow-up for early detection of MMR loss. Disclosures Rosti: BMS: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Castagnetti:Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Bristol Myers Squiib: Consultancy, Honoraria. Capodanno:Novartis: Honoraria; Incyte: Honoraria. Ferrero:Novartis: Honoraria. Crugnola:Novartis: Honoraria; Incyte: Honoraria. Elena:Pfizer: Consultancy; Novartis: Consultancy. Breccia:Pfizer: Honoraria; Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria; Incyte: Honoraria. Iurlo:Novartis: Other: Speaker Honoraria; Pfizer: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria. Bocchia:BMS: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Lunghi:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Cedrone:BMS: Honoraria; Novartis: Honoraria. Sgherza:Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria; Incyte: Honoraria. Santoro:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Giai:Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria. Caocci:Novartis: Honoraria; Celgene: Honoraria. Levato:Incyte: Honoraria; BMS: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Abruzzese:BMS: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Novartis: Consultancy. Saglio:Pfizer: Consultancy; Celgene: Consultancy; Incyte: Consultancy; Jansen: Consultancy; Ariad: Consultancy; Novartis: Consultancy; BMS: Consultancy. Fava:Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria; Incyte: Honoraria.

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BCR-ABL Fusion Transcript Do Not Significantly Influence the Outcome of Chronic Myeloid Leukemia Patients In Early Chronic Phase Treated with Imatinib Mesylate: a GIMEMA CML WP Analysis.

Blood ◽

10.1182/blood.v116.21.1230.1230 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1230-1230

Author(s):

Fausto Castagnetti ◽

Gabriele Gugliotta ◽

Francesca Palandri ◽

Massimo Breccia ◽

Giorgina Specchia ◽

...

Keyword(s):

Clinical Trials ◽

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Cumulative Incidence ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Fusion Transcript ◽

Advisory Committees ◽

Free Survival

Abstract Abstract 1230 Background: Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL fusion gene. Different types of BCR-ABL transcripts can be found, due to different genomic breakpoints and alternative splicing. The most frequent transcripts are the e13a2 (b2a2) and the e14a2 (b3a2), that codify for a p210 protein. Occasionally, both transcripts may be present. In the imatinib (IM) era, few data about the prognostic significance of the transcript type are available, particularly in the setting of early chronic phase (ECP): one study suggested that patients with the b2a2 transcript may be more sensitive to IM (de Lemos et al. Genet Mol Res 2005), while two larger studies suggested that patients with b3a2 transcript may have better responses to IM (Vega-Ruiz et al. ASH 2007; Lucas et al. Haematologica 2009). No systematic evaluations in the context of large prospective clinical trials have been performed. AIM: To investigate the influence of the type of BCR-ABL fusion transcript on the responses and the outcome of CML patients treated with IM in ECP. Methods: We performed an analysis of 3 concurrent clinical trials of the GIMEMA CML Working Party (Clin Trials Gov. NCT00514488, NCT00510926 and the observational trial CML/023). Response monitoring was based on conventional cytogenetic examination (bone marrow) and quantitative molecular (Q-PCR) evaluation (peripheral blood). Definitions: Complete Cytogenetic Response (CCgR): 0% Ph+; Major Molecular Response (MMR): BCR-ABL/ABL ratio <0.1% (International Scale); failures: according to the revised European LeukemiaNet criteria (Baccarani et al. J Clin Oncol 2009). Results: 559 consecutive CML patients in early CP have been enrolled from January, 2004 to January, 2007. Patients expressing rare transcript types (e1a2 and e19a2) and patients with the presence of both b2a2 and b3a2 transcripts were excluded: 493 out of 559 patients were evaluable, 203 (41%) with a b2a2 transcript and 290 with a b3a2 transcript (59%). The 2 groups were comparable (no significant difference in sex, age, Sokal and Hasford scores, clonal chromosomal abnormalities in Ph+ cells before IM and imatinib dose). The median observation time is currently 60 (extremes 2–80) months. In patients with b2a2 and b3a2 transcript, the observed 12-months CCgR rates were 77% and 80%, respectively; the cumulative incidence of CCgR was 89% and 88%, respectively (no significant differences). The time to MMR was significantly shorter for patients with b3a2 transcript (fig.1), but the cumulative incidence of MMR was not significantly different (81% and 86% in patients with b2a2 and b3a2 transcript, respectively). The probabilities of Failure-Free Survival, Progression-Free Survival and Overall Survival were 69% and 75%, 83% and 89%, 87% and 92% in patients with b2a2 and b3a2 transcript, respectively (fig. 1); no difference was statistically significant. Conclusions: In our experience, based on 493 early CP CML patients treated frontline with IM, the type of BCR-ABL fusion transcript had no relevant prognostic impact and no outcome differences have been observed so far. Acknowledgments: Work supported by European LeukemiaNet, COFIN, University of Bologna and BolognAIL. Disclosures: Castagnetti: Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Gugliotta:Novartis: Honoraria. Martinelli:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy. Saglio:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baccarani:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; Wyeth: Consultancy, Research Funding. Rosti:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau.

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