Phase Chronic Myeloid Leukemia Patients Research Articles

MiRNome profiling of LSC-enriched CD34+CD38−CD26+ fraction in Ph+ CML-CP samples from Argentinean patients: a potential new pharmacogenomic tool

Chronic myeloid leukemia (CML) is a myeloid stem cell neoplasm characterized by an expansion of myeloid progenitor cells and the presence of BCR-ABL1 oncoprotein. Since the introduction of specific BCR-ABL1 tyrosine kinase inhibitors (TKI), overall survival has improved significantly. However, under long-term therapy patients may have residual disease that originates from TKI-resistant leukemic stem cells (LSC). In this work, we analyzed the miRNome of LSC-enriched CD34+CD38−CD26+ and normal hematopoietic stem cells (HSC) fractions obtained from the same chronic phase (CP) CML patients, and stem and progenitor cells obtained from healthy donors (HD) by next-generation sequencing. We detected a global decrease of microRNA levels in LSC-enriched CD34+CD38−CD26+ and HSC fractions from CML-CP patients, and decreased levels of microRNAs and snoRNAs from a genomic cluster in chromosome 14, suggesting a mechanism of silencing of multiple non-coding RNAs. Surprisingly, HSC from CML-CP patients, despite the absence of BCR-ABL1 expression, showed an altered miRNome. We confirmed by RT-qPCR that the levels of miR-196a-5p were increased more than nine-fold in CD26+ (BCR-ABL1 +) vs. CD26− (BCR-ABL1 −) CD34+CD38− fractions from CML-CP patients at diagnosis, and in silico analysis revealed a significant association to lipid metabolism and hematopoiesis functions. In the light of recent descriptions of increased oxidative metabolism in CML LSC-enriched fractions, these results serve as a guide for future functional studies that evaluate the role of microRNAs in this process. Metabolic vulnerabilities in LSCs open the road for new therapeutic strategies. This is the first report of the miRNome of CML-CP CD34+CD38− fractions that distinguishes between CD26+ (BCR-ABL1 +) and their CD26− (BCR-ABL1 -) counterparts, providing valuable data for future studies.

Mortality rate in patients with chronic myeloid leukemia in chronic phase treated with frontline second generation tyrosine kinase inhibitors: a retrospective analysis by the monitoring registries of the Italian Medicines Agency (AIFA).

The introduction of tyrosine kinase inhibitors (TKIs) has improved the overall survival of chronic myeloid leukemia patients in chronic phase (CP-CML) and reduced the rate of disease-related mortality. Conflicting results have been however reported between data emerged from sponsored clinical trials and from population-based registries. Moreover, no data are so far available for patients treated with frontline second-generation TKIs, excluding those from sponsored studies. We analyzed the mortality rate of 2315 CP-CML patients treated with frontline second-generation TKIs through the Italian Medicines Agency (AIFA) registries and compared it with the ISTAT mortality rate of the general population. The estimated differences show that the increased rate of mortality in CP-CML patients is less than 1% for the class 0-29years, stable around 2% for the intervals 30-44years and 45-59years, and 1.4% for the interval 60-74years; interestingly this rate is reduced for patients aged 75years and more as compared to the general population (- 0.65%). The difference between potential and estimated deaths is higher among women in the age classes between 30 and 74years.

Contemporary practice patterns of tyrosine kinase inhibitor use among older patients with chronic myeloid leukemia in the United States.

Introduction:The choice of BCR-ABL1 tyrosine kinase inhibitors (TKI) for the first line of therapy (LOT) for chronic-phase chronic myeloid leukemia (CML) is tailored to disease risk and patient characteristics like comorbidities, which become more prevalent with age. However, contemporary evaluations of frontline TKI choice and the factors associated with TKI switching in this specific patient population are lacking.Methods:We sought to describe TKI use in older patients (age: 66–99 years) with CML in the United States. Using the Surveillance, Epidemiology, and End Results–Medicare-linked database, we identified 810 older (median age: 75 years, interquartile range: 70–80 years) patients diagnosed during 2007–2015.Results:Imatinib was the most common frontline TKI (63.1%) throughout the study period, but its utilization as such decreased from 76% in 2010 to 47% in 2015. Most patients (65.3%) used only one TKI, but 12.5% of the 281 patients who switched from frontline TKI received ⩾4 LOT. Among the 167 patients switching from frontline imatinib, 18.6% eventually returned to imatinib with nearly all as the third LOT, supporting its favorable safety profile and indicating that the initial switch from imatinib might have been premature. Older patients within our cohort, white patients and those with greater comorbidity were less likely to switch from frontline TKI. Diagnosis year, geographic region, and surrogates for socioeconomic status and healthcare access had no impact on TKI switching.Conclusion:As expected, our findings highlight the frequent use of imatinib as the treatment option for older CML patients despite the availability of second-generation TKIs.

Widespread Aberrant Alternative Splicing despite Molecular Remission in Chronic Myeloid Leukaemia Patients.

Simple SummaryThis study provides new insights into the changing transcriptomic and epigenomic landscapes in chronic myeloid leukaemia (CML) patients who are receiving tyrosine kinase inhibitor (TKI) therapy (often life-long). Alternative splicing, vital for cellular homeostasis, is dysregulated in human cancers. Remarkably, we found abnormal splicing patterns despite molecular remission in peripheral blood cells of chronic-phase CML patients. This phenomenon is independent of the TKI drug used and in striking contrast to the normalisation of gene expression and DNA methylation patterns.Vast transcriptomics and epigenomics changes are characteristic of human cancers, including leukaemia. At remission, we assume that these changes normalise so that omics-profiles resemble those of healthy individuals. However, an in-depth transcriptomic and epigenomic analysis of cancer remission has not been undertaken. A striking exemplar of targeted remission induction occurs in chronic myeloid leukaemia (CML) following tyrosine kinase inhibitor (TKI) therapy. Using RNA sequencing and whole-genome bisulfite sequencing, we profiled samples from chronic-phase CML patients at diagnosis and remission and compared these to healthy donors. Remarkably, our analyses revealed that abnormal splicing distinguishes remission samples from normal controls. This phenomenon is independent of the TKI drug used and in striking contrast to the normalisation of gene expression and DNA methylation patterns. Most remarkable are the high intron retention (IR) levels that even exceed those observed in the diagnosis samples. Increased IR affects cell cycle regulators at diagnosis and splicing regulators at remission. We show that aberrant splicing in CML is associated with reduced expression of specific splicing factors, histone modifications and reduced DNA methylation. Our results provide novel insights into the changing transcriptomic and epigenomic landscapes of CML patients during remission. The conceptually unanticipated observation of widespread aberrant alternative splicing after remission induction warrants further exploration. These results have broad implications for studying CML relapse and treating minimal residual disease.

A prospective study of the monitoring of patients with chronic myeloid leukemia upon withdrawal of tyrosine kinase inhibitor therapy

Introduction. The advent of tyrosine kinase inhibitors (TKIs) in clinical practice drastically improved prognosis in patients with chronic myeloid leukaemia (CML). Adverse events of the TKI therapy and its high financial burden warrant the trend to gradually abandon this treatment.Aim. To assess the results of CML patient monitoring after the withdrawal of TKI therapy.Patients and methods. This prospective study included 98 chronic phase CML patients satisfying the criteria: any receiving of TKI therapy for ≥3 years; deep molecular response (DMR, BCR-ABL ≤ 0.01 % IS) during ≥ 2 years. The withdrawal was followed by quantitative BCR-ABL estimation performed monthly for the first 6 months of the survey, bimonthly for 1 year and every 3 months from the second year onwards. Therapy was resumed at a loss of major molecular response (MMR, BCR-ABL ≥ 0.1 % IS).Results. The MMR loss upon the TKI withdrawal was observed in 48 (49 %) patients. Survival without MMR loss was 52 % past 24 months since withdrawal, with a median of 35 months (23–52). The duration of therapy, MR and the MR depth at the time of withdrawal significantly correlated with a conserved post-therapy MMR. Gender, age, a Sokal risk group, type and line of TKI therapy at withdrawal, and imatinib resistance in history were not observed to significantly impact molecular relapse-free remission. MMR was recovered in all 48 patients with TKI therapy resumed in molecular relapse. In 65 % of the patients, adverse therapy events observed during treatment completely resolved by 6 months of post-therapy monitoring. Musculoskeletal pain (withdrawal syndrome, WS) was reported in 42 % patients in the post-therapeutic period, which did not lead to TKI resumption. The WS development correlated with an elder age and longer therapy prior to withdrawal.Conclusion. Molecular relapse-free survival in CML patients with treatment-free remission (TFR) is comparable to other published evidence. Monitoring safety during TFR is attested by the lack of disease progression and MMR recovery upon TKI resumption in all patients.

The LEukemia Artificial Intelligence Program (LEAP) in chronic myeloid leukemia in chronic phase: A model to improve patient outcomes.

Extreme gradient boosting methods outperform conventional machine-learning models. Here, we have developed the LEukemia Artificial intelligence Program (LEAP) with the extreme gradient boosting decision tree method for the optimal treatment recommendation of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia in chronic phase (CML-CP). A cohort of CML-CP patients was randomly divided into training/validation (N = 504) and test cohorts (N = 126). The training/validation cohort was used for 3-fold cross validation to develop the LEAP CML-CP model using 101 variables at diagnosis. The test cohort was then applied to the LEAP CML-CP model and an optimum TKI treatment was suggested for each patient. The area under the curve in the test cohort was 0.81899.Backward multivariate analysis identified age at diagnosis, the degree of comorbidities, and TKI recommended therapy by the LEAP CML-CP model as independent prognostic factors for overall survival. The bootstrapping method internally validated the association of the LEAP CML-CP recommendation with overall survival as an independent prognostic for overall survival. Selecting treatment according to the LEAP CML-CP personalized recommendations, in this model, is associated with better survival probability compared to treatment with a LEAP CML-CP non-recommended therapy. This approach may pave a way of new era of personalized treatment recommendations for patients with cancer.

Plasma imatinib levels and ABCB1 polymorphism influences early molecular response and failure-free survival in newly diagnosed chronic phase CML patients

Achieving early molecular response (EMR) has been shown to be associated with better event free survival in patients with chronic phase chronic myeloid leukemia (CP-CML) on Imatinib therapy. We prospectively evaluated the factors influencing the 2-year failure free survival (FFS) and EMR to imatinib therapy in these patients including day29 plasma Imatinib levels, genetic variants and the gene expression of target genes in imatinib transport and biotransformation. Patients with low and intermediate Sokal score had better 2-year FFS compared to those with high Sokal Score (p = 0.02). Patients carrying ABCB1-C1236T variants had high day29 plasma imatinib levels (P = 0.005), increased EMR at 3 months (P = 0.044) and a better 2 year FFS (P = 0.003) when compared to those with wild type genotype. This translates to patients with lower ABCB1 mRNA expression having a significantly higher intracellular imatinib levels (P = 0.029). Higher day29 plasma imatinib levels was found to be strongly associated with patients achieving EMR at 3 months (P = 0.022), MMR at 12 months (P = 0.041) which essentially resulted in better 2-year FFS (p = 0.05). Also, patients who achieved EMR at 3 months, 6 months and MMR at 12 months had better FFS when compared to those who did not. This study suggests the incorporation of these variables in to the imatinib dosing algorithm as predictive biomarkers of response to Imatinib therapy.

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

Successful discontinuation of tyrosine kinase inhibitors has been achieved in patients with chronic-phase chronic myeloid leukemia (CML). Careful molecular monitoring after discontinuation warrants safe and prompt resumption of therapy. We retrospectively evaluated how molecular monitoring has been conducted in Italy in a cohort of patients who discontinued tyrosine kinase inhibitor (TKI) treatment per clinical practice. The outcome of these patients has recently been reported—281 chronic-phase CML patients were included in this subanalysis. Median follow-up since discontinuation was 2 years. Overall, 2203 analyses were performed, 17.9% in the first three months and 38.4% in the first six months. Eighty-six patients lost major molecular response (MMR) in a mean time of 5.7 months—65 pts (75.6%) during the first six months. We evaluated the number of patients who would experience a delay in diagnosis of MMR loss if a three-month monitoring schedule was adopted. In the first 6 months, 19 pts (29.2%) would have a one-month delay, 26 (40%) a 2-month delay. Very few patients would experience a delay in the following months. A less intense frequency of monitoring, particularly after the first 6 months off treatment, would not have affected the success of treatment-free remission (TFR) nor put patients at risk of progression.

A Pilot Study on Probing of Imatinib Induced Platelet Dysfunction in Patients with Chronic Myeloid Leukemia-Chronic Phase and Absence of Associated Bleeding Manifestation: Trying to Solve an Enigma.

Imatinib, the first Tyrosine Kinase Inhibitor (TKI) used for the treatment of chronic myeloid leukaemia (CML) has revolutionized the management by inhibiting BCR-ABL tyrosine kinase. According to earlier reports there are concerns regarding the adverse effect of imatinib on haemostasis by causing platelet dysfunction. Here we studied platelet function usingplatelet aggregometry, in 19 CML chronic phase (CML-CP) patients on imatinib therapy, in complete haematologic response (CHR). The median duration of imatinib therapy before performing the test was 154days. This study reveals that there are large inter-individual variations in platelet functions among imatinib treated patients and different levels of variability have been seen for different agonists. Most common aggregation abnormality (< 50% aggregation) was seen withlow dose collagen (1μg/ml) in 31.57% patients. Despite in-vitro platelet aggregation defects, none of the patients showed any bleeding symptoms. This enigma can possibly be explained by the fact that platelet specific agonists, epinephrine and collagen act in synergy for platelet aggregation compared against individual low dose agonists, supported by ex-vivo experiments in normal healthy control group (n = 5) (p value < 0.0004 for epinephrine, p value < 0.0001 for collagen). This experiment was also confirmed in a CML-CP patient. In future, more studies are needed to find out the exact mechanism of this inhibition.

Cognitive Dysfunction Associated with Tyrosine Kinase Inhibitors in Patients with CML in Chronic Phase

Introduction: The effect of tyrosine kinase inhibitors (TKIs) on cognition in patients with chronic myeloid leukemia in chronic phase (CML-CP) is not well understood. Memory impairments have been reported in limited studies in CML patients on dasatinib and in gastrointestinal stromal tumor patients on imatinib, but additional research is needed. At our institution, we have observed that CML-CP patients spontaneously report new cognitive dysfunction (CD) while on TKIs. We sought to determine the prevalence of CD in CML-CP patients on TKIs, the TKIs associated with cognitive changes, and the management and outcomes of CML-CP patients with CD at our institution. Methods: We performed a single-center, retrospective cohort study of active CML-CP patients in our Hematology clinic seen between January 2017 and December 2019. Patients were identified by ICD-10 codes and chart notes were reviewed for treatment course. Patients met criteria for CD if they reported new difficulties with cognition while on TKI treatment (as documented in the subjective or review of systems) and had no prior history of cognitive impairment. Descriptive statistics, Chi-square tests, and two-tailed t-tests were used to summarize the data. Results: We identified 216 CML-CP patients who were actively or previously treated with a TKI, with 29 patients (13.4%) reporting CD while taking a TKI. The median age for patients with CD was 51 years (range 23-73), compared to a median age of 56 years (range 20-91) in those without CD (P=0.114); there were no significant differences in sex (P=0.984) or in median time since diagnosis (P=0.167) (Table 1). The 29 patients generated 36 reports of CD, as 7 patients (24.1%) reported 2 types of cognitive changes while on TKI. The types of CD were documented as "mental fog" (n=19/36, 52.8%), memory problems (n=7/36, 19.4%), decreased mental acuity (n=6/36, 16.7%), problems with concentration (n=2/36, 5.6%), word-finding difficulties (n=1/36, 2.8%), and impaired creativity (n=1/36, 2.8%) (Figure 1). Of the 29 patients who reported CD, 5 experienced it on 2 different agents, leading to 34 individual reports of CD. Among the 216 patients with CML-CP treated with TKIs, many used more than 1 agent: 31 used bosutinib, 183 dasatinib, 132 nilotinib, and 10 ponatinib. The percentage of CD reported in patients treated with each TKI was as follows: bosutinib 12.9% (n=4/31), dasatinib 11.5% (n=21/183), imatinib 5.3% (n=7/132), nilotinib 4.1% (n=2/49), and ponatinib 0% (n=0/10) (Table 2). For management, 20.7% (n=6/29) underwent successful prescribed discontinuation, 27.6% (n=8/29) attempted discontinuation but resumed TKI after loss of MMR, 24.1% (n=7/29) underwent TKI dose reductions, 20.7% (n=6/29) changed TKIs, and 6.9% (n=2) had no change in management. In the 6 patients who successfully discontinued TKI, all but 1 (83.3%) reported complete resolution of their CD while off of TKI. For those who attempted discontinuation but had loss of MMR, 6 of 8 (75%) had documented improvement of CD off of treatment; after restarting TKI, CD returned in 5 patients (83.3%). Of the remaining patients who underwent TKI dose reductions (n=7), 1 patient had documented improvement of CD, 2 had no change, and 4 had unspecified outcomes. Of the patients who changed TKIs (n=6), 1 patient had documented improvement of CD, 4 had no change, and 1 had unspecified outcomes. In the 2 with no change in management, outcomes were not specified. Conclusion: Cognitive dysfunction in CML-CP patients was reported with all first- and second-generation TKIs; the analysis of ponatinib was limited by small numbers. Bosutinib had the highest proportion of CD in our cohort, an association that has not been previously reported. Our analysis supports that TKI-associated CD is reversible since it resolved in 78.6% (n=11/14) patients when off of TKI during discontinuation. While 13.4% of our CML-CP patients had CD, due to spontaneous reporting and subtle presentation of cognitive impairment, the true prevalence of CD in CML-CP patients on TKIs is likely substantially higher. Future studies should involve prospective data collection of objective cognitive testing and patient reported outcomes in CML-CP patients for further evaluation of TKI-associated cognitive dysfunction. Disclosures Schoenbeck: American Society of Hematology: Research Funding. Smith:Sanofi: Honoraria; FujiFilm: Other: Research support, Research Funding; Revolution Medicines: Other: Research Support, Research Funding; Astellas Pharma: Honoraria, Other: Research Support, Research Funding; Daiichi Sanyko: Consultancy, Honoraria; Abbvie: Other: Research Support, Research Funding. Shah:Bristol-Myers Squibb: Research Funding.

Excellent Outcomes Achieved with Medical Management of Chronic Phase CML Patients with Non-Hematologic TKI Intolerance

Introduction:Tyrosine kinase inhibitor (TKI) intolerance is commonly encountered in patients with chronic myeloid leukemia in chronic phase (CML-CP). Clinical trials define non-hematologic TKI intolerance as grade 3-4 toxicities, but lower grade toxicities may also impair patients' quality of life and lead to changes in medical management. We sought to compare TKI-intolerant and -tolerant CML-CP patients and their clinical outcomes, including molecular responses, rates of progression, survival, and utilization of allogeneic stem cell transplant (alloSCT). Methods:We performed a single-center, retrospective cohort study of active CML-CP patients in our Hematology clinic between January 2017 and December 2019. We defined TKI intolerance as any grade non-hematologic toxicity that led to a change in TKI management, such as dose reduction or change of TKI. We also reviewed CML-CP patients who underwent alloSCT in the TKI era (2002-2019). AlloSCT patients were identified for chart review by ICD-10 codes and query of the institution's transplant database. Descriptive statistics, Chi-Square tests, and two-tailed t-tests were used to summarize the data. Results:We identified 216 CML-CP patients (Table 1), and 161 (74.5%) met criteria for non-hematologic TKI intolerance. The median age was 59 years-old in TKI-intolerant patients and 49 in tolerant patients (P=0.011). Most patients experienced TKI-intolerance from symptoms (93.2%, n=150); symptoms included fatigue (n=77, 59.2%), arthralgias (n=36, 27.7%), nausea (n=29, 22.3%), headache (n=16, 12.3%), and edema (n=15, 11.5%). The remaining patients were TKI-intolerant based on abnormal laboratory findings such as transaminitis or hyperglycemia (6.8%, n=11/161). Of the 161 TKI-intolerant patients at last follow-up, 130 (80.7%) remained on TKI, 19 (11.8%) were on prescribed discontinuation, 6 (3.72%) were non-adherent, 5 (3.1%) were off TKI for non-CML medical problems, and 1 (0.6%) was on omacetaxine. Dose reductions occurred in the majority who remained on TKIs (n=103/130, 79.2%) and prior to TKI discontinuation (n=13/19, 68.4%). Most TKI-intolerant patients (n=122/161, 75.8%) switched TKIs, with a median of 2 agents used (range 1-5). Of 55 TKI-tolerant patients, 46 (83.6%) were on TKI, 8 (14.5%) were on discontinuation, and 1 (1.8%) was non-adherent. Only 19.6% (n=9/46) patients were dose-reduced, and they rarely changed TKIs (median of 1 agent used). MR4.5 was achieved in 49% (n=79/161) of TKI-intolerant and 41.8% (n=23/55) of TKI-tolerant patients. Only 1 patient in each group progressed to accelerated phase. TKI-intolerant and -tolerant patients had similar times since diagnosis (with a median follow up of 81.7 months and 79.7 months, respectively). Five of 161 (3.1%) TKI-intolerant patients died, all from causes unrelated to CML and TKI therapy. None of the TKI-tolerant patients died during the abstraction period. Twenty CML-CP patients underwent alloSCT from year 2002-2019; 10 (50%) were transplanted for TKI intolerance without other transplant indications (Tables 2 and 3). Three of those 10 patients also had hematologic intolerance. Four (40%) TKI-intolerant patients resumed TKI post-transplant: 3 for disease relapse, 1 for sclerotic GVHD. Seven (70%) developed GVHD, with most cases being chronic (n=6), extensive (n=6), and severe/moderate (n=6). While 80% of patients achieved MR4.5 post-transplant (n=8/10), 30% (n=3/10) experienced transplant-related mortality (TRM) with a mean post-transplant survival of 38.5 months; the remaining 7 patients were alive at a median follow-up of 37.1 months. Conclusion: CML-CP patients with non-hematologic TKI-intolerance achieved similar clinical outcomes as TKI-tolerant patients despite dose reductions and/or switching TKIs. The use of alloSCT was rare in our practice, and CML-CP patients transplanted for TKI intolerance commonly resumed TKI post-alloSCT and frequently developed extensive GVHD. In light of the high survival rate achieved with medical management in CML-CP patients with non-hematologic TKI-intolerance, including no disease- or treatment-related deaths, this analysis does not support the use of alloSCT for patients with non-hematologic TKI-intolerance. Disclosures Schoenbeck: American Society of Hematology:Research Funding.Olin:Astellas:Other: Site PI;Genentech:Consultancy;Daiichi Sankyo:Other: Site PI;Amgen:Consultancy;Genentech:Other: Site PI;Pfizer:Other: Site PI.Logan:Amphivena:Research Funding;Autolus:Research Funding;Jazz:Research Funding;Kadmon:Research Funding;Kite:Research Funding;Pharmacyclics:Research Funding;Abbvie:Consultancy;Amgen:Consultancy;Novartis:Consultancy.Smith:Revolution Medicines:Other: Research Support, Research Funding;Abbvie:Other: Research Support, Research Funding;FujiFilm:Other: Research support, Research Funding;Daiichi Sanyko:Consultancy, Honoraria;Astellas Pharma:Honoraria, Other: Research Support, Research Funding;Sanofi:Honoraria.Shah:Bristol-Myers Squibb:Research Funding.

Second Imatinib Discontinuation Outcomes in Patients Regaining Durable Deep Molecular Response in the Korean Imatinib Discontinuation Study; KID Study

Backgroud: Although multiple trials have shown that stopping tyrosine kinase inhibitor (TKI) treatment can be employed in CP CML patients with sustained deep molecular response (DMR) after enough TKI therapy, they emphasized the need for close monitoring because about 50-70% of patients experienced molecular relapse. However, most patients with molecular recurrence regain their initial molecular level after restarting TKI therapy. Aims: In this study, we analyzed second imatinib (IM) discontinuation outcomes in patients regaining durable DMR in the Korean multicenter prospective study (Korean Imatinib Discontinuation Study; KID Study) Methods: CP CML patients who were treated with IM for more than 3 years and maintained DMR for at least 2 years were eligible for the Korean multicenter prospective study and in cases of MMR loss on 2 consecutive assessments, IM treatment was re-introduced. After IM resumption, the molecular response was evaluated every month until re-achievement of MMR and every 3 months thereafter. The second stop was permitted in the patients who were in second DMR for at least 2 years. Results: Among the patients who maintained a second DMR for at least 2 years after IM resumption, 23 patients entered into a second IM stop. Prior to first discontinuation, the median duration of IM therapy was 73.2 months (range, 38.4-133.2 months) and the duration of sustained UMRD was 38.4 months (range, 24-102 months). After first attempt of IM discontinuation, they relapsed after a median duration of 3.7 months (range, 1.8-20.8 months) and re-achieved UMRD at a median of 5.8 months (range, 1.7-12.1 months) after IM resumption. After sustaining a second DMR for a median of 26.3 months, IM therapy discontinued for a second time. With a median follow-up of 29.5 months (range, 9-63 months) since second IM stop, 15/23 patients (65%) lost MMR after a median 2.9 months (range, 1.8-30.7 months), which was similar to those of the first IM discontinuation [median 3.7 (range, 1.8-20.8 months)]. The patients who lost MMR were retreated with IM for a median of 24.5 months (range, 1.2-49.7 months); 14 patients re-achieved MMR and one patient was in therapy for 1.2 months. Conclusion: Our data demonstrated that a second attempt might be possible and the median time to MMR loss after second discontinuation was similar to those of the first discontinuation. Further studies on the predictors to select patients for a trial of second TFR and novel strategies will be warranted. Disclosures Kim: Takeda: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sun Pharma.: Research Funding.

Sequential Treatments in Chronic Phase Chronic Myeloid Leukemia (CML) Patients without Optimal Response after Frontline Nilotinib or Dasatinib: An Italian CML Campus Study

INTRODUCTION: Frontline therapy with second generation (2G) tyrosine-kinase inhibitors (TKIs) in chronic phase (CP) chronic myeloid leukemia (CML) patients demonstrated higher efficacy as compared to imatinib, with less patients experiencing treatment failure and progression to advanced disease. However, limited information are currently available on the management and outcome of those CML pts not achieving an optimal response to first-line treatment with a 2G-TKI. AIM: To describe the clinical outcome of CP CML patients without an optimal response to a frontline 2G-TKI that switched to alternative TKIs. METHODS: We performed a retrospective analysis in 22 Centers cooperating within the Italian CML Campus Project. Main inclusion criteria were: 1) diagnosis of CP-CML after 2010; 2) first-line treatment with a 2G-TKI; 3) switch to second-line treatment in case of non-optimal response (either following ELN recommendations or as for clinical practice); 4) CML in CP at the time of switching to second-line treatment. The main exclusion criteria were a switch to second-line treatment for intolerance or for low adherence to therapy. RESULTS: The main findings of this analysis are summarized in the table. Seventy-one pts meeting the inclusion/exclusion criteria were identified; the median age of pts at CML diagnosis was 46 (21-80) years. Sokal risk score was low, intermediate, and high in 24 (34%), 30 (42%), and 17 (24%) pts, respectively. First-line treatment was performed with nilotinib in 47 (66%) pts and dasatinib in 24 (34%) pts. According to the ELN 2020 recommendations, 51 (72%) pts fulfilled the criteria for "failure" and 20 (28%) pts those for "warning". BCR-ABL mutations were identified in 12 of 65 (18%) evaluable pts (T315I in 1 pt). Additional chromosomal abnormalities in Ph+ cells were identified in 6 of 54 (11%) evaluable pts. Second-line treatment was started after a median time of 16 (4-72) months, with ponatinib (40 pts, 56%), dasatinib (21 pts, 30%), nilotinib (7 pts, 10%), or bosutinib (3 pts, 4%). Median follow-up from start of second-line treatment was 25 (2-90) months. Best response to second-line treatment was MR2 in 18 (25%) pts and MR3 in 37 (51%) pts. Nineteen (27%) pts (13 for resistance and 6 for intolerance) switched to third-line treatment (ponatinib, 11 pts; nilotinib, 3 pts; dasatinib, 4 pts; imatinib, 1 pt), after a median time of 8 (1-72) months. Mutations were identified in 2 of 17 evaluable pts, and both patients harbored a T315I mutation. MR3 was reached by 9 (47%) of these pts. Lastly, 7 (10%) pts switched (6 for resistance and 1 for intolerance) to fourth-line treatment (asciminib, 4pts; dasatinib, 2 pts, nilotinib, 1 pt). Overall, 44 (62%) patients reached with sequential TKI treatments a MR3 (31/51 pts among "failures"; 13/20 among "warnings"). Allogeneic stem-cell transplantation (SCT) was performed in 7 (9.5%) pts (6 among "failures"), after a median time of 20 (15-60) months from CML diagnosis. Progression to advanced phase occurred in 2 (3%) pts; both pts previously met the ELN2020 "failure" criteria. Estimated 4-y PFS was 92.5%. Death occurred in 3 (4%) pts (1 after progression to blast phase, 2 for cardiovascular adverse events). Estimated 4-y OS was 93.7% CONCLUSION Our findings show that CP-CML patients not achieving an optimal response to frontline 2G-TKI therapy, despite a complex management, still have a favorable prognosis and survival due to the availability of both multiple TKI options and SCT. Figure Disclosures Gugliotta: Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Galimberti:Novartis: Speakers Bureau; Incyte: Honoraria. Abruzzese:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bocchia:CELGENE: Honoraria; Incyte: Honoraria. Castagnetti:Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Di Raimondo:Amgen, Takeda, Novartis: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; GILEAD, Incyte: Research Funding; GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Rosti:Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau. Foà:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Incyte: Speakers Bureau. Saglio:Pfizer: Research Funding; Ariad: Research Funding; Roche: Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Breccia:Abbvie: Consultancy; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Efficacy and Safety of Ponatinib (PON) in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Who Failed One or More Second-Generation (2G) Tyrosine Kinase Inhibitors (TKIs): Analyses Based on PACE and Optic

Efficacy and Safety of Ponatinib (PON) in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Who Failed One or More Second-Generation (2G) Tyrosine Kinase Inhibitors (TKIs): Analyses Based on PACE and Optic

Predictive Factors for Overall Survival in Chronic Myeloid Leukemia Patients: An Analysis By the Gimema Cml Italian Study

Predictive Factors for Overall Survival in Chronic Myeloid Leukemia Patients: An Analysis By the Gimema Cml Italian Study

Long-Term Outcome of Chronic Phase Chronic Myeloid Leukemia Patients Treated with Nilotinib Front-Line

Long-Term Outcome of Chronic Phase Chronic Myeloid Leukemia Patients Treated with Nilotinib Front-Line

NOVEL-1st: A Non-Interventional, Multi-Center Observational Study to Assess the Safety and Efficacy of Nilotinib in Newly Diagnosed Patients with Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) in Taiwan

Background Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), has been approved for the treatment of patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) globally, including Taiwan. However, the real-world evidence regarding the long-term safety (primary) and effectiveness (secondary) of nilotinib in newly diagnosed untreated Ph+ CML-CP is limited in Taiwan. Methods The NOVEL-1st study was a non-interventional, multi-center study. A total of 129 patients with newly diagnosed and previously untreated Ph+ CML-CP were enrolled from 11 centers. The objective was to collect the long-term safety (primary) and effectiveness (secondary) data in patients treated with nilotinib under the real clinical practice for up to three years. Results Of the 129 enrolled patients, 32 patients (24.8%) discontinued the study, predominately due to AEs (n = 8; 6.2%), discontinuing nilotinib or switching to other treatments (n = 7; 5.4%), and death (n = 5; 3.9%). The median age of the study population was 49 years (range, 20 - 53 years), of whom 77 were male (59.7%). At enrollment, the median time from initial CML diagnosis was 22 days (range, 0.0 - 602 days), and three of them had their CML diagnosed for more than one year. Across the 3-year observational period, a total of 1,466 AEs were reported in 127 (98.4%) patients, of which 151 AEs in 44 (34.6%) patients were serious adverse events (SAEs) and 524 AEs in 37 (29.1%) patients were nilotinib-related. The most commonly reported non-hematological AEs (regardless of relationship to nilotinib, incidence ≥ 20 %) were rash (24.8%); while that for hematological AEs were thrombocytopenia (31.0%; Grade 3 or above: 13.2%) (Table 1). Nilotinib discontinuation, and dose reduction or interruptions were only reported in 9 (7.1%) and 11 (8.7%) patients, respectively. Five (3.9%) patients expired, of whom 2 were due to CML progression. Favorable efficacy outcomes were observed in this real-world study. From 3 to 36 months, the rates of clinical response increased over time, from 72.5% to 98.3% for complete hematological response (CHR), from 48.3% to 92.5% for complete cytogenetic response (CCyR), from 16.7% to 85.8% for major molecular response (MMR), from 4.2% to 65.0% for MR4.0 (BCR-ABL ≥ 4 log reduction), and from 3.3% to 45.0% for MR4.5 (BCR-ABL ≥ 4.5 log reduction) (Figure 1). The median time to CHR, CCyR, MMR, and MR4.0 were 4, 5, 9, and 25 months, respectively (not reached for MR4.5). Early molecular response (EMR), defined as BCR-ABL ≤ 10% at Month 3, was seen in 87.6% of patients. Non-hematological and hematological AEs were comparable with previous studies, with no new safety signal detected. This NOVEL-1st study demonstrated a lower percentage of patients withdrawing nilotinib owing to AEs (NOVEL-1st vs. prior: 7.1% vs. 10.0%) and an extremely lower incidence of AEs leading to dose reduction or interruption (8.7% vs. 37 - 55%). It was inferred that the high tolerability and patient adherence further contributed to high treatment response in terms of complete molecular response (CMR [i.e., MR4.5], 45% vs. 32%), molecular response 4.0 (MR4.0, 65% vs. 50%), and major molecular response (MMR, 85.5% vs. 73%) at 3 years. Over the 3 years of follow-up, there was no newly onset of hepatitis or hepatitis B flare. This NOVEL-1st study also reported lower incidence rates of CV events (NOVEL-1st vs. prior: 2.3% vs. 3.5 - 6.0%), diabetes (2.3% vs. 20.2%), and hyperglycemia (3.1% vs. 42.1%) than prior studies. None of them was judged as related to nilotinib treatment (Table 1). Conclusions Across the 3-year observational period, nilotinib demonstrated comparable efficacy and had lower risk of hepatitis flare, CV event, diabetes and hyperglycemia among Ph+CML-CP patients in a real world setting in Taiwan. Long-term good patient adherence and holistic care could contribute to good treatment outcome in this chronic disease under the first-line treatment with nilotinib. Disclosures Chen: Novartis: Current Employment. Lee:Novartis: Current Employment. Ku:Novartis: Current Employment.

Next-Generation Sequencing in Non-BCR-ABLMechanisms Resistance in Patients with Chronic Myeloid Leukemia: Results of a Pilot Study

Introduction.In recent times, more and more data are available on the mechanisms of development of primary and secondary resistance to therapy with tyrosine kinase inhibitors (TKIs) in patients with CML. The use of next-generation sequencing (NGS) allows detecting mutations in theBCR-ABLkinase domain (KD) in some patients with resistance to TKI therapy. However, the reasons for resistance in patients without mutations in theBCR-ABLKD are still unclear. Aim.To determineBCR-ABL-independent molecular genetic markers of resistance to TKI therapy in patients with CML using NGS. Materials and methods.We examined blood samples from 15 patients with resistant CP CML (8 men and 7 women) aged 32 to 59 years (Me = 44 years). Resistance to TKI therapy was determined according to the ELN 2013 criteria. In this group: 2 patients received therapy with 2 TKIs, 8 patients with 3 TKIs, 3 patients - 4 TKIs, and 2 patients received 5 TKIs (Me = 3 TKIs). Cytogenetic test revealed trisomy 8 in 3 patients. One patient was diagnosed with the T315I mutation at once. The patients underwent NGS examination of the myeloid panel, which included 55 genes, with an average reading depth of 1000x using a MiSeq device (Illumina). The 2% threshold of variant allele frequency (VAF) was used. The clinical significance of mutations was evaluated using the COSMIC, ClinVar and OMIM databases. Results.By NGS we identified genetic aberrations in all patients: an average of 5 mutations (from 1 to 10 in one patient). A total of 77 mutations with unclear clinical significance were identified: 54 of them were missense mutations, 22 were synonymous mutations, and 1 frameshift mutation. The most common abnormalities were found in theNF1(10),TET2(8),ATRX(7), andSTAG2(6) genes. In 2 patients, the simultaneous presence of mutations in theATRXandNF1genes was found, they had a primary-resistant course of the disease, MMR was not achieved even on the 3rd and 4th lines of targeted therapy. Three patients were found to have simultaneous mutations in theNF1andSTAG2genes, including two patients who also had a primary-resistant course of the disease, and one of them showed resistance to all 5 TKIs. In 2 patients with the simultaneous presence of mutations in theATRXandTET2genes, resistance to 2 TKIs was registered; CCyR without MMR was achieved only with ponatinib. In 3 patients with singleSTAG2mutations, MMR was achieved on the third line of TKI. One patient with 3 mutations inTET2also achieved MMR only on the third line TKI. Mutations inTET2are more common in Ph-negative MPNs. In our study, mutations were most often detected in theNF1,ATRXandSTAG2genes. Although mutations in theNF1andATRXgenes have been described previously, they were found in responding patients with CP CML (Kim et. al. Blood 2017). In our study, mutations in these genes were found in therapy-resistant patients with an unfavorable course of the disease. TheNF1gene encodes a GTPase activating protein (GAP), which is involved in inhibiting the RAS/MAPK signal transduction pathway and is a tumor suppressor. Mutations in this gene are often associated with the development of CMML and JMML, resistance to therapy and decreased overall survival. TheATRXgene encodes a protein involved in chromatin remodeling, regulation of transcription, replication, and maintenance of telomere structure. TheSTAG2gene encodes a protein that is part of the cohesin complex. Possibly, abnormalities in these genes may belong to a clone of leukemic stem cells (Vetrie et. al. Nature 2020), cause their resistance to TKI,BCR-ABL-independent proliferative potential and their genetic instability. In addition, some of these mutations, possibly, are preleukemic - they could precede the emergence of the Ph-clone in such patients by the mechanism of clonal hematopoiesis of indeterminate potential and may cause an unfavorable prognosis. This allowed us to suggest the prognostic and therapeutic value of mutations in theNF1,ATRXandSTAG2genes in CP CML patients with resistance to TKI therapy. Conclusion.The obtained results of a pilot study of NGS use for predictingBCR-ABL-independent resistance to TKI therapy in patients with CML can serve as a basis for further research aimed at developing prognostic models and choosing a treatment method for resistance to targeted therapy. Disclosures Voloshin: Novartis:Honoraria, Speakers Bureau.Fominykh:Novartis:Honoraria, Speakers Bureau;Pfizer:Honoraria, Speakers Bureau;BMS:Honoraria, Speakers Bureau.Shuvaev:Novartis:Honoraria, Speakers Bureau;BMS:Honoraria, Speakers Bureau;Pfizer:Honoraria, Speakers Bureau.Martynkevich:Pfizer:Honoraria, Speakers Bureau;BMS:Honoraria, Speakers Bureau;Novartis:Honoraria, Speakers Bureau.

Retro-Prospective Observational Study on the Risk of Progression in Chronic Phase-Chronic Myeloid Leukemia (CML) Patients Eligible for Tyrosine Kinase Inhibitor Discontinuation (TFR-PRO)

Retro-Prospective Observational Study on the Risk of Progression in Chronic Phase-Chronic Myeloid Leukemia (CML) Patients Eligible for Tyrosine Kinase Inhibitor Discontinuation (TFR-PRO)

Real World Efficacy Evaluation of Branded and Copy Imatinib in Chronic Myeloid Leukemia: A Retrospective Multicentric Study from Argentina

Background: Data on the safety and efficacy of copy drugs is usually unavailable. Imatinib mesylate is used to treat chronic myeloid leukemia (CML) patients in Argentina since 2002. During the last decade more than ten different imatinib copies are marketed by the different health-care systems in the country, usually for cost issues. In spite of the undoubted benefit of this tyrosine-kinase inhibitor indication in CML, there is no solid evidence that supports copy drug equivalent outcomes for this patient population. Aim: To compare the clinical presentation, treatment response and outcome of a chronic phase (CP) CML patient cohort treated with branded and copy imatinib in the real-life setting. Methods: Multicentric, retrospective trial based on data obtained from medical charts of adult CP CML patients treated with imatinib in 9 centers in Argentina from 2002 to 2020.We analyzed demographic characteristics and clinical characteristics described for branded and copy imatinib treated cohorts. Frequency of complete cytogenetic response (CCyR) at 12 months, Major molecular response or better(≥MMR) at 12, 18 and 24 months and overall MR4.0, MR4.5 and deep molecular response (MR4.0 +MR4.5 IS) were analyzed. Event was defined as failure, progression or CML related death. Kaplan Meier comparison of event free, progression free and overall survival. Statistics: IBM SPSS version 1. Results: A total of 568 CP CML adult patients (pt) treated with imatinib were included. Mean age at diagnosis: 45.7 years (range 18 - 85). Male 55.6% (316/568). Sokal Score was recorded in 471 pt: 57% (269/471) low, 26% (122/471) intermediate and 17% (80/471) high-risk. Median follow-up 107 months (RIQ: 36-149). Branded imatinib treatment 330 (58%) and imatinib copies 238 (42%). For branded and copy imatinib cohorts mean age 46,1 (18-85) and 45.3(18-80), male 53% (175/330) and 59% (141/238), median follow up 102 (RIQ 101-130) and 61 (RIQ 62-146) respectively. Sokal score low 58% (164/284) and 56% (105/187), intermediate 27% (77/284) and 24% (45/187) and high 15% (43/284) and19% (37/187). Frequency of CCyR at 12 months 71% (67/94) and 69% (41/59), ≥MMR at 12 months 57% (79/138) and 43% (39/89), ≥MMR 18m 66 % (61/92) and 71% (43/60), ≥MMR 24m 65% (96/147) and 79% (58/73). Overall MR4, MR 4.5 and Deep MR with branded imatinib 62.4% (186/298), 42% (118/276) and 63% (189/300), compared to 45(97/214), 24% (50/207) and 46% (99/215) with copies. Difference in evaluation throughout the treatment periods with loss of data did not allow response rate statistical comparison in predetermined timepoints. Kaplan Meier Event free survival median 229 months vs 75 months p 0.001, Progression free survival mean 318 months vs 208 pt 0.034 and Overall Survival mean 275 months vs 206 months for branded and copy imatinib respectively. Discussion: Several case reports have shown poor outcomes in patients treated with imatinib copy drugs, including loss of responses previously attained with branded imatinib. This study reports data from a large cohort of CP CML patients treated in daily practice during a long period of time. Treatment results at determined timepoints is comparable. Although management and treatment decisions were performed in different time periods, results show different outcomes in EFS and PFS between patients treated with branded vs copy imatinib. Overall survival in both cohorts is comparable. As studies assesing the safety and efficacy of the copy drugs compared with branded imatinib will hardly be performed this evidence calls for careful attention and strict follow up measures when managing CML patients with copy imatinib. Figure Disclosures Varela: Novartis: Consultancy, Speakers Bureau. Pavlovsky:Pint Pharma: Speakers Bureau; Pfizer: Speakers Bureau; BMS: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Freitas:Pfizer: Consultancy, Other: Advisory Board. Pavlovsky:Varifarma: Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau. Moiraghi:Novartis: Speakers Bureau; BMS: Speakers Bureau.