Chronic Phase CML Research Articles

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.

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.

Characteristics Affecting Durability and Tolerability of Imatinib in Patients Switched from Brand to Generic and Newly Diagnosed Patients Initially Prescribed Generic Imatinib for Chronic Myeloid Leukemia

Characteristics Affecting Durability and Tolerability of Imatinib in Patients Switched from Brand to Generic and Newly Diagnosed Patients Initially Prescribed Generic Imatinib for Chronic Myeloid Leukemia

Prognostic Relevance of Genetic Abnormalities in Blastic Transformation of Chronic Myeloid Leukemia

Prognostic Relevance of Genetic Abnormalities in Blastic Transformation of Chronic Myeloid Leukemia

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

Mutated Cancer-Related Genes Detected at Diagnosis of CML and a Novel Class of Variant Associated with the Philadelphia Translocation Are Both Independent Predictors of Inferior Outcomes

Background We previously reported a high incidence of mutated cancer-related genes at CML diagnosis in selected chronic phase patients with a poor outcome compared to those with a good outcome. We also found a novel class of variant associated with the formation of the Ph chromosome comprising fusions and/or rearrangement of genes on the translocated chromosomes, with evidence of fragmentation, inversion, and imperfect sequence reassembly. These were termed 'Ph-associated events' and were more frequent in patients with poor outcome. However, the risk attributable to these mutational events at diagnosis has not been defined in unselected cohorts. Aim To assess the impact of genomic events in a cohort of consecutively treated patients at diagnosis of chronic phase CML. Methods A hybridization capture sequencing method targeting genes implicated in myeloid and lymphoid malignancies was applied to diagnostic RNA of patients enrolled in the TIDEL II trial. Patients were treated with upfront imatinib with active intervention, dose escalation or nilotinib switch, primarily for lack of time-dependent molecular milestones. Single base variants, small insertions/deletions, splice variants, gene fusions, and focal gene deletions were assessed with pre-defined criteria for pathogenicity. These were further classified as pathogenic mutations in cancer-related genes or Ph-associated events. Univariate and multivariate analyses were performed to evaluate the influence of mutational events and other key clinical and demographic variables on outcome at 4 years. Failure events were as defined by the ELN 2020 recommendations. Results 160/210 TIDEL II patients have so far been sequenced. 33 relevant mutations with variant allele frequencies ≥5% were identified in 9 genes in 25 patients (16%). ASXL1 was most frequently mutated (10% of all patients) and other recurrently mutated genes at diagnosis were RUNX1, BCORL1, IKZF1 and DNMT3A. Ph-associated events occurred in 25 patients (16%). Most of these (14/25 patients) involved fusions between genes on chromosomes 9 and 22 consistent with deletions adjacent to BCR and ABL1, or fusions between BCR or ABL1 and genes/regions on chromosomes other than 9 or 22. These were consistent with variant translocation and some were cytogenetically cryptic. Among these and other Ph-associated events were complex rearrangements involving inversions and large duplications. These were detected in 14/25 patients. Five patients had both cancer-related gene mutations and Ph-associated events, totalling 45 patients (28%) with at least 1 genomic event. Cancer-related mutations at diagnosis were associated with inferior progression-free survival (PFS) 82% vs 91% P=.03, and failure-free survival (FFS) 55% vs 83% P<.001. Molecular outcomes were also inferior: MMR 71% vs 89% P=.02; and MR4 27% vs 71%; P=.01. Similarly, Ph-associated events predicted inferior outcomes: FFS 63% vs 81% P=.01; MMR 70% vs 88% P=.01; and MR4 47% vs 68% P=.01. Importantly, patients with either or both of these mutational events had an increased likelihood of progression to accelerated phase or blast crisis or development of a BCR-ABL1 kinase domain mutation (Figure). Independent predictors of all survival and molecular outcomes were assessed with univariate and multivariate modelling (Table). Candidate prognostic variables were age at diagnosis, sex, transcript, Sokal and ELTS scores and the genomic variables. The only independent predictor of PFS was mutations in cancer-related genes. Cancer-related gene mutations, Ph-associated events and the ELTS score were independent predictors of FFS, MMR and MR4. We evaluated whether genomic data could be additive to the ELTS risk score. Low risk ELTS patients with any mutational event had inferior outcomes: FFS 76% vs 86%, P=.07; MMR 75% vs 92%, P=.02; MR4 41% vs 75%, P=0.006. Similar findings were observed in Intermediate risk ELTS patients: FFS 22% vs 91%, P<.001; MMR 81% vs 84%, P=.06; MR4 9% vs 72%, P=0.047. The number of high risk ELTS patients were inadequate to perform this analysis. Conclusion Despite a proactive strategy for TKI switch and a higher imatinib starting dose, the presence of cancer-related gene mutations or Ph-associated events conferred inferior outcomes. Combining the ELTS score with any mutational event further differentiated patient outcomes, demonstrating the power of integrating genomic data with current risk stratification. Disclosures Shanmuganathan: Janssen: Other: travel expenses; Novartis: Honoraria, Other: Travel expenses; Gilead: Other: Travel expenses; Amgen: Other: travel expenses. Hughes:BMS: 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. Branford:Bristol Myers Squibb: Honoraria; Cepheid: Honoraria, Membership on an entity's Board of Directors or advisory committees; Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, 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.

Comparison of microRNA Expression Profile in Chronic Myeloid Leukemia Patients Newly Diagnosed and Treated by Allogeneic Hematopoietic Stem Cell Transplantation.

Chronic myeloid leukemia (CML) results from a translocation between chromosomes 9 and 22, which generates the Philadelphia chromosome. This forms BCR/ABL1, an active tyrosine kinase protein that promotes cell growth and replication. Despite great progress in CML treatment in the form of tyrosine kinase inhibitors, allogeneic-hematopoietic stem cell transplantation (allo-HSCT) is currently used as an important treatment alternative for patients resistant to these inhibitors. Studies have shown that unregulated expression of microRNAs, which act as oncogenes or tumor suppressors, is associated with human cancers. This contributes to tumor formation and development by stimulating proliferation, angiogenesis, and invasion. Research has demonstrated the potential of microRNAs as biomarkers for cancer diagnosis, prognosis, and therapeutic targets. In the present study, we compared the circulating microRNA expression profiles of 14 newly diagnosed patients with chronic phase-CML and 14 Philadelphia chromosome-negative patients after allo-HSCT. For each patient, we tested 758 microRNAs by reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis. The global expression profile of microRNAs revealed 16 upregulated and 30 downregulated microRNAs. Target genes were analyzed, and key pathways were extracted and compared. Bioinformatics tools were used to analyze data. Among the downregulated miRNA target genes, some genes related to cell proliferation pathways were identified. These results reveal the comprehensive microRNA profile of CML patients and the main pathways related to the target genes of these miRNAs in cytogenetic remission after allo-HSCT. These results provide new resources for exploring stem cell transplantation-based CML treatment strategies.

CML-366: Baseline Cytogenetic Response Level Impact on Survival of Chronic Phase Chronic Myeloid Leukemia Patients Treated with Tyrosine Kinase Inhibitors as Third-Line Therapy: Real-World Data in Five Russian Centers

Context Tyrosine kinase inhibitors in third-line therapy (TKI-3L) in chronic-phase chronic myelogenous leukemia (CP CML) is effective in a portion of patients. Meanwhile, it is unclear which patients may benefit from TKI-3L. Objective To identify the factors affecting the outcome of TKI-3L therapy in CP CML. Design A retrospective study was conducted in five centers of St. Petersburg and Leningrad Region in 2019. All CP CML patients who ever obtained TKI-3L in these centers were included, except patients (pts) with complete cytogenetic response (CCyR). Results Seventy-three pts (male=26) with baseline median age 51 (25–88) were included in the study. There were 51 (70%) pts without any CyR, including 27 (37%) cases without complete hematologic response in baseline. For other patients, the best baseline cytogenetic response was minimal or minor (mmCyR) in 12 (16%) and partial (PCyR) in 10 (14%). BCR-ABL mutations were detected in 30/73 (42%) cases at any time before TKI-3L. Reasons for switching to TKI-3L were resistance in 56 (77%) or intolerance in 17 (23%). Dasatinib, Nilotinib, Bosutinib, or Ponatinib were used as TKI-3L in 43 (59%), 18 (25%), 9 (12%), and 3 (4%) pts, respectively. The median time of TKI-3L treatment duration was 15 (1–120) months. CCyR was achieved in 8/51 (16%) and 14/22 (64%) pts without CyR and with mmCyR/PCyR, respectively(p=0.001). CCyR subsequently had been lost 5/8 (62.5%) and 5/14 (29%) pts initially without or with any CyR (p=0.01). MMR was achieved in 3/51 (6%) and 6/22 (27%) pts without or with any CyR (p>0.05). Estimated overall 1-year, 3-year, and 5-year OS were 95%, 81%, and 65%, respectively. The median follow-up was 26 (3–136) months. There were 14 (19%) death: 11 due to CML progression and 3 after allo-SCT. All deaths occurred in pts without any CyR at baseline. Transformation to accelerated phase and blast crisis was occurred in 13 (18%) pts only in pts group without any CyR initially. The median time to progression was 15 (6–102) months. The only relevant baseline factor for CCyR, OS, and PFS probability in multivariant analysis was the presence of any CyR at baseline (p Conclusion Initial presence of any CyR was a favorable factor for long-term results of TKI third-line treatment in CP CML. TKI-3L should be considered as an appropriate tool in CML treatment for this group.

Lymphoblastic predominance of blastic phase in children with chronic myeloid leukaemia treated with imatinib: A report from the I-CML-Ped Study

BackgroundChronic myeloid leukaemia (CML) is a rare disease in children. The frequency and outcome of children evolving to accelerated phase (AP) or blastic phase (BP) under treatment with imatinib is unknown. The aim of the current study is to assess the incidence of progression from CML in chronic phase with imatinib frontline in a paediatric setting and describe the management and outcome of these patients. Patients and methodsIn the I-CML-Ped Study database (www.clinicaltrials.gov, #NCT01281735), 19 of 339 paediatric patients in chronic phase treated with imatinib in the frontline evolved to CML-AP or CML-BP. ResultsWith a median follow-up of 38 months (range: 2–190 months), the cumulative incidence of progression at 1 and 3 years was 3% (confidence interval [CI] 95%: 1–5%) and 7% (CI 95%: 4–11%), respectively. We observed a large predominance of lymphoid-BP (70%) over myeloid-BP (30%) with imatinib in frontline therapy. Sixteen patients underwent haematopoietic stem cell transplantation, and eight were treated with a tyrosine kinase inhibitor after transplant. Only the transplanted patients are alive. The 5-year overall survival rate of children with CML-AP/BP is 44%, with no statistical difference between the lymphoid-BP and myeloid-BP outcome. ConclusionChildren evolving to AP or BP under treatment with imatinib have a very poor prognosis with an overall survival under 50%, much worse than children with advanced phase at diagnosis.

Abstract 3792: Imetelstat inhibits RNA-editing mediated myeloproliferative neoplasm stem cell self-renewal

Abstract Introduction: Myeloproliferative neoplasms (MPN) including blast crisis (BC) CML and myelofibrosis (MF) are characterized by the clonal proliferation of hematopoietic cell lineages, mostly in the marrow. BC CML gives rise to TKI resistant myeloid progenitors that activate Wnt/β-catenin signaling pathway. However, BCR-ABL TKI resistant BC CML exhibits a robust telomerase activity and presents at very low or undetectable level in normal cells, and telomerase plays a pivotal role in cancer cell growth and may serve as an ideal target for anticancer therapeutics. In addition, β-catenin had been reported to transcriptionally regulate human telomerase reverse transcriptase (TERT). Telomerase is composed of the enzymatic reverse transcriptase protein TERT and the RNA template TERC. Thus, we investigated the capacity of imetelstat, a telomerase inhibitor, which binds to the TERC subunit with high affinity to prevent self-renewal of malignant progenitors. Recent clinical trials showed early signs of efficacy in MF. But, it's role in selectively inhibiting leukemia stem cell (LSC) self-renewing in CML has not been elucidated. Methods and Results: Progenitors from BC CML were compared with chronic phase (CP) CML and primary normal samples, RNA-seq results revealed upregulation of TERT suggesting a role for TERT activation in BC CML progenitor transformation. Human MPN progenitor co-culture experiments revealed that combined treatment with dasatinib at 1 nM, and imetelstat at 1 or 5 uM significantly inhibited (p < 0.001, ANOVA) in vitro replating of BC CML compared with aged bone marrow progenitors. Also, imetelstat (5 mM) significantly reduced replating of MF compared with normal progenitor samples. Treatment of humanized MPN mouse models, established with 5 different BC CML and 4 different MF samples, at 30 mg/kg of imetelstat, three times a week for 4 weeks resulted in a significant reduction of malignant progenitors and human CD45+ cells (p < 0.001, t test) in BC CML, and a significant reduction of human CD45+ cells (p<0.01, t test) in MF in both marrow and spleen, when compared with vehicle controls. FACS analysis revealed a significant reduction of activated β-catenin protein in BC CML engrafted human progenitors after imetelstat treatment (p < 0.01, t test) compared with vehicle control. In addition, a significant inhibition of TERT (p = 0.03) and TERC (p = 0.02) was observed in BC CML LSC isolated from imetelstat treated mouse marrow when compared with vehicle control. Notably, imetelstat treatment spares normal human cells in humanized normal stem cell mouse models. Recent RNA-sequencing analysis showed an increase in ADAR1 expression during MPN progression, and our RNA-seq analysis demonstrated a decreased ADAR1 gene expression (p < 0.005) as well as overall adenosine to inosine editing rates as measured by edits per million reads (p <0.005) following imetelstat treatment of BC CML engrafted mice when compared to mismatch control. Conclusions: Niche responsive interactions between the telomerase complex and the Wnt/β-catenin self-renewal pathway sensitize β-catenin activated MPN progenitors to imetelstat treatment in both the in vitro co-culture and in vivo humanized MPN mouse models thereby providing a strong rationale for studies assessing eradication of malignant progenitors using imetelstat. Citation Format: Wenxue Ma, Larisa Balaian, Cayla Mason, Raymond Diep, Jessica Pham, Qingfei Jiang, Jeremy Lee, Sheldon Morris, Phoebe Mondala, Ping Chen, Thomas Whisenant, Mary Donohoe, Benjamin Heyman, Edward Ball, Fei Huang, Catriona Jamieson. Imetelstat inhibits RNA-editing mediated myeloproliferative neoplasm stem cell self-renewal [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3792.

Timing of allogeneic hematopoietic cell transplantation (alloHCT) for chronic myeloid leukemia (CML) patients

While TKI are the preferred first-line treatment for chronic phase (CP) CML, alloHCT remains an important consideration. The aim is to estimate residual life expectancy (RLE) for patients initially diagnosed with CP CML based on timing of alloHCT or continuation of TKI in various settings: CP1 CML, CP2 + [after transformation to accelerated phase (AP) or blast phase (BP)], AP, or BP. Non-transplant cohort included single-institution patients initiating TKI and switched TKI due to failure. CIBMTR transplant cohort included CML patients who underwent HLA sibling matched (MRD) or unrelated donor (MUD) alloHCT. AlloHCT appeared to shorten survival in CP1 CML with overall mortality hazard ratio (HR) for alloHCT of 2.4 (95% CI 1.2–4.9; p = .02). In BP CML, there was a trend toward higher survival with alloHCT; HR = 0.7 (0.5–1.1; p = .099). AlloHCT in CP2 + [HR = 2.0 (0.8–4.9), p = .13] and AP [HR = 1.1 (0.6–2.1); p = .80] is less clear and should be determined on a case-by-case basis.

Interim analysis (IA) of OPTIC: A dose-ranging study of three ponatinib (PON) starting doses.

7502 Background: In PACE (NCT01207440) heavily pretreated patients (pts) with chronic-phase CML (CP-CML) had deep, lasting responses to PON; long-term follow-up showed increasing rates of arterial occlusive events (AOEs). We present IA results from OPTIC (NCT02467270), evaluating the association between PON exposure, efficacy, and safety, and response-based dose reduction in pts with CP-CML. Methods: This ongoing, multicenter, randomized phase 2 trial enrolled pts with CP-CML resistant or intolerant to ≥2 TKIs or with a T315I mutation to receive PON at a starting dose of 45 mg (cohort A), 30 mg (B), and 15 mg (C) qd. Doses were reduced to 15 mg qd on achievement of ≤1% BCR-ABL1IS in A/B. Primary endpoint: 12 mo ≤1% BCR-ABL1IS; secondary endpoints include cytogenetic and molecular response and AOE, VTE, and TEAE rates. Results are descriptive at this IA and will be inferential by adjusting multiplicity across 3 cohorts at final analysis. Results: 283 pts were randomized (A/B/C: n = 94/95/94); median age 48 y (18‒81 y). 26% had hypertension history; 2/43/55% received 1/2/≥3 TKIs; 40% had ≥1 baseline (BL) mutations, with 23% T315I. At IA data cutoff (20 Jul 2019), 162 pts (57%; n = 57/51/54) remained on study treatment. Among 282 pts in the safety population, median duration of exposure was ≈1 y (A/B/C, 12.9/11.2/11.0 mo). At 12 mo, 39% (95% CI, 27.6, 50.6), 27% (17.6, 39.1), and 26% (16.5, 38.6) in A, B, and C, respectively, achieved ≤1% BCR-ABL1IS. Additional efficacy in Table. Dose reductions due to efficacy (A/B): 35/21%. Most common TEAEs (any grade/≥3): thrombocytopenia 39/27%, neutropenia 25/17%. AOEs/serious AOEs were reported by (A, B, C) 5%/2%, 4%/3%, and 1%/0%. Dose reductions due to TEAEs: (A/B/C): 44/31/28%; discontinuations due to TEAEs: 18/15/14%. There were 4 (1.4%) on-study deaths; A, sudden death, n = 2; C, pneumonia, n = 2; no deaths were due to AOEs. Clinical trial information: NCT01207440 . Conclusions: OPTIC IA shows a trend toward dose-dependent efficacy and safety and may provide a refined understanding of the PON benefit:risk profile and its relation to dose. Data from longer follow-up may support an alternate dosing regimen for pts with CP-CML. [Table: see text]

The EBMT activity survey on hematopoietic-cell transplantation and cellular therapy 2018: CAR-T\u2019s come into focus

Hematopoietic-cell transplantation (HCT) is widely used for acquired and congenital disorders of the hematopoietic system. Number of transplants performed in Europe and associated countries continues to rise with 47,468 HCT in 42,901 patients [19,630 allogeneic (41%) and 27,838 autologous (59%)] reported by 701 centers in 50 countries in 2018. Main indications were myeloid malignancies 10,679 (25%; 97% allogeneic), lymphoid malignancies 27,318 (64%; 20% allogeneic), solid tumors 1625 (4%; 2.9% allogeneic), and nonmalignant disorders 3063 (7%; 81% allogeneic). This year’s analysis focuses on cellular therapies with the marked growth in CAR T-cell therapies from 151 in 2017 to 301 patients reported in 2018. Other cellular therapy numbers show less significant changes. Important trends in HCT include a 49% increase in allogeneic HCT for chronic phase CML (although transplant numbers remain low) and a 24% increase in aplastic anemia. In autologous HCT, there is an ongoing increase in autoimmune diseases (by 19%), predominantly due to activity in multiple sclerosis. This annual report reflects current activity and highlights important trends, useful for health care planning.

T‐cell blast crisis of chronic myelogenous leukemia presented with coexisting p210 and p190 BCR‐ABL transcripts and t(10;11)(q11;p15)

BackgroundBlast transformation of chronic myelogenous leukemia (CML) to T lymphoblastic lymphoma/acute lymphoblastic leukemia (T‐LBL/ALL) is rare, and the molecular mechanism is still unclear.Case reportA 28‐year‐old woman who developed T‐ALL with coexpressing both p210 and p190 BCR‐ABL transcripts five years after the initial diagnosis of CML in chronic phase. The proliferation of bone marrow was extremely active with blast cells over 20%. Chromosome analysis revealed t(9;22)(q34;q11) and t(10;11)(q25;p15). Flow immunophenotyping showed that blasts expressed CD4, CD7, CD11b, CD38, CD34, CD33, and cCD3.ConclusionIt is the first T‐cell blast of CML case with coexisting p210 and p190 as well as additional chromosome translocations. Through review this case and previous reports, we will reveal that CML patients with T‐lymphocyte transformation depend on potential molecular and pathological mechanism.

Phase 2 study of nilotinib in pediatric patients with Philadelphia chromosome–positive chronic myeloid leukemia

AbstractChronic myeloid leukemia (CML) is rare in children and accounts for ≤15% of all myeloid leukemia cases. When we initiated this study with nilotinib, imatinib was the only tyrosine kinase inhibitor indicated for pediatric patients with Philadelphia chromosome–positive (Ph+) CML in chronic phase (CP); alternative treatment options were needed, particularly for patients who developed resistance or intolerance (R/I) to imatinib. This phase 2 study enrolled pediatric patients with either Ph+ CML-CP R/I to imatinib or dasatinib or newly diagnosed Ph+ CML-CP. Data presented are from analyses with minimum follow-up of up to 24 cycles (1 cycle is 28 days). Fifty-nine patients with Ph+ CML-CP were enrolled, and 58 were treated (R/I, n = 33; newly diagnosed, n = 25). Major molecular response (MMR) rate at cycle 6 in the R/I cohort was 39.4% (primary end point); 57.6% of patients achieved or maintained MMR and 81.8% achieved or maintained complete cytogenetic response (CCyR) by 24 cycles. In patients with newly diagnosed disease, rates of MMR by cycle 12 and CCyR at cycle 12 were 64.0% each (primary end points); by cycle 24, cumulative MMR and CCyR rates were 68.0% and 84.0%, respectively. The safety profile of nilotinib in pediatric patients was generally comparable with the known safety profile in adults, although cardiovascular events were not observed in this study, and hepatic laboratory abnormalities were more frequent; no new safety signals were identified. In summary, nilotinib demonstrated efficacy and a manageable safety profile in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov as #NCT01844765.

Longer Hydroxyurea Administration Prior to Imatinib Mesylate is Risk Factor for Unsuccessful Major Molecular Response in Chronic-Phase Chronic Myeloid Leukemia: Possibility of P-Glycoprotein Role.

Objective:This study aimed to identify the association between duration of HU administration prior to IM treatment and MMR achievement in chronic-phase CML while evaluating the role of MDA, HIF-1α and P-gp. Methods:The study was conducted at Dr. Cipto Mangunkusumo National General Hospital and Dharmais Cancer Hospital, Jakarta using retrospective cohort design to analyse the association between the duration of HU before IM and its MMR achievement and cross-sectional design to analyse the association between MDA, HIF-1α and P-gp expressions with MMR achievement. Main subjects were chronic-phase CML patients treated by HU prior to IM for ≥ 12 months and HU only. The subjects were divided into four main groups: (1) chronic-phase CML patients treated with HU ≤ 6 months + IM ≥ 12 months and (2) HU > 6 months + IM ≥ 12 months (3) HU only (≤ 6 months), (4) HU only ( >6 months). Subjects were obtained from January 2015 to May 2016. Data were gathered through history taking, physical examination, medical record evaluation, and blood sample analysis. Bivariate analysis was conducted using chi square, independent T-test, and Mann-Whitney according to the variables. Results:Administration of HU for more than 6 months prior to IM was associated with unsuccessful MMR achievement (RR 1.60; 95%CI 1.29-2.00). MDA level, HIF-1α, P-glycoprotein expression were not associated with MMR achievement but the mean MDA level (0.63±0.31 vs 0.75±0.41 p=0.461) and median P-glycoprotein expressions {16,92 (0,04 – 43,86) vs. 5,15 (0,02–39,64); p=0.311} were found to be higher in patients receiving HU for > 6 months group than in HU ≤ 6 months group consecutively. Conclusion:Administration of HU for more than 6 months prior to IM was associated with unsuccessful MMR achievement in chronic-phase CML. The study suggested that P-glycoprotein overexpression as the predictor for unsuccessful MMR achievement.

Comparison of chronic myeloid leukemia stem cells and hematopoietic stem cells by global proteomic analysis

Tyrosine kinase inhibitors (TKIs) that target BCR-ABL are the standard first-line therapy for patients with chronic-phase CML. However, TKIs cannot eliminate quiescent leukemia stem cells (LSCs) which persist in all patients on long-term therapy and provides a reservoir for disease progression and recurrence. Many researches have confirmed that TKI-resistant LSCs compartment can be captured within CD26 + fraction. In order to analyze distinctive biological characteristics of TKI-resistant LSCs, we isolated the CD34 + CD38−CD26+, CD34 + CD38−CD26−and CD34 + CD38 + cells from 8 CML patients utilizing magnetic and flow sorting, and analyzed the global proteomic expression through high-resolution LC-MS/MS analysis. In the work, we discovered that a list of dysregulated proteins involved in energy metabolism and carcinogenesis, including PPARD, IL1-RAP, HNF, S15A2, PCLO, VA0D1, CKLF5, were extremely upregulated in the CD26 + LSCs while some majoring in DNA mismatch repair or related to cell senescence, such as MLH3, NOLC1, were downregulated. Additionally, we verified the upregulation of PPARD in both CML patients-derived CD26 + LSCs and donor-derived BCR-ABL1 overexpressed HSCs. These results open in turn new therapeutic avenues for targeting TKI-insensitive LSCs.

Dose Optimization in Elderly CML Patients Treated with Bosutinib after Intolerance or Failure of First-Line Tyrosine Kinase Inhibitors

Dose Optimization in Elderly CML Patients Treated with Bosutinib after Intolerance or Failure of First-Line Tyrosine Kinase Inhibitors

Treatment Free Remission for Chronic Phase Chronic Myelogenous Leukemia Patients Who Stopped Tyrosine Kinase Inhibitor Therapy Due to Intolerance

Introduction: Chronic Myelogenous Leukemia (CML) is a myeloproliferative neoplasm that is often diagnosed in adults between the ages of 25-60. The outcome of the chronic phase CML has dramatically changed due to Tyrosine Kinase Inhibitor (TKI) therapy. There are well established guidelines from NCCN and ESMO on stopping TKI for patients achieving prolonged remissions with TKIs. We report clinical outcomes from a single tertiary care center in patients who stopped TKI therapy for reasons other than prolonged remission status. Methods: We retrospectively reviewed all the CML patients who were treated at our institution in the past 10 years (January 1st,2009 - December 31st,2018). We excluded patients who had accelerated or blast phase CML, atypical CML, patients on non-TKI therapy, and patients who received an allogeneic stem cell transplant. Results: A total of 117 patients were diagnosed with chronic phase CML at our institution in the past 10 years. Among the 117 patients, 12 of these discontinued TKI therapy. Six patients stopped TKI after achieving prolonged remission with TKI therapy and the remaining patients discontinued due to intolerance to treatment, fear of side effects, and loss of insurance. The median age of the whole cohort is 66 years (range 42-85). Six patients were male and 6 were females. Six patients were diagnosed with CML prior to year 2009 and rest after 2009. Prior to stopping, six patients received only 1 kind of TKI, 2 patients were treated with 2 types of TKIs, 2 patients received 3 types of TKIs, and 2 patients had 4 lines of TKIs (See Table). Cohort 1: 6 patients who stopped due to prolonged remission, median major molecular remission - MMR4 (BCR-ABL <0.01% IS by RT-PCR testing) prior to stopping TKI is 6 years (range 3-13 years). Of the six, only 1 relapsed (within 1 month of stopping) and was initiated back on the same TKI (imatinib). The relapsed patient has not achieved MMR4 level remission to date. Median treatment free remission for this cohort is 13 months (range 1-24 months). Cohort 2: Of those 6 patients who stopped TKI for other reasons: 4 stopped due to side effects/intolerance, 1 stopped due to fear of side effects after FDA label was updated, and 1 patient discontinued due to a loss of insurance. Median duration of MMR4 prior to stopping is 4 years (range 1-11 years). 5 of these 6 patients relapsed in the median time of 6 months (range 3-16 months). Of these 5, 4 were started back on the TKI therapy (three on the same TKI and one on a different TKI). Median treatment free remission for this cohort is 4 months (range 2-16 months). Conclusion: In this small cohort from a single institution's experience, CML patients who discontinued TKI therapy after achieving MMR4 for reasons other than prolonged remission have experienced poor outcomes including a higher rate of relapse and a shorter treatment free remission. We need studies with larger samples sizes and longer follow up to assess outcomes in patients stopping TKI therapy for various reasons. Disclosures No relevant conflicts of interest to declare.