Outcome Of Chronic Myeloid Leukemia Research Articles

Analysis of predictive effect of European treatment and outcome study long term survival score on survival outcomes in children with chronic myeloid leukemia of chronic phase

Objective: To explore the predictive effect of European treatment and outcome study long term survival (ELTS) score on survival outcomes in chronic myeloid leukemia of chronic phase (CML-CP) children. Methods: A single-center retrospective cohort study was conducted. Clinical data of 216 children with CML-CP in Peking University People's Hospital from January 2010 to December 2023 were analyzed. Children were divided into low, intermediate and high-risk groups according to ELTS score. The survival outcomes and prognostic factors were analyzed. Kaplan-Meier method and Log-Rank test were used for survival analysis.Cox regression model was applied for analysis of prognostic factors. Results: Among the 216 children with CML-CP, there were 122 males and 94 females, with the diagnosis age of 11.0 (8.0, 14.7) years. The follow-up time was 77 (57, 99) months. According to ELTS score, 145, 52, and 19 children were classified as low, intermediate and high-risk group. For the low-risk and intermediate/high-risk groups, the 6-year failure-free survival (FFS) rates were (83.0±3.1)% and (64.6±5.7)%, the 6-year progression-free survival (PFS) rates were (91.4±2.3)% and (78.7±4.8)%, and the 6-year event-free survival (EFS) rates were (80.8±3.3)% and (64.2±5.7)%, with statistically significant difference (χ2=9.45, 7.16, 7.40, P=0.002, 0.007, 0.007), respectively.The 6-year overall survival (OS) rates were (98.5±1.0)% and (95.6±2.4)%, without statistically significant difference (χ2=0.35, P=0.550). Multivariate analysis showed that ELTS score was an independent prognostic factor or tendency for FFS (HR=1.97, 95%CI 1.11-3.49), PFS (HR=2.95, 95%CI 1.18-7.39), and no independent prognostic factor for EFS and OS were found. Conclusions: ELTS score at diagnosis can help stratify the risk of children with CML-CP. The children in intermediate/high-risk group are more likely to have treatment failure, disease progression than those in low-risk group, but the predictive ability of ELTS score for OS is limited.

Chronic Myeloid Leukemia in Bulgaria in the New Millennium: Identification of Directions for Improvement in Management and Outcomes Reporting

Background: In the last two decades, tyrosine kinase inhibitors (TKIs) and advances in molecular diagnostics have revolutionized management and long-term clinical outcomes in chronic myeloid leukemia (CML). Real-world data from different countries allow for the identification of country-specific issues in the clinical management and development of specific plans for improvement. Here, we aimed to analyze the trend in overall survival in Bulgarian CML patients since 2000. Methods: We retrieved publicly available Bulgarian CML data from several sources such as the Bulgarian National Cancer Registry, Bulgarian National Statistical Institute, and National Health Insurance Fund since 2000. We used the retrieved data of a total of 1513 Bulgarian CML patients to describe the trends in overall survival (OS), conditional overall survival, life expectancy, and life years lost over five time periods. We also described the trends in healthcare expenditures for TKIs and CML patients’ coverage with TKIs since 2014. Results: In both uni- and multivariate models, we found a constant increase in OS over the three 5-year periods until 2014. The period 2015–2019 was not associated with an additional increase in OS. Identical dynamics in the improvement in life expectancy (LE) and in life years lost (LYLs) was observed. Additionally, conditional 5-year survival did not improve during 2015–2019 in comparison to 2010–2014. Population-level data did not show consistent changes in the documented number of deaths due to CML since 2013. The period after 2013 is marked by a constant increase in the annual expenditures for TKIs, reaching to about 2.0 EUR/capita. The number of patients who received at least one TKI also increased during that period. Conclusions: After the initial significant improvement in the clinical outcomes for Bulgarian CML patients until 2014, subsequent periods did not bring further benefit in spite of the improved coverage with second- and third-line TKIs. Multiple factors may contribute to these suboptimal outcomes. Therefore, one can propose several additional measures at the country level, which could lead to additional improvement in the OS of Bulgarian CML patients.

Frequency of comedication of proton pump inhibitors with crystalline dasatinib in chronic myeloid leukemia and effects on TKI-bioavailability.

6561 Background: Tyrosine kinase inhibitors (TKI), including dasatinib, have profoundly improved clinical outcome in chronic myeloid leukemia (CML). However, solubility, bioavailability and systematic exposure of the crystalline formulation of dasatinib (Sprycel) is reduced at higher gastric pH levels. This is problematic for comedication with acid reducing agents as lower bioavailability may reduce clinical response. Methods: We investigated proton pump inhibitor (PPI) and TKI comedication, including dasatinib, in a large real world CML cohort. Furthermore, we assessed the influence of timing of PPI comedication on the absorption and bioavailability of dasatinib. Results: Using the Swedish CML- and Prescribed Drug-Registries, we identified 1,328 chronic phase CML patients, diagnosed 2002-2018. 1,261 (95%) had received specified/known TKI treatment and 685 of those (54%) were prescribed a PPI (ATC-code: “A02BC”) at some point after CML diagnosis. TKIs and PPIs prescribed within 12 months of CML diagnosis were prescribed by different HCPs in 66% of cases (284/432). Of the 388 patients treated with dasatinib, 91 (23.5%) received a concomitant PPI. The PPI prescription rate increased to 53% (204/388) in the dasatinib cohort after dasatinib treatment had ended. Further, we assessed the drug-drug interaction (DDI) in 18 healthy volunteers given crystalline dasatinib (100mg) alone or together with omeprazole (40mg, at steady state) administered 9 hours apart; a time point when a high effect on bioavailability is expected. Compared to dosing with crystalline dasatinib alone, Cmax and AUC0-24 were reduced by 96% and 88% by omeprazole comedication (Table). Conclusions: Despite warnings, comedication with PPI is common among dasatinib treated CML patients. Further, an even larger proportion of patients need PPI co-treatment, which however, cannot fully be administered due to its negative impact on dasatinib pharmacokinetics. Moreover, with an optimized study design, we observed a higher than previously reported negative interaction of PPI comedication on crystalline dasatinib bioavailability. This may compromise clinical efficacy and risk CML disease progression. For patients in need of PPI, selection of a non-crystalline, less pH-sensitive formulation of dasatinib therefore appears more appropriate. Clinical trial information: NCT06145217 . [Table: see text]

Changes in chronic myeloid leukemia treatment modalities and outcomes after introduction of second-generation tyrosine kinase inhibitors as first-line therapy: a multi-institutional retrospective study by the CML Cooperative Study Group.

This study investigated changes in treatment modalities and outcomes of chronic myeloid leukemia in the chronic phase (CP-CML) after the approval of second-generation tyrosine kinase inhibitors (2G-TKIs) for first-line therapy. Patients were grouped into those who underwent TKI therapy up to December 2010 (imatinib era group, n=185) and after January 2011 (2G-TKI era group, n=425). All patients in the imatinib era group were initially treated with imatinib, whereas patients in the 2G-TKI era group were mostly treated with dasatinib (55%) or nilotinib (36%). However, outcomes including progression-free survival, overall survival, and CML-related death (CRD) did not differ significantly between groups. When stratified by risk scores, the prognostic performance of the ELTS score was superior to that of the Sokal score. Even though both scoring systems predicted CRD in the imatinib era, only the ELTS score predicted CRD in the 2G-TKI era. Notably, the outcome of patients classified as high-risk by ELTS score was more favorable in the 2G-TKI era group than in the imatinib era group. Thus, expanding treatment options may have improved patient outcomes in CP-CML, particularly in patients classified as high-risk by ELTS score.

Impact of Mutations in Blood Cancer-Related Genes on Clinical Outcomes in Chronic Myeloid Leukemia in Chronic Phase (CML-CP) after ≥2 Tyrosine Kinase Inhibitors (TKIs) in the Ascembl Trial

CONCLUSIONS Somatic mutations in blood cancer-related genes are commonly detected in CML-AP. The most frequently mutated genes are RUNX1, ASXL1IKZF1 (submicroscopic deletions), and BCR:: ABL1 (kinase domain mutations). ASXL1 is the most frequently detected mutation at CML diagnosis (≈9%). However, the incidence and impact of mutations in blood cancer-related genes in patients (pts) with CML-CP previously treated with ≥2 TKIs have not been described since genomic studies have focused on pts at diagnosis or at progression. With >2 years of follow-up in the phase 3 ASCEMBL study, asciminib (ASC) has continued to demonstrate superior efficacy vs bosutinib (BOS) in pts with CML-CP after ≥2 prior TKIs, and analysis of cancer gene somatic mutations in this population has the potential to reveal additional insights into pts' response to study treatments or characteristics of the disease in later lines of therapy. Here we present a descriptive analysis of variants in the ASCEMBL pt population, including frequencies, co-occurrences, and association of mutations with clinical outcomes, specifically major molecular response (MMR) and treatment failure (TF; defined as discontinuation due to lack of efficacy or intolerance). Adults with CML-CP previously treated with ≥2 TKIs with intolerance of their last TKI or lack of efficacy per 2013 European LeukemiaNet recommendations and without BCR:: ABL1 T315I or V299L mutations were randomized 2:1 to ASC 40 mg twice daily or BOS 500 mg once daily. DNA was isolated from blood collected at baseline (BL) and end of treatment (EOT; defined as treatment discontinuation for any reason or completion of the study). A next-generation sequencing panel of 89 commonly mutated genes in blood cancers, including ABL1 and IKZF1 deletion, was used to detect somatic mutations that met criteria for pathogenicity. Only samples with BCR::ABL1IS ≥2%, which was the level demonstrated to detect mutations in leukemic cells, were tested. A multivariable Cox proportional hazards regression model adjusted for age, sex, treatment, and reason for prior TKI discontinuation (intolerance vs lack of efficacy) was used to determine the prognostic value of BL mutations. A total of 233 pts were randomized to ASC (n=157) or BOS (n=76). Of 162 pts (ASC, n=110; BOS, n=52) with available sequencing data at BL, 102 had ≥1 mutation: 69 (63%) on ASC and 33 (63%) on BOS. Overall, 159 mutations were detected in 23 genes at BL, ranging from 0 to 5 per pt. The median variant allele frequency (VAF) was 19.6% (range, 0.9%-58%). ASXL1 (in 31% of pts) and ABL1 kinase domain (in 17% of pts) mutations were the most frequently detected. Of 27 pts with ≥1 ABL1 mutation at BL, 85% had ≥1 other mutated cancer gene. Co-occurrence of ASXL1 and ABL1 mutations at BL was reported in 12 of 162 pts (7.4%), which was higher than the expected 2.9% based on these genes' individual frequencies in this data set. RUNX1 and IKZF1 mutations were rare in CML-CP at BL. Of 162 pts tested at BL, 73 had TF and available samples for analysis at EOT with only 3 pts discontinuing due to disease progression. The presence of any mutation at BL was significantly prognostic of TF in the total cohort of 162 pts (Figure 1). In an unadjusted analysis, the presence of an ASXL1 mutation with VAF >5% at BL was a prognostic factor of TF. In 73 pts with TF, most BL mutations were also detected at EOT (110/116 mutations in 48/54 carriers) (Figure 2). Of 15 pts who acquired ≥1 mutation at EOT, 9 acquired ABL1 mutations. No single mutations at an individual or gene level were prognostic of MMR. Mutations were not predictive of MMR or TF when pts were examined by their assigned treatment of ASC or BOS. ASXL1 mutations are most frequently detected at CML diagnosis and were enriched at BL in this study of pts with CML-CP previously treated with ≥2 TKIs, which is consistent with a role in TKI resistance. RUNX1 and IKZF1 mutations, which are associated with progression to accelerated or blast phase in CML, were very rare in this pt population, supporting their role in CML disease progression. The high frequency of co-occurrence of BCR:: ABL1 mutations and blood cancer gene mutations in CML-CP is an important finding since cancer gene mutations could modify response to TKIs in individual pts. The presence of any somatic blood cancer mutation at BL was prognostic of TF. These mutations may serve as potential biomarkers that can identify pts who may be at higher risk of TF in later lines of therapy.

Role of Lama4 Expression in Bone Marrow Niche for the Progression and Treatment Response of Chronic Myeloid Leukemia

Although tyrosine kinase inhibitors (TKIs) have dramatically improved the treatment outcomes of chronic myeloid leukemia (CML), TKIs cannot eliminate CML-initiating stem cells (LSCs), leading to CML persistence and relapse post TKI-discontinuation. Thus, it is imperative to develop more effective therapeutic options to overcome the treatment challenges. Targeting the bone marrow (BM) niche has become one of the research focuses in drug discovery since increasing evidence suggests that BM niches protect CML LSCs. Laminin alpha4 chain (Lama4), a functional chain for several laminin isoforms, is widely expressed in bone marrow (BM). We have recently shown the critical impact of LAMA4 expression in the microenvironment for hematopoiesis regeneration including megakaryocyte maturation and acute myeloid leukemia progression in mice (Cai et al., Blood, 2022). Furthermore, we have by RNA sequencing shown downregulation of LAMA4 mRNA in freshly isolated BM mesenchymal stem cells (MSCs) from newly diagnosed patients with CML (Dolinska, Cai, Mansson, et al., Blood, 2023). However, the functional impact of the LAMA4 expression on CML LSCs remains to be investigated. We have here explored the role of LAMA4 in CML development and drug response by using both mouse models and primary patient BM samples. To first assess the in vivo impact of LAMA4 expression in BM niches on CML development, we transplanted BM cells (CD45.2) from Scl- tTA× TRE-BCR-ABL1 (BCR-ABL1) mice prior or following tetracycline withdrawal into irradiated Lama4+/+ and Lama4-/- CD45.1mice and analyzed CML progression and BCR-ABL1 LSC activity by flow cytometry and droplet digital PCR (ddPCR). Following transplantation of unfractionated BM cells from the BCR-ABL1 mice with CML induced by tetracycline withdrawal, Lama4-/- recipients showed significantly increased platelet counts in blood compared to Lama4+/+ recipients at 2-8 weeks post-transplantation (P=0.005 at week 2, P= 0.008, n=7-8, at week 8), which is in contrast to the impaired platelet recovery in non-transplanted Lama4-/- mice following sublethal irradiation. This suggests that Lama4 deficient microenvironment is favorable for platelet production from BCR-ABL1 CML cells. Consistent with this, megakaryocyte-erythrocyte progenitors (MEPs) derived from BCR-ABL1+ cells were significantly increased in Lama4 -/- BM at the endpoint (8 weeks, p=0.02, n=3). Megakaryocyte progenitors (MkPs) seemed to be increased in Lama4-/- recipient BM (P=0.05, n=3). Intriguingly, when LIN -SCA1 +KIT + CD150 + hematopoietic stem cells from BCR-ABL1 mice without prior tetracycline withdrawal were transplanted, the donor-derived MEPs were significantly reduced in Lama4-/- BM (P=0.02, n=4-6), which is accompanied with a trend of reduction in MkP but no changes in platelets. ddPCR analysis indicated that the ratio of BCR-ABL1 + cell fraction to total CD45.2 + cells (detected by FACS) seemed to be lower in Lama4-/- recipients (33.6%) than that in Lama4+/+ recipients (41.5%), raising a possibility that Lama4-/- niches is less suitable for maintenance of BCR-ABL1 + cells. Together, these data point to a possible differential regulation of CML stem and progenitor cells by the Lama4 expression. More work will be done to dissect the regulatory mechanisms through in vitro co-cultures, transplantation and confocal imaging. In parallel, the functional impact of LAMA4 on human CML LSC survival was evaluated by a revised long-term culture-initiating cell assay using CML patient derived MSCs. The preliminary result indicated that recombinant LAMA4 peptides appeared to inhibit CML patient BM-derived CD34 +CD38 - cell growth. In conclusion, LAMA4 is downregulated in BM MSCs and endothelial cells of CML patients at diagnosis. Lama4-/- microenvironment might act differentially in regulating BCR-ABL1 + hematopoietic stem and progenitor cell activity post-transplantation. However, more work is required to validate the finding and the effect of LAMA4 peptides on the megakaryocyte differentiation and maturation.

Validation of imatinib therapy failure score (IMTF) in chronic phase chronic myeloid leukemia in real life practice

The outcome of chronic myeloid leukemia (CML) patients improved in the last decade. Clinical prognostic scoring systems aim to provide information about survival in the long-term, without determining from baseline the subset of patients who require a strictly monitoring because at increased risk of failure. Imatinib, the first-generation tyrosine kinase inhibitor (TKI), is still widely used as frontline treatment: recently, the imatinib therapy failure (IMTF) score was proposed to identify the failure free survival. Aim of our study was to validate this index in a large cohort of patients treated with imatinib.

Treatment after failure of frontline therapy of chronic myeloid leukemia in chronic phase including allogeneic hematopoietic stem cell transplantation.

The treatment outcomes of chronic myeloid leukemia in chronic phase (CML-CP) have dramatically improved with comparable life-expectancy to average of general population in tyrosine kinase inhibitor (TKI) era. However, less than a half of patients who started with TKI can remain on frontline TKI. The reasons of switching TKI can be either intolerance or the lack of efficacy. Although a kinase domain (KD) mutation can guide to select salvage TKI from the point of view on the efficacy of TKIs, many factors need to be considered before choosing next-line TKI such as the high-risk features of CML, the adverse events with prior TKI, and the comorbidities of patients. The therapeutic options for CML-CP after failing frontline TKI due to treatment failure or suboptimal responses will be reviewed including allogeneic hematopoietic stem cell transplantation.

Association of obesity under different metabolic status with adverse outcomes in patients with chronic myeloid leukemia: A retrospective cohort study.

Little is known about the association between abnormal metabolic obesity states and the outcomes of chronic myeloid leukemia (CML), especially in patients with obesity with different metabolic status. Here, we used the Nationwide Readmissions Database to assess the effects of metabolically defined obesity on adverse outcomes of CML. Of the 35 460 557 (weighted) patients, we included 7931 adults with discharge diagnoses of CML from January 1, 2018 to June 30, 2018. The study population was observed until December 31, 2018 and divided into four groups based on body mass index and metabolic status. The primary outcome was the adverse outcomes of CML, including nonremission (NR)/relapse and severe mortality risk. Multivariate logistic regression analysis was performed to analyze data. Metabolically unhealthy normal weight and metabolically unhealthy obesity were all risk factors for adverse outcomes of CML compared with metabolically healthy normal weight (all p < 0.01), and a significant difference was not found in the metabolically healthy obese. Female patients with metabolically unhealthy normal weight and metabolically unhealthy obesity had 1.23-fold and 1.40-fold increased NR/relapse risk, while male patients did not have this risk. Moreover, patients with a higher number of metabolic risk factors or with dyslipidemia were at higher risk of adverse outcomes, regardless of obesity status. Metabolic abnormalities were associated with adverse outcomes in patients with CML, irrespective of obesity status. Future treatment of patients with CML should consider the effects of obesity on their adverse outcomes under different metabolic status, especially in female patients.

A single-cell atlas identifies pretreatment features of primary imatinib resistance in chronic myeloid leukemia

AbstractPrimary resistance to tyrosine kinase inhibitors (TKIs) is a significant barrier to optimal outcomes in chronic myeloid leukemia (CML), but factors contributing to response heterogeneity remain unclear. Using single-cell RNA (scRNA) sequencing, we identified 8 statistically significant features in pretreatment bone marrow, which correlated with either sensitivity (major molecular response or MMR) or extreme resistance to imatinib (eventual blast crisis [BC] transformation). Employing machine-learning, we identified leukemic stem cell (LSC) and natural killer (NK) cell gene expression profiles predicting imatinib response with >80% accuracy, including no false positives for predicting BC. A canonical erythroid-specifying (TAL1/KLF1/GATA1) regulon was a hallmark of LSCs from patients with MMR and was associated with erythroid progenitor [ERP] expansion in vivo (P < .05), and a 2- to 10-fold (6.3-fold in group A vs 1.09-fold in group C) erythroid over myeloid bias in vitro. Notably, ERPs demonstrated exquisite TKI sensitivity compared with myeloid progenitors (P < .001). These LSC features were lost with progressive resistance, and MYC- and IRF1-driven inflammatory regulons were evident in patients who progressed to transformation. Patients with MMR also exhibited a 56-fold expansion (P < .01) of a normally rare subset of hyperfunctional adaptive-like NK cells, which diminished with progressive resistance, whereas patients destined for BC accumulated inhibitory NKG2A+ NK cells favoring NK cell tolerance. Finally, we developed antibody panels to validate our scRNA-seq findings. These panels may be useful for prospective studies of primary resistance, and in assessing the contribution of predetermined vs acquired factors in TKI response heterogeneity.

Association between bariatric surgery and outcomes in chronic myeloid leukemia.

Bariatric surgery is the most effective weight loss intervention. However, it can also decrease the bioavailability of oral medications. Tyrosine kinase inhibitors, the mainstay treatment for chronic myeloid leukemia (CML), are the most successful example of an oral targeted therapy. The impact of bariatric surgery on CML outcomes is unknown. In a retrospective analysis, we screened 652 patients with CML and identified 22 with prior bariatric surgery, and compared their outcomes to a matched cohort of 44 patients with no prior bariatric surgery. The rate of early molecular response (3-month BCR::ABL1 < 10% International Scale) was lower in the bariatric surgery group compared with the control group (68% vs. 91%; p=.05), with longer median times to achieve complete cytogenetic (6vs. 3months; p=.001) or major molecular responses (12vs. 6months; p=.001). Bariatric surgery was associated with inferior event-free survival (5-year, 60% vs. 77%; p=.004) and failure-free survival (5-year, 32% vs. 63%; p<.0001). In a multivariate analysis, bariatric surgery was the only independent predictor for the risk of treatment failure (hazard ratio, 9.40; 95% CI, 2.71-32.55; p=.0004) or event-free survival (hazard ratio, 4.24; 95% CI, 1.67-12.23; p=.008). Bariatric surgery is associated with suboptimal responses that require adapted treatment strategies.

DNA Damage Response (DDR) Is Associated With Treatment-free Remission in Chronic Myeloid Leukemia Patients.

DNA Damage Response (DDR) Is Associated With Treatment-free Remission in Chronic Myeloid Leukemia Patients.

Heavy chain deposition disease (HCDD) of the kidney in a patient of treated chronic myeloid leukemia with imatinib

Chronic myeloid leukemia is a clonal disorder of myeloid origin which transforms into more aggressive phenotypes, either acute myeloid leukemia or acute lymphoblastic leukemia. The long-term outcome of chronic myeloid leukemia has significantly improved with tyrosine kinase inhibitor imatinib. In contrast, heavy chain deposition disease is a disorder of lymphoid origin due to a plasma cell clone classified under monoclonal immunoglobulin deposition disease with truncated monoclonal heavy chain deposition along basement membranes of many organs, predominantly the kidneys causing significant organ dysfunction. The connection between the two disorders seems to be vague and undefined. We report a novel case of treated chronic myeloid leukemia with imatinib in sustained clinical and cytogenetic remission who presented with heavy chain deposition disease of the kidney, causing renal dysfunction and nephrotic range proteinuria that responded to clone-directed therapy. Given these disorders’ two different cell lines, their association could be fortuitous only. However, in the light of a few dozen cases published thus far in which the prototypical plasma cell disorders multiple myeloma and monoclonal gammopathy of undetermined significance have evolved from cases of treated CML, this association seems to be genuine, the possible genesis of which is discussed in this manuscript. Long-term exposure of chronic myeloid leukemia patients to imatinib could predispose some rare, vulnerable patients to a plasma cell disorder, including heavy chain deposition disease.

The Prognostic Impact of HMGCLL1 Gene Variant on Treatment Outcomes in Chronic Myeloid Leukemia (CML) Patients: Adverse Impact on the Response, Failure, and Progression with Imatinib Which Can be Abrogated By the Use of 2nd Generation Tyrosine Kinase Inhibitor (TKI) Upfront Therapy

BackgroundHMGCLL1 is characterized as a lyase activity enzyme located in the extramitochondrial region. Its biological and physiological role is not fully elucidated. Our previous study (Leukemia 2019) demonstrated that: 1) The HMGCLL1 gene variant, ACGTAATG haplotype (A-haplotype) is associated with increased expression of overall levels and isoform 3 (IS3) of the HMGCLL1 gene and predicts a decreased likelihood of deep molecular response after Imatinib (IM) therapy, 2) blockade of HMGCLL1 IS3 results in G0/G1 cell cycle arrest, leading to increased eradication of CML cell lines and CML leukemic stem cells, 3) blockade of HMGCLL1 isoform 3 significantly suppressed CD34+ fractions in CML patients (pts). It was unclear whether a second-generation tyrosine kinase inhibitor (2G-TKI) can reverse the adverse impact of the HMGCLL1 gene variant in CML pts. The present study assessed the prognostic impact of the HMGCLL1 gene variant in CML pts treated with IM or 2G-TKI, and its impact on treatment-free remission (TFR) after TKI discontinuation. Patients and methods Samples from 387 pts were sequenced. Group 1 included 252 pts from 2 centers whose samples were archived retrospectively. These pts were treated with IM (n=190, 75.3%) or second-generation TKIs (n=62) including Dasatinib (n=15, 6.0%), Nilotinib (n=37, 14, 7%), and Bosutinib (n=10; 4.0%). Group 2 included 135 patient samples from 4 countries that attempted to discontinue TKI for TFR. We applied our internal CML-specific smMIP panel with 332 amplicon probes including 8 HMGCLL1 SNPs (rs10948926, rs10948927, rs9370435, rs4546489, rs4275061, rs9475323, rs9475327, rs9296791). Linkage disequilibrium (LD) was assessed using Haploview software (Bioinformatics 2005). For Group 1, treatment outcomes were evaluated concerning major molecular response (MMR), molecular response (MR) with 2 log/deeper (MR2) or 4 log/deeper (MR4), failure-free survival (FFS), progression, and overall survival (OS). Disease characteristics and treatment outcomes were evaluated and compared according to the HMGCLL1 variants using a dominant model. For Group 2, molecular relapse-free survival (RFS) was calculated from the date of TKI discontinuation to the date of confirmed loss of molecular response (either loss of major MMR or two consecutive episodes of MR loss). Kaplan-Meier survival estimate was used to evaluate RFS and Cox's proportional hazard regression model was applied using the dominant model. Results HMGCLL1genotype and haplotype As shown in Fig A, the LD plot showed no recombination among the 8 SNPs, leading to one block for the 8 SNPs to construct a haplotype. Two haplotypes were constructed as CTCAGGCA (C-) or ACGTAATG (A-haplotype) with MAF of 0.674:0.279 in Group 1, and 0.703:0.216 in Group 2, respectively. Summary of outcomes in table 1. Treatment outcomes following TKI therapy according to the HMGCLL1 haplotype Homozygous A-haplotype (A/A) was associated with worse outcomes, showing a lower MR2 (65.9% vs 78.9% at 12 months, p=0.012), lower MMR (64.4% vs 86.8% at 3 years, p=0.00029), lower MR4 (34.7% vs 62.3% at 5 years, p=0.0001; worse FFS (62.8% vs 77.3% at 3 years, p=0.0014), higher risk of progression (16.2% vs 3.4% at 5 years, p=0.000678), and worse OS (56.1% vs 77.7% at 10 years, p=0.0021). The adverse impact of A/A-haplotype was more prominent in the pts treated with Imatinib: A/A-haplotype pts showed a 30-50% lower chance of MR2, MMR, and MR4 achievement, and 2-3 times higher risk of TFR and progression in comparison to those having C-haplotype when treated with Imatinib. However, the use of 2G-TKIs could abrogate the adverse impact of the A/A-haplotype. Impact of HMGCLL1 variant on treatment-free remission following TKI discontinuation While the 12-month RFS rate was 59.9% in overall pts (n=135), an inferior 12-month RFS rate was noted in A/A haplotype (43.8% vs 62.3%) but with borderline significance (p=0.116). Conclusion: The present study demonstrated that the HMGCLL1 gene variant is confirmed as predictive of CML outcomes. Moreover, our result suggests that the adverse impact of the HMGCLL1 genotype can be abrogated by using 2G-TKIs as upfront therapy. We aim to validate this data in a larger cohort of pts treated with 2G-TKI therapy to reach a clearer conclusion on this result. HMGCLL1 genotype information would be helpful to guide CML therapy given that pts with adverse HMGCLL1 genotypes could benefit from 2G-TKI therapy as front-line therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of Chronic Myeloid Leukemia with No Major Molecular Response within 2 Years of Tyrosine Kinase Inhibitor Therapy

Introduction: Achieving a major molecular response (MMR) defined as BCR::ABL1 ≤ 0.1% IS, is an important milestone for optimal response in patients with chronic myeloid leukemia (CML), and decreased risk of transformation to advanced CML. However, the long-term clinical impact of not achieving this milestone is unknown, especially whether it affects chances of survival in older patients. Therefore, we sought to examine responses and outcomes associated with BCR::ABL1 > 0.1% IS after 2 years of treatment with tyrosine kinase inhibitors (TKI). Methods: In a retrospective analysis, we screened our databases for CML patients treated at our institution between 2001 and 2020 and identified those who never achieved MMR within 2 years of TKI therapy. Overall survival (OS) was measured from treatment start date to death from any cause or censored at last follow-up, whereas CML-specific OS assessed only death due to CML complications as events. Progression-free survival (PFS) was measured from TKI start date to progression to either accelerated or blast phase or death. The role of various prognostic factors on survival was evaluated in a multivariate analysis Results: We identified 131 patients who never achieved MMR within 2 years (Table 1). Among them, 79 (60%) eventually achieved MMR at a median of 49.4 months from time of TKI start (range 27-187 months). 24 (30%) of these patients achieved MMR by continuing the same TKI, 48 (61%) by switching to a different therapy and 9 (11%) by undergoing stem cell transplant (Table 1). The remaining 52 patients had different levels of cytogenetic response as highlighted in (Table 1). The 10-year CML-specific OS of this cohort was 89%, with a 10-year OS of 76% and 10-year PFS of 74%. Patients who achieved only minor or no cytogenetic response (BCR::ABL1 > 10%) within the first two years had worse 10-year OS (64%) compared to those who achieved major cytogenetic response (BCR::ABL1 ≤ 10% - MCyR) (88%, P=0.01) or complete cytogenetic response (BCR::ABL1 ≤ 1% - CCyR) (85%, P=0.05) within the same period. These trends were similar when evaluating CML-specific OS (Figure 1). In patients aged ≥ 60 years at CML diagnosis, the 10-year OS was 55%; however, none of these deaths were attributed to CML complications (10-year CML-specific OS of 100%) and only 1 (4%) patient progressed to blast phase. In a multivariate analysis of patients included in this cohort, MCyR within 2 years was identified as the only independent prognostic factor associated with improved CML-specific OS with a hazard ratio of 0.19 (95% CI 0.04 - 0.89; P=0.04). Conclusion: CML related mortality remains low among patients who do not achieve MMR within the first 2 years of TKI therapy. Favorable outcomes were seen even among patients with BCR:ABL1 levels between 1% to 10% IS. This is particularly evident for those above the age of 60, where mortality is mainly due to CML-unrelated comorbidities. These findings may help the new considerations in European LeukemiaNet (ELN) recommendations and National Comprehensive Cancer Network (NCCN) guidelines. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Kinase Domain Mutation Testing and Clinical Outcome in a Nationwide Chronic Myeloid Leukemia Patient Population

Background: ABL1 kinase domain mutations (KDM) are associated with resistance to tyrosine kinase inhibitors (TKI) and inferior outcome in chronic myeloid leukemia (CML) patients. Current guidelines recommend KDM testing in case of failure or resistance during TKI treatment. In this analysis, we aimed to assess (1) the clinical practice of KDM testing in the Netherlands, (2) the observed responses to subsequent TKI in the presence of a KDM in relation to the in vitro half-maximal inhibitory concentration (IC50)-values, and (3) the clinical outcome of patients for whom KDM testing was done. Methods: Data were obtained from a nationwide population based CML registry (Pharos-HemoBase) and six CML-reference centers in the Netherlands. We included adult Ph+ CML patients who were treated with a TKI and who had at least one KDM analysis after December 2005, when second generation TKI became available in the Netherlands. Reasons for KDM testing were categorized in three main groups based on the pattern of TKI failure: (1) primary resistance (no response), (2) suboptimal response and (3) loss of response. A suboptimal response was defined as failure to achieve the ELN response milestones, but with the achievement of at least 1-log BCR::ABL1 reduction. Loss of response was defined as losing a previously achieved ELN response milestone. A cox regression model was used for the survival analysis. Results: A total of 391 KDM analyses performed in 275 patients between December 2015 and March 2022 were included. When focusing on CP CML, most KDM analyses were performed because of a suboptimal TKI response (n=155), however in only nine (6%) a KDM was detected. In patients with primary TKI resistance, a KDM was detected in 17 of 81 analyses (21%). The highest yield of KDM was in patients losing a previously achieved response with 43 of 89 (49%) of analyses showing a mutation. Twenty-five KDM analyses were performed outside the context of TKI failure (e.g. BCR::ABL1 fluctuations but no loss of MMR, molecular relapse after a TFR attempt) and in none of them a mutation was detected. In total, 84 KDM were detected (panel A). Sixty-nine (25%) patients harbored at least one KDM of whom 24 the T315I mutation and eight a compound mutation. Most KDM analyses were done with Sanger Sequencing (SS). Fifty-four TKI treatment lines were assessable for response for patients who harbored a KDM with known in vitro IC50-values for predicted effectiveness of TKI. Of the patients who were treated with a TKI with a good predicted response, 34 of 42 (81%) indeed obtained a durable major molecular response, while seven patients experienced failure (4 no response, 3 loss of response). In patients who were treated with a TKI for which intermediate sensitivity was predicted, 4 of 6 (67%) responded well. In patients who were treated with a TKI for which resistance was predicted, only 3 of 6 (50%) responded. Progression to advanced stage disease (AP/BC), hematopoietic stem cell transplantation (HSCT) and death occurred more often in patients with a KDM compared to patients without a KDM: AP/BC in 25 (36%) versus 29 (14%) patients, HSCT in 20 (29%) versus 43 (21%), death in 26 (38%) versus 29 (14%) and CML-related death in 12 (17%) versus 10 (5%), respectively. Ten-year overall survival (OS) after the first KDM analysis was 49% versus 82% in patients with versus without a KDM, respectively, with a median follow-up of 7.2 years (panel B). The HR of harboring a KDM for OS was 0.355 (95% CI, 0.209-0.603; p<0.001). After correction for age, sex, disease phase and Sokal score, the HR was 0.356 (95% CI, 0.182-0.696; p=0.003). Discussion: This is the first study describing the nationwide practice of KDM testing and assessing the clinical outcome of patients with a KDM in relation to IC50-values. More than 70% of the KDM were detected in patients with primary TKI resistance or in patients who lost a previously achieved response. Observed responses to TKI after the detection of a KDM were mainly in accordance with expected responses based on the IC-value, supporting the use of these in vitro derived predictions in clinical practice. In line with previous studies, the presence of a KDM translated in inferior outcomes with higher prevalence of progressive disease and (CML-related) death. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Racial and Ethnic Disparities in Survival Outcomes in Chronic Myeloid Leukemia

Introduction Minority populations within the United States bear a disproportionate burden of health disparities, which has been demonstrated across studied malignancies. The effect that race plays on treatment access and overall survival (OS) in chronic myeloid leukemia (CML) is poorly understood. Using a large national database, we aim to identify how racial and ethnic identity effects access to treatment and survival outcomes in CML Methods Using the National Cancer Database we identified CML patients (pts) diagnosed from 2004-2019. Demographic and treatment characteristics were compared for White, Black, Asian, Hispanic and other minority populations, with race and ethnicity self-identified by pts. Excluding pts who were managed with upfront allogeneic stem cell transplant, Kaplan Meier and adjusted Cox regression survival analysis were used to compare OS by race and ethnicity, with repeat analysis for the <65 year (yr) old cohort. Multivariable Cox regression was adjusted for age, Charlson-Deyo comorbidity index, sex, insurance, and zip code income and education level quartiles to compare OS by race. Results We identified 38,763 pts diagnosed with CML, of which 81% (N=17,739) identified as White, 12% (N=4,672) Black, 3% (N=1,125) Asian, and 4% (N=1,422) identified as Other race. 3,304 pts (9%) were Hispanic ethnicity. The median age of all CML pts was 57 yrs (interquartile range [IQR] 44-70), with White pts presenting at an older age (median 59 yrs [IQR 45-71]) than other races, with a median age of 53 yrs [IQR 40-64] in the Black population and a median age in the Asian and Other races of 50 (IQR 35-63). Compared to White pts, Black pts were more likely to reside in low-income zip codes (44% vs. 16% of White pts), be uninsured (11% vs. 6%), insured by Medicaid (19% vs. 8%) and be treated at academic centers (47% vs. 36%). Hispanic pts presented at a younger age (median 46 yrs [IQR 34-59] vs 58 yrs [IQR 45-71 yrs] in the non-Hispanic population), and were more likely to reside in low-income areas (29% vs 19%), be uninsured (21% vs 5%), or Medicaid insured (23% vs 9%), all p<0.001. All races were equally likely to receive disease directed therapy at diagnosis. The median OS for all CML cases was 14.4 yrs (95% confidence interval (CI) 13.9-14.9), with a 1-, 5- and 10- yr OS of 90%, 73%, and 60%, respectively. The 5-yr OS for both White and Black pts was 73% (p=0.114), with 82% 5-yr OS for Asian pts (p<0.001), and 84% for other races (p<0.001). In pts <65 yrs old, the White population had a 1-, 5- and 10-yr OS of 96%, 87%, and 78%, which was significantly longer than in the Black population, at 94%, 87%, and 78%, p<0.001. On Cox regression adjusted for age, Black race was associated with reduced OS (HR 1.24 [95% CI 1.17-1.31], p<0.001) while pts who identified as either Asian race (HR 0.84 [95% CI 0.73-0.97], p=0.020) or other race (HR 0.79 [95% CI 0.69-0.90], p<0.001) were found to have significantly improved OS, referenced to the White population. On Cox regression adjusted for age, race, ethnicity, comorbidity and socioeconomic features, Black race was not associated with worse outcomes over White race (HR 1.03 [95% CI 0.96-1.10), p=0.378). Asian or Other race, and Hispanic ethnicity were associated with significantly improved OS, with HR 0.82 (95% CI 0.71-0.96), HR 0.79 (95% CI 0.67-0.64) and HR 0.77 (95% CI 0.70-0.85), respectively, all p<0.05. Characteristics associated with reduced OS included age (HR 1.05 [1.05-1.06], p<0.001), increased comorbidity burden (HR 1.32 [0.29-1.35], p<0.001), uninsured status (HR 1.98 [1.78-2.20], p<0.001), Medicaid (HR 2.16 [1.98-2.36], p<0.001), Medicare (HR 1.56 [1.47-1.66], p<0.001), and residing is areas with low income (HR 1.17 [95% CI 1.08-1.27) and low education level (HR 1.19 [95% CI 1.09-1.29]), all p<0.001. Discussion We present the largest study to date examining the influence of race and ethnicity on OS in CML pts. Despite advances in diagnosis and treatment options over the past decade, pts from traditionally underserved populations, including Black, uninsured, and low-income populations, continue to have reduced OS. Black pts have particularly poor survival when compared to White pts of similar ages, however, when adjusted for socioeconomic features associated with healthcare access, the survival gap improves. This indicates that access to treatment remains a significant barrier in this population, highlighting the need for targeted actions to improve outcomes in this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Retrospective Study of Treatment Free Remission in Patients with Chronic Myeloid Leukaemia(CML) Treated at Tertiary Care Oncology Centre from India

Background Tyrosine kinase inhibitors (TKI) have dramatically improved outcomes in Chronic Myeloid Leukemia(CML) patients, but lifelong TKI therapy can negatively impact patients' quality of life due to chronic adverse events. Treatment free remission(TFR) is now the new goal of CML therapy. Studies have shown this is feasible in developed countries. Literature on discontinuation of TKI therapy in resource limited countries such as India is scarce. The purpose of this study was to investigate whether some chronic myeloid leukemia patients with excellent and sustained molecular responses to tyrosine kinase inhibitor treatment can gradually de-escalate TKI therapy and stop therapy in Indian setting. Methods We included all patients above the age of 18years with diagnosis of CML in first Chronic Phase (CP) on TKI therapy of minimum 3 years duration with major molecular response (MMR i.e., <0.1% BCR-ABL1 transcript) of minimum of 2 years duration, enrolled for treatment free remission between January 2018 to December 2021. Starting dose of imatinib was 400mg once daily, dasatinib 100mg once daily and nilotinib 300mg twice a day. In this study the dose of these drugs was reduced by 25% every 6 months . This dose reduction was done with 2 monthly outpatient clinic visits and 2 monthly BCR-ABL1 quantitative PCR monitoring. Patients who maintained MMR during 6 months of dose de-escalation qualified for next level of dose de-escalation. Eventually treatment was stopped completely and monitoring continued. This was retrospective medical record based study done at a tertiary care centre in North India. Results Between Jan 2018 to Dec 2021, 29 patients were enrolled for dose de-escalation and treatment cessation. Among these 29 patients, 19 were on imatinib, 2 on dasatinib and 8 patients on nilotinib. Median age was 39 years( range 21 years to 67 years). Twelve patients were male and 17 female. Median duration of TKI therapy prior to de-escalation was 8 years (range 4years-14 years). Median duration of major molecular response prior to dose reduction was 6 years( range 3years-12 years). In our study 17 of 29 patients had an outcome, while 12 patients are still on de-escalation phase with maintained MMR and are not included in the outcome analysis. Eight patient had loss of MMR(47.05%), 6 while on dose de-escalation and 2 after cessation of TKI. All eight patients achieved MMR after re-initiation of the prior dose, out of these 6 patients had sustained MMR(>6months) at reduced TKI dosing compared to conventional dose. Nine patients (52.9%) have successfully stopped TKI for median duration of 11months (range 6 to 19 months). Conclusion TKI de-escalation was safe for most patients with excellent prior response to TKI therapy. This way of dose reduction , ensured motivation and commitment of patients by doing regular OPD follow ups and BCR-ABL1 PCR testing. In our study 52.9% patient could successfully maintain TFR at a median follow up of 11 months of stopping the drug. We also identified that a subgroup of patients(35.29%) who were unsuccessful in complete cessation of therapy but maintained their molecular response at reduce dose of TKI . These findings show that lower TKI doses might maintain molecular responses in these patients, implying that such patients could be overtreated with routine dosing. More studies of dose de-escalation are warranted.

Real World Outcomes of Chronic Myeloid Leukemia in Era of Tyrosine Kinase Inhibitors a Single Center Experience

Introduction: Obtaining a major molecular response (MMR) correlates with a higher probability of achieving a complete molecular response (CMR) and suboptimal molecular responses are associated with increased risk of resistance. Methods: We retrospectively analyzed patients with a diagnosis of chronic myeloid leukemia who were treated at Penn State Cancer Institute between January 2008 to December 2018. These patients had bone marrow biopsy for confirmation for diagnosis of CML and were monitored by bcr-abl PCR to document molecular response: Complete (CMR ) vs. Major (MMR). Results: A total of 74 patients F :32; M:42 were diagnosed with CML between 2008 and 2018 with median age at diagnosis 52 years (22yrs -89yrs). The majority of these patients had CML in chronic phase (n=68;92% ) and 4%(n=3) were in accelerated phase (CML AP) and 4% (n=3) had blastic phase (CML BC). High Sokal score was seen in 42% (31/74) patients with concordance seen in most patients with high Sokal scores.Highest Sokal score was infinity in a patient with massively enlarged spleen with Hasford score 2179. Highest Hasford score was 5625 with discordant Sokal score of 558. Imatinib was used in front line in 45 /74 patients. Dasatinib and nilotinib were used as first line 18 vs 5, second line in 19 vs 6 and third line in 3 vs 7 patients. Ponatinib was used second line in 2 patients vs. third, forth and fifth line in 1 patient each. A total of 8 patients received allogeneic transplant ( 1 cord ) and all 8/8 achieved CMR remained in CR for medan of 12 years . Only 30/66(45%) achieved CMR who did not undergo transplant and 24/66 (36%) achieved MMR and 10 (15%) patients did not achieve MMR and remaining had progression. TKI resistance and TKI intolerance was seen in 7/66 (4.6%) patients. second cancers were seen in 9% (n=6) patients. Conclusion: Allogeneic transplant still appears to have role to achieve long term CR. Use of drugs targeting CML leukemia stem cells along with TKIs may be needed to yield more complete metabolic responses (CMR) cure CML.

Future Management of Chronic Myeloid Leukemia: From Dose Optimization to New Agents.

The outcome of chronic myeloid leukemia (CML) patients in chronic phase has changed after the introduction of tyrosine kinase inhibitors (TKIs). The life expectancy is actually similar to that of the general population. Although outstanding results were achieved, about 20-30% of patients failed to achieve molecular milestones or experienced a severe toxicity and needed to switch to a second line. The aim of this review is to report on possible future management in CML, from dose optimization to avoid long-term off-target events to new agents for the treatment of resistant and/or intolerant patients. Broad research on Medline, Embase and archives from EHA and ASH congresses was performed. New TKIs have been developed to counteract resistance and/or intolerance in the setting of T315I mutated patients. The benefits of ponatinib dose optimization have been recently reported in the OPTIC trial. New trials to test the dose optimization are ongoing. Reduction of the standard dose could be performed to reduce the specific TKI toxicity. Selective TKIs could be prescribed in the future as third line treatment.