Treatment Of CML Research Articles

Dasatinib Induced Reversible Nephrotic Range Proteinuria Occurs More Frequently Compared to Other Tyrosine Kinase Inhibitors in the Treatment of Chronic Myeloid Leukemia

Introduction: Dasatinib is an oral inhibitor of Abl and Src family of kinases. Dasatinib can cause a pleural effusion in 14% to 30% of patients as well as pulmonary arterial hypertension. Its mechanism is not fully elucidated although vascular endothelial growth factor (VEGF)-mediated mechanism has been proposed. In the literature, there are sporadic case reports of dasatinib-induced proteinuria/nephrotic syndrome. It is also suggested that dasatinib-induced kidney injury involves the interruption of VEGF signaling pathway.In the present study, we present a series of 6 patients, who developed nephrotic-range proteinuria while on dasatinib therapy that resolved after switch to other TKIs or discontinuation. Also, we have analyzed the risk of TKI-associated proteinuria according to the TKI subtype in 256 CML patients having available results of urine protein level.Patients and Methods: A total of 256 patients with CML on TKIs, with available urine testing were reviewed. TKI therapy was as follows: Imatinib (n=147), dasatinib (n=67), nilotinib (n=13), ponatinib (n=13) and bosutinib (n=16). First, we have reviwed spot urinalysis result for proteinuria screening, and further reviewed in detail the result of 24-hour urine protein measurement. If proteinuria is detected, we had in-depth chart review on the case to exclude other causes of proteinuria such as diabetes, renal failure, urinary tract infecion or urinary tract malignancies, etc. After excluding other causes of proteinuria, we have calculated the incidence rate of proteinuria using 1,000 person-year considering duration of exposure to TKI therapy.Results: With median duration of 35 months of dasatinib therapy, 6 patients (8.9%) developed nephrotic range proteinuria, after excluding other secondary causes of proteinuria. All received dasatinib as 2nd line following Imatinib front line therapy. Out of 6 patients with proteinuria, 4 patients developed pleural effusion prior to the development of proteinuria. All of them showed optimal molecular response to dasatinib therapy at the time of proteinuria development including MR4.5 (n=4), MR4.0 (n=1) or MMR (n=1).One patient underwent renal biopsy which showed chronic glomerular endothelial cell injury and thin basement membrane nephropathy, consistent with finding of minimal change disease. All 6 cases had discontinued (n=3) or switched to other TKI therapy (imatinib n=1; botutinib n=1; nilotinib n=1) with complete resolution of proteinuria. In the 3 patients who had MR4.5 or deeper response when dasatinib was discontinued due to proteinuria, one lost MMR after 3 months, one maintained MMR (+13 months), and another without losing undetectable transcript level (+21 months).The incidence rate of TKI-associated proteinuria was analyzed according to the TKI subtype in 256 CML patients. Median follow-up duration was 31 months for 35 months for dasatinib (1-105 months), imatinib (1-172 months), 27 months for nilotinib (1-63 months), 5 months for bosutinib (1-22 months), and 1 month for ponatinib (1-14 months), respectively. The exposure year was 201.8 years in dasatinib (n=67), 523.2 years in imatinib (n=147), 31.4 years in nilotinib (n=13), 6.1 years in bosutinib (n=16) and 1.4 years in ponatinib (n=13). The incidence rate of proteinuria in dasatinib treated group was calculated as 29/1,000 person-year, while it was 0 in imatinib, nilotinib, bosutinib, ponatinib-treated group, respectively due to no case confirmed to have proteinuria after excluding secondary causes of proteinuria (Fisher's exact test p<0.001).Conclusion: Development of nephrotic range proteinuria can be a toxicity from dasatinib therapy in CML treatment. Incidence rate is unexpectedly high at 29/1,000 person-year while there are no cases of nephrotic range proteinuria with exposure to other TKIs. All the proteinuria events were reversed completely after discontinuation/switch of dasatinib. Medical attention is to be paid for this unusual toxicity related to dasatinib therapy. Further study is strongly warranted to reach a clear conclusion for the incidence of this toxicity in a larger cohort. DisclosuresKim:BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Paladin: Consultancy; Pfizer: Consultancy.

Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: 12-Month Patient-Reported Outcomes from the BFORE Trial

Introduction: Since many patients with chronic phase chronic myeloid leukemia (CP CML) achieve long-term survival, health-related quality of life (HR-QOL) as assessed by PROs is an important consideration. Bosutinib is a SRC/ABL tyrosine kinase inhibitor approved for Philadelphia chromosome-positive CML treatment in adults resistant or intolerant to prior therapy. In the BFORE trial (NCT02130557) of bosutinib versus imatinib a significantly higher major molecular response rate at 12 months (the primary endpoint) occurred with bosutinib. Here we report initial PRO results from BFORE.Methods: BFORE is an ongoing, multinational, phase 3, open-label study in patients with newly diagnosed CP CML. Patients are randomized 1:1 to bosutinib 400 mg once daily or imatinib 400 mg once daily. PROs, assessed as exploratory endpoints, included functional status using the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) and the European Quality of Life-5 Dimensions-Visual Analog Scale (EQ-5D-VAS) instruments. Assessments were conducted at baseline and every 3 to 6 months, to continue for up to 5 years after treatment initiation. Outcomes at month 12 are reported herein.Results: Bosutinib and imatinib mean FACT-Leu scores were similar at baseline and at month 12 (Table). At month 12, significant improvement from baseline in FACT-Leu total score was observed for both bosutinib (mean change 3.1, P=0.0425) and imatinib (mean change 4.8, P=0.0008). For bosutinib at month 12, all FACT-Leu combined and subscale scores demonstrated either improvement (emotional well-being; leukemia symptoms; FACT-Leu total score) or maintenance (physical, functional, social well-being; FACT-General total score; trial outcome index).Bosutinib and imatinib mean EQ-5D-VAS scores were similar at baseline and at month 12 (Table). At month 12, significant improvement in mean EQ-5D-VAS was observed for both bosutinib (mean change 4.4, P=0.0014) and imatinib (mean change 9.3; P <0.0001). Additional FACT-Leu and EQ-5D analyses yielded similar findings. For example, mean [SD] Functional Health Status as measured using the EQ-5D Utility Score was similar between groups at baseline (bosutinib: 0.688 [0.2710] and imatinib: 0.657 [0.2929]) and improved from baseline for subjects in both treatment arms, with comparable scores seen at Month 12 (bosutinib: 0.722 [0.2953] and imatinib: 0.724 [0.2717]).Conclusion: In the BFORE trial of first-line CP CML therapy, PROs for bosutinib indicated improvement or maintenance of HRQoL at month 12, with effects comparable to those observed for imatinib, the standard of care for first-line CML treatment. These exploratory PRO results indicate fewer symptoms, better HRQoL, and improved functional health status at month 12 relative to baseline for both therapies. [Display omitted] DisclosuresCortes:ARIAD: Consultancy, Research Funding; Sun Pharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Teva: Research Funding. Gambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Deininger:Novartis: Consultancy, Research Funding; Incyte: Consultancy; ARIAD: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; BMS: Consultancy, Research Funding; Celgene: Research Funding; Gilead: Research Funding. Mauro:Bristol-Myers Squibb: Consultancy. Chuah:Chiltern: Honoraria; BMS: Honoraria, Other: Travel; Novartis: Honoraria; Avillion: Honoraria. Kim:Il-Yang: Consultancy, 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Milojkovic:ARIAD: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria. le Coutre:Incyte: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; ARIAD: Honoraria. García Gutiérrez:BMS: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Reilly:Avillion LLP: Employment. Jeynes-Ellis:Avillion LLP: Employment, Equity Ownership. Crescenzo:Pfizer: Employment, Equity Ownership. Mamolo:Pfizer: Employment, Equity Ownership. Reisman:Pfizer: Employment. Bardy-Bouxin:Pfizer: Employment, Equity Ownership. Hochhaus:Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Ariad: Research Funding; MSD: Research Funding; BMS: Research Funding. Brümmendorf:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Bosutinib Vs Imatinib for Newly Diagnosed Chronic Myeloid Leukemia in the BFORE Trial: Results By 3-Month BCR-ABL1 Transcript Level

Introduction: Bosutinib is a potent SRC/ABL tyrosine kinase inhibitor approved for treatment of Philadelphia chromosome-positive CML in adults resistant or intolerant to prior therapy. This analysis evaluated the efficacy of first-line bosutinib versus imatinib in the BFORE study (NCT02130557) by 3-month BCR-ABL1 transcripts ≤10% versus >10% and examined baseline and on-treatment characteristics as predictors of time to major molecular response (MMR).Methods: In this ongoing, multinational, phase 3, open-label study, 536 patients were randomized 1:1 to bosutinib 400 mg or imatinib 400 mg once daily. The present analysis is based on ≥12 months of follow-up. Baseline and on-treatment time-dependent covariates were analyzed using a proportional subdistribution hazards model predicting time to initial MMR. No adjustment for multiple comparisons was made.Results: The intent-to-treat (ITT) population included 268 patients in the bosutinib arm and 268 patients (including 3 untreated patients) in the imatinib arm. Among evaluable patients (≥3000 ABL1 analyzed) at 3 months in the ITT population, more patients in the bosutinib arm than in the imatinib arm had BCR-ABL1 transcripts ≤10% (80.6% of 248 patients vs 60.5% of 253 patients; P <0.0001). The MMR rate at 12 months was higher in evaluable patients who had transcripts ≤10% versus >10% at 3 months with bosutinib (117 [58.5%] vs 7 [14.6%], P <0.0001) and with imatinib (83 [54.2%] vs 14 [14.0%], P <0.0001). The cumulative MMR rates were also higher in evaluable patients with transcripts ≤10% with bosutinib (138 [69.0%] vs 12 [25%]; P <0.0001) and with imatinib (100 [65.4%] vs 30 [30.0%]; P <0.0001). In the ITT population, transcripts ≤10% (vs >10% or not evaluable) at 3 months was a predictor of time to MMR in both arms (Table; bosutinib: hazard ratio [HR]=6.44, P <0.0001; imatinib: HR=3.69, P <0.0001). The only other predictor of time to MMR among the covariates examined was not having a bosutinib dose reduction to 300 mg due to an adverse event.Conclusion: BOS treatment was associated with a higher number of patients presenting transcripts ≤10% at 3 months than those treated with IMA. Patients with transcripts ≤10% at 3 months had higher rates of 12-month MMR and achieved response faster than those with transcripts >10%. These findings suggest that the transcript level at 3 months may be a predictor of response to first-line bosutinib and imatinib. [Display omitted] DisclosuresHochhaus:Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Ariad: Research Funding; MSD: Research Funding; BMS: Research Funding. Gambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Deininger:BMS: Consultancy, Research Funding; ARIAD: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Gilead: Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Research Funding. Mauro:Bristol-Myers Squibb: Consultancy. Chuah:Chiltern: Honoraria; BMS: Honoraria, Other: Travel; Novartis: Honoraria; Avillion: Honoraria. Kim:Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Milojkovic:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Honoraria, Speakers Bureau; ARIAD: Consultancy, Honoraria. le Coutre:BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; Incyte: Honoraria; ARIAD: Honoraria. García Gutiérrez:Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Reilly:Avillion LLP: Employment. Jeynes-Ellis:Avillion LLP: Employment, Equity Ownership. Crescenzo:Pfizer: Employment, Equity Ownership. Leip:Pfizer: Employment, Equity Ownership. Bardy-Bouxin:Pfizer: Employment, Equity Ownership. Brümmendorf:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; Teva: Research Funding; Sun Pharma: Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

Interim Results of the Canadian Tyrosine Kinase Inhibitor Discontinuation Trial for 2nd Attempt of Treatment Free Remission: Treatment Free Remission Accomplished By Dasatinib (TRAD)

Interim Results of the Canadian Tyrosine Kinase Inhibitor Discontinuation Trial for 2nd Attempt of Treatment Free Remission: Treatment Free Remission Accomplished By Dasatinib (TRAD)

First-line treatment outcomes of CML patients in a real-world data setting in Lebanon.

e19031 Background: BCR–ABL-targeting tyrosine kinase inhibitors (TKIs) constitute the cornerstone of treatment of CML leading to a life expectancy that is currently very close to that of age matched individuals in the general population. The aim of the current study was to describe aspects of CML in a real world data setting in Lebanon including responses to first lines with a specific focus on the impact of first-line treatment with imatinib compared to that of the second-generation TKI, dasatinib and nilotinib. We also evaluated what proportion of patients become eligible to attempt to stop their TKI treatment. Methods: Chronic myeloid leukemia registry was analyzed to evaluate response rates in the first line and eligibility for a treatment cessation attempt in adults diagnosed between 2003 and 2019. The registry covered 60 patients. 46 eligible patients were included in the study. BCR-ABL1 levels of ≤ 0.1%, ≤0.01% and ≤0.0032% on the international scale were defined as the molecular response end-points major molecular response(MMR), MR4.0 and MR,4.5 respectively. In the case of a switch in TKI therapy, the clinical chart was reviewed for the reason why the treating physician had changed the therapy (‘treatment failure’ or ‘TKI intolerance’). For the determination of eligibility to stop TKI, the inclusion criteria for the EURO-SKI trial were applied. Results: Seventy-two percent of the patients were treated with imatinib, 28% with a second-generation tyrosine kinase inhibitor (nilotinib and dasatinib). 15% of patients had discontinued their first-line treatment, mainly due to intolerance (10%) or treatment failure (5%). At 24 months, deep molecular response (MR 4.0 and MR4.5) were achieved at 16.7% and 38.9% respectively for imatinib, and at 22.2% and 33.3% respectively for second generation (p=1). The 5-year cumulative incidence of eligibility for a tyrosine kinase cessation attempt, according to EURO-SKI criteria, was 37%. Conclusions: In the current study we report the experience in CML from two health care institutions in Beirut, Lebanon. Our findings showed no statistically significant difference in response between the first and second generations. The criteria for an attempt to stop tyrosine kinase inhibitor therapy are met by a third of the patients.

Potential treatment for chronic myeloid leukemia using microRNA: in silico comparison between plants and human microRNAs in targeting BCR-ABL1 gene

BackgroundChronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the expression of the BCR-ABL1 fusion gene. Tyrosine kinase inhibitors (TKI) are used to treat CML, but mutations in the tyrosine kinase domain contribute to CML chemo-resistance. Therefore, finding alternative molecular-targeted therapy is important for the comprehensive treatment of CML. MicroRNAs (miRNA) are small non-coding regulatory RNAs which suppress the expression of their target genes by binding to the 3′ untranslated region (3′UTR) of the target mRNA. Hypothetically, the miRNA-mRNA interaction would suppress BCR-ABL1 expression and consequently reduce and inhibit CML cell proliferation. Thus, our objective was to determine the target interaction of human and plant miRNAs targeting the 3′UTR region of BCR-ABL1 in terms of miRNA binding conformity, protein interaction network, and pathways using in silico analysis. The 3′UTR sequence of BCR-ABL1 is obtained from Ensembl Genome Browser while the binding conformity was determined using the PsRNATarget Analysis Server, RNA22, Target Rank Server, and DIANA TOOLS. Protein-protein interaction network and pathway analysis are determined using STRING, Cytoscape, and KEGG pathway analysis.ResultsFive plants and five human miRNAs show strong binding conformity with 3′UTR of BCR-ABL1. The strongest binding conformity was shown by Oryza sativa’s Osa-miR1858a and osa-miR1858b with −24.4 kcal/mol folding energy and a p value of 0.0077. Meanwhile, in human miRNA, the hsa-miR-891a-3p shows the highest miTG score of 0.99 with −12 kcal/mol folding energy and a p value of 0.037. Apart from ABL1, osa-miR1858a/osa-miR1858b and hsa-miR891a-3p also target other 720 and 645 genes, respectively. The interaction network of Osa-miR1858a/osa-miR1858b and hsa-miR891a-3p identifies nineteen and twelve ABL1’s immediate neighboring proteins, respectively. The pathways analysis focuses on the RAS, MAPK, CML, and hematopoietic cell lineage pathway.ConclusionBoth plant and human miRNAs tested in this study could be a potential therapeutic prospect in CML treatment, but thermodynamically, osa-miR1858a/osa-miR1858b binding to ABL1 is more favorable. However, it is important to carry out more research in vitro and in vivo and clinical studies to assess its efficacy as a targeted therapy for CML.Graphical abstract

Recent advances in understanding chronic myeloid leukemia: where do we stand?

While the need for complete eradication of leukemic stem cells (LSCs) in chronic myeloid leukemia may be controversial, it is agreed that remaining LSCs are the cause of relapse and disease progression. Current efforts are focused on the understanding of the persistence of immunophenotypically defined LSCs, which feature abnormalities in signaling pathways relating to autophagy, metabolism, epigenetics, and others and are influenced by leukemia cell-extrinsic factors such as the immune and bone marrow microenvironments. In sum, these elements modulate response and resistance to therapies and the clinical condition of treatment-free remission (TFR), the newly established goal in CML treatment, once the patient has achieved a durable molecular remission after treatment with tyrosine kinase inhibitors. Novel combination therapies based on these identified vulnerabilities of LSCs, aimed at the induction or maintenance of TFR, are being developed, while other research is directed at the elucidation of factors mediating progression to blast crisis.

Circulating miRNAs can serve as potential diagnostic biomarkers in chronic myelogenous leukemia patients

IntroductionChronic Myelogenous Leukemia (CML) is a myeloproliferative disorder described as a malignant blood disorder by accounts for 15–20% of all adult leukemia. MicroRNAs (miRNAs) play an important role in post-transcriptional regulation of gene expressions. Expression level of tumor suppressor-miRNAs, described as miRNAs that target the oncogens, can contribute to diagnosis and prognosis of some malignant disorders including CML. We theorized that according to the excessive proliferation and alteration in miRNA expressions, there could be a change in the expression of miRNAs in plasma carried by exosomes. MethodsWe consequently decided to detect the differences between normal and aberrant miRNA expression in human plasma sample to find out the possibility of diagnosis by these alterations. The expression of candidate miRNAs were compared using RNA extracted from the plasma of 50 patients, as well as 30 healthy individuals. We analysed the plasma miR-16-1, miR-20, miR-106, miR-126, miR-155, miR-222, and miR-451 expression levels in CML patients by individual real-time quantitative RT-PCR. ResultsAll selected miRNAs were found to be upregulated in newly diagnosed CML patients compared to the control, while upregulation of only three (miR-20, 106 and 222) were significant (17.4, 19 and 74.95 fold change, respectively; p<0.0001). In conclusionmicroRNAs have a potential use in treatment of CML, as they can target the genes involved in cell cycle, MAPK, growth inhibition, TGF beta, and p53 signaling pathways. Therefore, these miRNA signatures provide the basis for their utilization as biomarkers in CML.

Efficacy and safety of Bosutinib in Patient with Chronic myeloid leukemia who was intolerant to DASTANIB,NILOTUNIB -Case report

Treatment for Chronic myeloid leukemia has been revolutionized because of availability of different tyrosine kinase inhibitors. Each TKI come with its on toxicity profile as this needs to be taken in account before starting therapy with particular agent in a patient. Most of the adverse effects related to TKI are mild and can be managed by either symptomatic treatment or either by dose reduction. But some patients can become intolerant and to switch to other TKI remains the only option. Bosutinib is currently approved for treatment of chronic phase CML in patients who are either resistant or intolerant to previous TKI. We present a case of 59 year old male patient with CML who was intolerant to Dastanib and Nilotinib but showed excellent hematological and major molecular response to bosutinib

Case reports of chronic myeloid leukemia and tuberculosis: Is imatinib the link between the two?

Current standard of care for treatment of CML is based on tyrosine kinase inhibitors (TKI's). Imatinib is most frequently used first line tyrosine kinase inhibitor. Various side effects of TKI's are known, but some may still be unknown. We are reporting three cases of CML who developed tuberculosis while on treatment with imatinib or dasatinib. Two cases developed CNS tuberculosis and other one was tubercular pleural effusion. These cases indicate that imatinib and other TKI's probably interfere with immunological functions and predispose patients for tuberculosis.

Rare Transformation of Chronic Myeloid Leukemia into Acute Lymphoblastic Leukemia in a 14-Year Old Patient

Abstract: Chronic myeloid leukemia is a myeloproliferative neoplasm. It is a common disease of elderly, rarely affecting pediatric, adolescent or young adults. The median age of presentation is 65 years. The incidence is 1‐2 cases per 100,000 adults. Tyrosine kinase inhibitors (TKIs) are highly successful and have good remission rates in the CML treatment; though multiple factors are associated with failure of treatment. We present a patient of 14 years old male who was diagnosed as CML. He was seven months into TKI therapy, transformed into B-Lineage acute lymphoblastic leukemia. Keywords: Chronic myeloid leukemia, Rare, Acute lymphoblastic leukemia, Pediatric, Transformation.

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.

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 &amp;lt; 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 &amp;lt; 0.001, t test) in BC CML, and a significant reduction of human CD45+ cells (p&amp;lt;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 &amp;lt; 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 &amp;lt; 0.005) as well as overall adenosine to inosine editing rates as measured by edits per million reads (p &amp;lt;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.

Inclusion of molecular monitoring (BCR-ABL1) in the treatment of chronic myeloid leukemia in the Brazilian Public Health System (SUS): an urgent need for treatment management.

IntroductionChronic Myeloid Leukemia (CML) is a myeloproliferative disease that affects mainly adults between 50 and 55 years. In Brazil, information from the Sistema Único de Saúde (SUS) Outpatient Information System indicates that 12,531 patients had the Autorização de Procedimento Ambulatorial (APAC) approved for the CML treatment in 2017. Disease monitoring through molecular response evaluation is critical to the care of CML patients. The quantitative PCR test (real-time polymerase chain reaction) provides adequate evaluation parameters that allow the health professional to intervene at the right moments in order to reduce the chance of progression of the disease, providing the best outcome to the patient, including the possibility of treatment discontinuation for eligible patients. Although the test is included in the Clinical Protocol and Therapeutic Guidelines (PCDT) of CML, it is not possible to monitor the molecular response within SUS since there is no reimbursement for this test.ObjectiveObtain expert recommendations on the importance, financing, and reimbursement of molecular monitoring in SUS.MethodsSix CML experts with different perspectives participated in the panel. The discussion was based in the main publications about the quantitative PCR test in CML monitoring.ResultsExperts’ recommendations:1)Molecular monitoring should be part of the integral treatment of patients with CML to reduce the chances of disease progression and costs to the health system;2)The government should put into practice what is provided in the PCDT of Chronic Myeloid Leukemia in Brazil: performing the monitoring of the molecular response via quantitative PCR;3)The government should create a code with adequate nomenclature and reimbursement value in SIGTAP, so that the test is carried out and covered by the public health network, as it is contained in the PCDT of the disease and the existing APAC does not cover the operational costs for its performance;4)Patients with chronic phase CML should perform a quantitative PCR every 3 months and, after reaching the MMR, should perform the examination every 6 months, as recommended by international guidelines;5)Patients should be monitored in reference laboratories that are standardized according to the international scale;6)The laboratories that are within the reference public centers could absorb all the test demand in Brazil, and other centers could be qualified through an ABHH accreditation;7)Adequate molecular monitoring may allow some patients to stop taking drugs and selffinancing the molecular test for all SUS patientsConclusionA solution for the molecular test (BCR-ABL1) funding is urgent to ensure the monitoring of CML patients in SUS. The savings that might be generated with patients that stop taking the medication when adequately monitored may finance the test.

The First Report of the Prevalence of COVID-19 in Chronic Myelogenous Leukemia Patients in the Core Epidemic Area of China: A Multicentre, Cross-Sectional Survey

Background: Since late December 2019, the outbreak of the novel coronavirus disease, COVID-19, that began in Wuhan, has become endemic in China and more than 100 countries and regions in the world. There is no report about the prevalence of COVID-19 in CML patients untill now. We aimed to describe the clinical course, outcomes of CML patients with COVID-19 and prevalence of COVID-19 in CML patients. Methods: In this multi-center survey, cross-sectional survey, observational study, the clinical data of CML patients with COVID-19 in each center were collected. Simultaneously, an online survey was conducted for information about the CML patients under the management at each center by asking the CML patients to complete a questionnaire,from February 15, 2020 to February 21, 2020. The questionnaire includes demographic data, place of residence, smoking status, CML diagnosis and treatment, comorbidities, combined medications, epidemiological history, symptoms (fever, cough, shortness of breath, etc) during the epidemic. Additional clinical data was collected on respondents suspected or confirmed to have COVID-19. We described and analyzed the prevalence of COVID-19 in CML patients, and focus on the clinical characteristics and outcomes of COVID-19 patients. Data were compared between the CML patients with optimal response and those with non-optimal response. The primary outcome was prevalence of COVID-19 in CML patients, as of Feb 21, 2020. Secondary outcomes included the history of epidemiology of CML patients, the clinical characteristics and outcomes of CML patients with COVID-19. Findings: Of 392 respondents, 223(56.9%) were males, and 240(61.2%) were 50 years or younger. Only 10 patients took drugs irregularly due to the influence of the epidemic because of traffic control, pharmacies unable to operate normally, etc. In the history of epidemiology, there were 4 patients with definite contact with COVID-19, of which 3 were remote contact and 1 was close contact. 12 respondents had fever, cough or shortness of breath during the epidemic, 1 case (common type) was confirmed with COVID-19 and cured after treatment. 1 patient was clinically diagnosed and succumbed. 1 of 299 (0.3%) patients with an optimal response was diagnosed with COVID-19. Of the 50 patients who failed to respond to CML treatment or had a poor response, 1 patient (2%) had a clinical diagnosis of COVID-19. Interpretation: While the 392 CML respondents required regular referrals to hospitals, they did not have much contact with COVID-19 patients during the outbreak. Patients who failed to achieved an optimal response to CML therapy appear more likely to have a symptomatic infection with SARS-CoV-2. Older patients with comorbidities are at increased risk of death. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China(NSFC)(81873440&81700142). Declaration of Interests: All participants have no competing interests. Ethics Approval Statement: The investigation was approved by the ethics committee of the Union hospital of the Tongji Medical College, which is part of the Huazhong University of Science and Technology.

Cancer-associated Gene Mutations in CML Treatment With TKIs by NGS

Cancer-associated Gene Mutations in CML Treatment With TKIs by NGS

Outcomes of allogenic hematopoietic cell transplantation for childhood chronic myeloid leukemia: Single‐center experience

Despite the apparent efficacy and favorable toxicity profile of TKIs, allogeneic SCT remains the only curative treatment for CML especially in younger patients, but TRM should be considered. We evaluated the clinical outcomes of pediatric CML patients who had SCT in our center. This retrospective study included children with CML, who received an allogeneic SCT at Children Cancer Hospital Egypt, 57357, from 2007 to 2017. All patients received myeloablative conditioning chemotherapy containing busulfan/cyclophosphamide followed by stem cell infusion from MRD. From 121 patients diagnosed with CML, 43 had available MRD and subjected to HSCT while 78 patients continued TKI therapy. The median time to transplant from diagnosis was 13months. At initial diagnosis, there were 39 patients in CP and 4 had blastic crises. Bone marrow harvest was the stem cell source in 32 patients, while 11 cases received mobilized peripheral blood stem cells with average stem cell dose of 4.45×106 /kg. The probabilities of overall survival and event-free survival at 5years were 97.4% and 79.8%, respectively. TRM at 100days and TRM at 1-year post-transplant were 0%. The incidence of chronic GVHD was significantly higher in peripheral blood than bone marrow stem cell source (P=.004). Considering the excellent survival rates and very low TRM, HSCT is still a valid option for pediatric patients with newly diagnosed CML with best using marrow stem cell source to avoid a significant risk of cGVHD and its related complications.

Haploidentical CD34-Selected Peripheral Blood Stem Cell Transplantation (PBSCT) from Related Donors in Pediatric Patients with Malignant and Non-Malignant Disorders

Background Hematopoietic stem cell transplantation (HSCT) from HLA-haploidentical related donors is increasingly considered for transplant candidates who lack a histocompatible related or unrelated donor. Since October 2015, we have been performing haploidentical PBSCT, utilizing a two-step approach first described by Grosso et al. (Biol Blood Marrow Transplant 21:646, 2015), in which the lymphoid and CD34+ cell populations are administered separately. Selective depletion of alloreactive T-cell clones is accomplished by administering high-dose cyclophosphamide (CY) after the donor lymphocyte infusion but prior to infusion of the CD34-selected peripheral blood stem cell product. Methods As of June 2019, 15 pts have undergone haploidentical PBSCT from related donors for treatment of AML (n=1), ALL (n=8), MDS (n=3), CML (n=1) JMML (n=1) and HLH (n=1). Median age at transplant was 11 years (range, 0.7-23.5 years). Twelve pts were conditioned with TBI 1200 cGy and CY 60 mg/kg IV x 2, while 3 pts received fludarabine 35 mg/m2 IV x 4, busulfan 0.8-1 mg/kg IV q6h x 16 doses, and CY 60 mg/kg IV x 2. The mother served as the donor for 8 pts, the father for 6 pts and an adult sister for 1 pt. Donor lymphocytes containing 2 × 108 CD3+ cells/kg were infused after completion of TBI or busulfan, depending on the conditioning regimen utilized, followed 66 hours later by administration of CY 60 mg/kg daily x 2. CD34+ selected peripheral blood stem cells were infused 48 hours after the second dose of CY. GvHD prophylaxis consisted of tacrolimus and mycophenolate, both begun on Day -1. In the absence of GvHD, mycophenolate was discontinued at Day +30 and tacrolimus was tapered over 1 month, beginning on Day +60. Results Median CD34+ cell dose was 7.9 × 106/kg (range, 4.1-12.3). Neutrophil and platelet (>20,000/microliter) engraftment occurred at a median of 9 days (range, 8-10 days) and 9.5 days (range, 8-20 days), respectively. All pts achieved full donor chimerism, with no secondary graft failure. Pts were discharged a median of 22 days post-transplant (range, 15-77 days). Grade II-III acute GvHD (mostly transient skin involvement) was observed in 5 pts and 1 pt developed Stage IV acute liver GvHD. Chronic skin GvHD (1 mild, 1 extensive) was observed in 2 pts. Two pts have died, one from progressive disease and one from multiorgan failure in the setting of severe acute liver GvHD. Six pts (1 JMML, 1 AML, 1 MDS, 3 ALL) have suffered disease relapse, 68-446 days post-transplant. All 3 ALL pts subsequently received CAR T-cell therapy. Eight pts remain relapse-free survivors a median of 2.4 years (range, 0.3-3.8 years) post-transplant. Conclusion Haploidentical HSCT using this two-step methodology is a safe and effective approach for pts lacking a suitably compatible donor. Relapse of disease remains the most frequent obstacle to successful treatment.

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.

Successful Treatment of Chronic Myeloid Leukemia With Dasatinib After Kidney Transplantation: A Case Report

ObjectiveChronic myeloid leukemia (CML) is a rare malignancy in kidney transplant (KT) recipients. Although dasatinib is the first-line treatment for CML, it has inhibitory activity against CYP3A4; this might increase the blood concentration of tacrolimus (administered to KT patients for immune suppression). Furthermore, tacrolimus can also increase blood concentrations of dasatinib through P-glycoprotein inhibition. MethodsHere, we report a case of sustained molecular remission of CML with prolonged first-line dasatinib therapy in a KT recipient being treated with tacrolimus. A 61-year-old woman developed CML-chronic phase (CML-CP) 38 months post KT. Her maintenance immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil, and methylprednisolone. Considering the potential drug interaction with tacrolimus, dasatinib was administered at a low dose of 50 mg/day. Her immune status was evaluated regularly by assessing the mixed lymphocyte reaction (MLR) using an intracellular carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeling technique; immunosuppressive therapy was adjusted accordingly. ResultsThe patient achieved complete hematologic remission (CHR) after 1 month of dasatinib treatment. Six months after dasatinib treatment, she achieved a major molecular response. During the observation period, neither antibody-mediated nor acute cellular rejection were encountered in the patient. She remained in CHR with a major molecular response 12 months after the diagnosis of CML-CP. ConclusionData obtained from immune monitoring assays using CFSE-MLR helped us to successfully manage a KT recipient with CML-CP being treated with dasatinib. Drug-drug interactions are a key consideration while designing treatment regimens; such strategies would ensure that drug-drug interactions do not negatively affect the treatment outcomes.