Mutations in myeloid transcription factors and activated signaling genes predict chronic myeloid leukemia outcomes.

ABSTRACT: Advancements in genomics are transforming the clinical management of chronic myeloid leukemia (CML) toward precision medicine. The impact of somatic mutations on treatment outcomes is still under debate. We studied the association of somatic mutations in epigenetic modifier genes and activated signaling/myeloid transcription factors (AS/MTFs) with disease progression and treatment failure in patients with CML after tyrosine kinase inhibitor (TKI) therapy. A total of 394 CML samples were sequenced, including 254 samples collected at initial diagnosis and 140 samples taken during follow-up. Single-molecule molecular inversion probe (smMIP)-based next-generation sequencing (NGS) was conducted targeting recurrently mutated loci in 40 genes, with a limit of detection of 0.2%. Seventy mutations were detected in 57 diagnostic samples (22.4%), whereas 64 mutations were detected in 39 of the follow-up samples (27.9%). Carrying any mutation at initial diagnosis was associated with worse outcomes after TKI therapy, particularly in AS/MTF genes. Patients having these mutations at initial diagnosis and treated with imatinib showed higher risks of treatment failure (hazard ratio, 2.53; 95% confidence interval, 1.13-5.66; P = .0239). The adverse prognostic impact of the mutations was not clear for patients treated with second-generation TKIs. The multivariate analysis affirmed that mutations in AS/MTF genes independently serve as adverse prognostic factors for molecular response, failure-free survival, and progression risk. Additionally, there was an observable nonsignificant trend indicating a heightened risk of progression to advanced disease and worse overall survival. In conclusion, mutations in the AS/MTF genes using smMIP-based NGS can help identify patients with a potential risk of both treatment failure and progression and may help upfront TKI selection.

Long-Term Follow-Up in Patients With Chronic Myeloid Leukemia Treated With Ponatinib in a Real-World Cohort: Safety and Efficacy Analysis.

BACKGROUND: Ponatinib is a third-generation tyrosine-kinase inhibitor (TKI), indicated in patients with chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML), who are resistant or intolerant to ≥2 prior TKIs, patients for whom subsequent treatment with imatinib is not appropriate, and patients who have a T315I mutation. PATIENTS AND METHODS: We aimed to evaluate outcomes of ponatinib treatment, including safety, with focus on cardiovascular toxicity, in real-world patients from Argentina. Data from patients with CP CML treated with ponatinib was retrospectively retrieved from 2013 to 2023 in 7 centers. RESULTS: Seventy-two patients were included (median age: 44 years; male: 55.5%; T315I mutation: 32%: median treatment duration: 36 months. At baseline, 57 patients (79%) had a breakpoint cluster region-Abelson (BCR::ABL1) transcript level >10% on the international reporting scale (BCR::ABL1 IS). A molecular response (MR, BCR::ABL1 (IS) <1%) was achieved at 12 months in 51.6% of evaluable patients; 57% maintained MR at last follow-up. Overall, 43% and 25% maintained major MR (MMR) or deep MR (DMR) (MR4.0-MR5.0), respectively at last follow-up. Twelve (16.6%) ponatinib-resistant patients were rescued with allogeneic hematopoietic stem cell transplantation. The estimated 2-year progression-free survival (PFS) was 84%. Ponatinib dose was reduced during treatment in 22 patients; nevertheless, MMR was maintained in 50% of these patients. Severe arterial occlusive events (AOE) were reported in 10.9% of patients after a median treatment of 5 months. CONCLUSION: CV toxicity was consistent with clinical trials and other real-world registries. Older age, hypercholesterolemia and a SCORE risk >2% were significantly associated with higher risk of AOEs. Controlling CV risk factors and reducing doses at optimal time points may help to optimize ponatinib use in daily practice.

In-depth characterization of NK cell markers from CML patients who discontinued tyrosine kinase inhibitor therapy.

Introduction: Treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase is considered a safe option if suitable molecular monitoring is available. However, the question arises as to which factors can contribute to the maintenance of TFR, and immunologic surveillance of the remaining leukemic cells is believed to be one of them. Argentina Stop Trial is an open-label, single-arm, multicenter trial assessing TFR after tyrosine kinase inhibitors interruption, that after more than 4 years showed a successful TFR rate of 63%. Methods: In this context, we set up an immunological study by flow cytometry in order to analyze specific NK cell subsets from peripheral blood patient samples both at the time of discontinuation as well as during the subsequent months. Results: At the time of discontinuation, patients show a mature NK cell phenotype, probably associated to TKI treatment. However, 3 months after discontinuation, significant changes in several NK cell receptors occurred. Patients with a higher proportion of CD56dim NK and PD-1+ NK cells showed better chances of survival. More interestingly, non-relapsing patients also presented a subpopulation of NK cells with features associated with the expansion after cytomegalovirus infection (expression of CD57+NKG2C+), and higher proportion of NKp30 and NKp46 natural cytotoxicity receptors, which resulted in greater degranulation and associated with better survival (p<0.0001). Discussion: This NK cell subset could have a protective role in patients who do not relapse, thus further characterization could be useful for patients in sustained deep molecular response.

Inequalities in access to treatment in Argentina: Differences in management of CLL and multiple myeloma?

Health equity is today an important objective to evenly reach the population among different health care systems. This article will focus on diagnosis and treatment access inequalities in Argentina. Although different aspects must be optimized to overcome access barriers worldwide, access inequalities in some regions of Argentina may depend basically on the type of health coverage or insurance. Health care in Argentina is divided into Public, Social security and Private care systems. Access to diagnosis and disease monitoring will vary according whether the patient is under each of these systems. Reducing inequalities may help target some important aspects not covered today and that may directly impact patients' outcome. Disparities in health cancer care were analyzed according to Public, Social security and Private sectors. A disadvantage in resource access, inadequate funding and limited medical infrastructures are common characteristics of the public health care systems. In our country the disparity between the public and private sectors in terms of timely diagnosis, stage of disease at diagnosis, accuracy of diagnosis, access to novel agents and transplantation is notorious, with the public sector lagging behind in access to diagnostic and treatment resources. While the Private sector has treatment outcomes comparable to those of high-income countries, challenges remain in the Public sector for patients who rely on early and accurate diagnosis and timely access to treatment. There is an urgent need to provide equitable care for multiple myeloma and CLL patients and reduce the emotional and financial consequences of the disease for the patient. A survey about diagnosis and therapeutic resources was conducted between April and May 2023 among large centers in the Public, Social security and Private systems. A total of 49 hematologists from 31 institutions from five provinces of Argentina participated in the survey. We observed differences between the different systems with more access for the Private system on genetic diagnosis (FISH-IGVH access). More CLL patients in the public and social security systems were treated with CIT reflecting the inaccessibility in these sectors of more expensive targeted therapies rather than a gap in information since the Public centers surveyed were large hospitals with knowledgeable physicians. Access to different treatments both in first-line and relapsed settings was more equitable in the treatment of multiple myeloma for the different systems with the exception of access to daratumumab in first-line that was extremely infrequent in the public coverage. With increasing cost and treatment complexity as the introduction of CARTs and BITEs for CLL and MM, the gap will probably deepen more if the problem is not treated comprehensively by all the actors of the health sector: government, physicians, patients' organizations and pharmaceutical companies.

Elevated plasma levels of IL-6 and MCP-1 selectively identify CML patients who better sustain molecular remission after TKI withdrawal.

Treatment-free remission (TFR) in chronic myeloid leukemia (CML) is safe under adequate molecular monitoring, but questions remain regarding which factors may be considered predictive for TFR. Argentina Stop Trial (AST) is a multicenter TFR trial showing that 65% of patients sustain molecular remission, and the prior time in deep molecular response (DMR) was associated with successful TFR. Luminex technology was used to characterize cytokines in plasma samples. Using machine learning algorithms, MCP-1 and IL-6 were identified as novel biomarkers and MCP-1low/IL-6low patients showed eightfold higher risk of relapse. These findings support the feasibility of TFR for patients in DMR and MCP-1/IL-6 plasma levels are strong predictive biomarkers.

BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib.

Patients with chronic lymphocytic leukemia (CLL) progressing on ibrutinib constitute an unmet need. Though Bruton tyrosine kinase (BTK) and PLCG2 mutations are associated with ibrutinib resistance, their frequency and relevance to progression are not fully understood. In this multicenter retrospective observational study, we analyzed 98 patients with CLL on ibrutinib (49 relapsing after an initial response and 49 still responding after ≥1 year of continuous treatment) using a next-generation sequencing (NGS) panel (1% sensitivity) comprising 13 CLL-relevant genes including BTK and PLCG2. BTK hotspot mutations were validated by droplet digital polymerase chain reaction (ddPCR) (0.1% sensitivity). By integrating NGS and ddPCR results, 32 of 49 relapsing cases (65%) carried at least 1 hotspot BTK and/or PLCG2 mutation(s); in 6 of 32, BTK mutations were only detected by ddPCR (variant allele frequency [VAF] 0.1% to 1.2%). BTK/PLCG2 mutations were also identified in 6 of 49 responding patients (12%; 5/6 VAF <10%), of whom 2 progressed later. Among the relapsing patients, the BTK-mutated (BTKmut) group was enriched for EGR2 mutations, whereas BTK-wildtype (BTKwt) cases more frequently displayed BIRC3 and NFKBIE mutations. Using an extended capture-based panel, only BRAF and IKZF3 mutations showed a predominance in relapsing cases, who were enriched for del(8p) (n = 11; 3 BTKwt). Finally, no difference in TP53 mutation burden was observed between BTKmut and BTKwt relapsing cases, and ibrutinib treatment did not favor selection of TP53-aberrant clones. In conclusion, we show that BTK/PLCG2 mutations were absent in a substantial fraction (35%) of a real-world cohort failing ibrutinib, and propose additional mechanisms contributing to resistance.

Challenges in Chronic Myeloid Leukemia Management in South America.

PURPOSE OF REVIEW: Chronic myeloid leukemia (CML) management in developing countries has improved in the last years, but the availability of therapeutic resources, monitoring, reimbursement, and financial issues may be a challenge and interfere with the best practices and results of CML treatment. This review points out the main challenges in CML management in South America. RECENT FINDINGS: In this review, we describe the access to tyrosine kinase inhibitors and monitoring in different countries of South America. We also address the ongoing discontinuation trials, the progress, and limitations of hematopoietic stem cell transplantation in the last years. There are still many challenges for achieving the best outcomes for CML patients in South America. The continuous efforts to provide continuous education, access to tyrosine kinase inhibitors, and monitoring, providing reference centers for CML management and hematopoietic stem cell transplantation may improve patients' outcomes.

Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial.

In PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270.

Treatment-free remission in patients with chronic myeloid leukemia: recommendations of the LALNET expert panel.

Tyrosine kinase inhibitors (TKIs) have dramatically changed the survival of chronic myeloid leukemia (CML) patients, and treatment-free remission (TFR) has recently emerged as a new goal of CML treatment. The aim of this work was to develop recommendations for TKI discontinuation in Latin America (LA), outside of clinical trials. A working group of CML experts from LA discussed 22 questions regarding TFR and reached a consensus for TFR recommendations in the region. TFR is indicated in patients in first chronic phase, with typical BCR-ABL transcripts, under TKI treatment of a minimum of 5 years, in sustained deep molecular response (DMR; molecular response 4.5 [MR4.5]) for 2 years. Sustained DMR must be demonstrated on at least 4 international reporting scale quantitative polymerase chain reaction (PCR) tests, separated by at least 3 months, in the immediate prior 2 years. After second-line therapy, TFR is indicated in previously intolerant, not resistant, patients. Molecular monitoring is recommended monthly for the first 6 months, every 2 to 3 months from months 7 to 12, and every 3 months during the second year, indefinitely. Treatment should be reintroduced if major molecular response is lost. Monitoring of withdrawal syndrome, glucose levels, and lipid profile is recommended after discontinuation. After TKI reintroduction, molecular monitoring is indicated every 2 to 3 months until MR4.0 achievement; later, every 3 to 6 months. For the TFR attempt, having standardized and reliable BCR-ABL PCR tests is mandatory. These recommendations will be useful for safe discontinuation in daily practice and will benefit patients who wish to stop treatment in emergent regions, in particular, with TKI-related chronic adverse events.

Chronic myeloid leukaemia.

Tyrosine-kinase inhibitors have changed the natural history of chronic myeloid leukaemia in such a way that patients with adequate access to these agents, who are properly managed, and who respond well to this treatment can expect a near-normal life expectancy. Achieving this goal requires an adequate understanding of the patient's treatment goals, careful monitoring for the achievement of optimal response hallmarks, implementation of proper interventions according to the attainment of such endpoints, adequate recognition and management of adverse events, and acknowledgment of the relevance of comorbidities. Treatment with tyrosine-kinase inhibitors, once considered lifelong, has become terminable for at least some patients, and promising new agents are emerging for those whose disease does not respond to any of the multiple therapeutic options currently available. If these advances reach all patients with chronic myeloid leukaemia, cure might eventually become a reality in most instances.

COVID-19 in chronic myeloid leukemia patients in Latin America.

This observational, multicenter study aimed to report the clinical evolution of COVID-19 in patients with chronic myeloid leukemia in Latin America. A total of 92 patients presented with COVID-19 between March and December 2020, 26% of whom were severe or critical. The median age at COVID-19 diagnosis was 48 years (22-79 years), 32% were 60 years or older, and 61% were male. Thirty-nine patients presented with at least one comorbidity (42.3%). Eighty-one patients recovered (88%), and 11 (11.9%) died from COVID-19. There was one case of reinfection. Patients with a major molecular response presented superior overall survival compared to patients with no major molecular response (91 vs. 61%, respectively; p = 0.004). Patients in treatment-free remission and receiving tyrosine kinase inhibitors showed higher survival rates than patients who underwent hematopoietic stem cell transplantation and those who did not receive tyrosine kinase inhibitors (100, 89, 50, and 33%, respectively; p < 0.001).

Real-world analysis of treatment patterns and clinical outcomes in patients with newly diagnosed chronic lymphocytic leukemia from seven Latin American countries.

OBJECTIVE: To describe chronic lymphocytic leukemia (CLL) treatment patterns and patient outcomes in Latin America. METHODS: This chart review study (NCT02559583; 2008-2015)evaluated time to progression (TTP) and overall survival (OS) outcomes among patients with CLL who initiate done (n = 261) to two (n = 96) lines of therapy (LOT) since diagnosis. Differences in TTP and OS were assessed by Kaplan-Meier analysis, with a log-rank test for statistical significance. Association between therapeutic regimen and risk for disease progression or death was estimated using Cox proportional hazard regression. RESULTS: The most commonly prescribed therapies in both LOTs were chlorambucil-, followed by fludarabine- and cyclophosphamide (C)/CHOP-based therapies. Chlorambucil- and C/CHOP-based therapies were largely prescribed to elderly patients (≥65 years) while fludarabine-based therapy was predominantly used by younger patients (≤65 years). In LOT1, relative to chlorambucil-administered patients, those prescribed fludarabine-based therapies had lower risk of disease progression (hazard ratio [HR] and 95% confidence interval [CI] 0.32 [0.19-0.54]), whereas C/CHOP-prescribed patients had higher risk (HR 95%CI 1.88 [1.17-3.04]). Similar results were observed in LOT2. There was no difference in OS between treatments in both LOTs. DISCUSSION: Novel therapies such as kinase inhibitors were rarely prescribed in LOT1 or LOT2in Latin America. The greater TTP observed forfludarabine-based therapies could be attributed to the fact that fludarabine-based therapies are predominantly administered to young and healthy patients. CONCLUSION: Chlorambucil-based therapy, which has limited benefits, is frequently prescribed in Latin America. Prescribing novel agents for fludarabine-based therapy-ineligible patients with CLL is the need of the hour. Trial registration: ClinicalTrials.gov identifier: NCT02559583.

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

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

Epidemiology of Hematologic Malignancies in Real-World Settings: Findings From the Hemato-Oncology Latin America Observational Registry Study.

PURPOSE: Limited information is available on multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL) management in Latin America. The primary objective of the Hemato-Oncology Latin America (HOLA) study was to describe patient characteristics and treatment patterns of Latin American patients with MM, CLL, and NHL. METHODS: This study was a multicenter, retrospective, medical chart review of patients with MM, CLL, and NHL in Latin America identified between January 1, 2006, and December 31, 2015. Included were adults with at least 1 year of follow-up (except in cases of death within 1 year of diagnosis) treated at 30 oncology hospitals (Argentina, 5; Brazil, 9; Chile, 1; Colombia, 5; Mexico, 6; Panama/Guatemala, 4). RESULTS: Of 5,140 patients, 2,967 (57.7%) had NHL, 1,518 (29.5%) MM, and 655 (12.7%) CLL. Median follow-up was 2.2 years for MM, 3.0 years for CLL, and 2.2 years for NHL, and approximately 26% died during the study observation period. Most patients had at least one comorbidity at diagnosis. The most frequent induction regimen was thalidomide-based chemotherapy for MM and chlorambucil with or without prednisone for CLL. Most patients with NHL had diffuse large B-cell lymphoma (DLBCL; 49.1%) or follicular lymphoma (FL; 19.5%). The majority of patients with DLBCL or FL received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. CONCLUSION: The HOLA study generated an unprecedented level of high-quality, real-world evidence on characteristics and treatment patterns of patients with hematologic malignancies. Regional disparities in patient characteristics may reflect differences in ethnoracial identity and level of access to care. These data provide needed real-world evidence to understand the disease landscape in Latin America and may be used to inform clinical and health policy decision making.

Ponatinib in the treatment of chronic myeloid leukemia and philadelphia chromosome positive acute lymphoblastic leukemia.

Philadelphia chromosome, reciprocal translocation between chromosome 9 and 22, leading to a constitutively active fusion protein BCR-ABL1 is the common feature among Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML). The discovery of tyrosine kinase inhibitors (TKIs) has led to significant improvement in the treatment of CML and Ph+ ALL. Ponatinib is a third-generation TKI that is currently approved as per label when no other TKIs are indicated for the treatment of patients with CML and Ph+ ALL after failing treatment with second-generation TKIs or if presence of T315I mutation is discovered. This review summarizes the ponatinib development, approved indications as well as ongoing clinical studies in CML and Ph+ ALL.

Evaluation of the primitive fraction by functional in vitro assays at the RNA and DNA level represents a novel tool for complementing molecular monitoring in chronic myeloid leukemia.

Quantification of BCR-ABL1 mRNA levels in peripheral blood of chronic myeloid leukemia patients is a strong indicator of response to tyrosine-kinase inhibitors (TKI) treatment. However, additional prognostic markers are needed in order to better classify patients. The hypothesis of leukemic stem cells (LSCs) heterogeneity and persistence, suggests that their functional evaluation could be of clinical interest. In this work, we assessed the primitive and progenitor fractions in patients at diagnosis and during TKI treatment using functional in vitro assays, defining a "functional leukemic burden" (FLB). We observed that the FLB was reduced in vivo in both fractions upon treatment. However, different FLB levels were observed among patients according to their response to treatment, suggesting that quantification of the FLB could complement early molecular monitoring. Given that FLB assessment is limited by BCR-ABL1 mRNA expression levels, we developed a novel detection method of primitive cells at the DNA level, using patient-specific primers and direct nested PCR in colonies obtained from functional in vitro assays. We believe that this method could be useful in the context of discontinuation trials, given that it is unknown whether the persistent leukemic clone represents LSCs, able to resume the leukemia upon TKI removal.

Chronic Myeloid Leukemia: What Is the Best Strategy to Start and Monitor Treatment Outside Academic Centers?

The introduction of tyrosine kinase inhibitors (TKI) has dramatically changed the outcome of chronic myeloid leukemia (CML). Over the last decade, imatinib positioned itself as the gold standard of care, until second-generation TKIs were introduced as first-line treatment. Multiple therapeutic options available today in CML make the decision of the first-line therapy a difficult choice. However, a gap still exists, in the management of CML outside academic centers. Important advances in molecular monitoring have been developed worldwide; nevertheless, monitoring in the "real world" continues to be a challenge in part because international scale (IS) standardized laboratories are not available worldwide, and also because physicians still have some resource barriers and lack of familiarity restricting guideline adoption and consider optimal molecular monitoring a challenge. This review addresses CML first-line treatment, monitoring aspects and giving practical advice, identifying prognostic factors, and guiding management of CML for non-academic centers.

Nilotinib dose-optimization in newly diagnosed chronic myeloid leukaemia in chronic phase: final results from ENESTxtnd.

The Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Extending Molecular Responses (ENESTxtnd) study was conducted to evaluate the kinetics of molecular response to nilotinib in patients with newly diagnosed chronic myeloid leukaemia in chronic phase and the impact of novel dose-optimization strategies on patient outcomes. The ENESTxtnd protocol allowed nilotinib dose escalation (from 300 to 400 mg twice daily) in the case of suboptimal response or treatment failure as well as dose re-escalation for patients with nilotinib dose reductions due to adverse events. Among 421 patients enrolled in ENESTxtnd, 70·8% (95% confidence interval, 66·2-75·1%) achieved major molecular response (BCR-ABL1 ≤ 0·1% on the International Scale) by 12 months (primary endpoint). By 24 months, 81·0% of patients achieved major molecular response, including 63·6% (56 of 88) of those with dose escalations for lack of efficacy and 74·3% (55 of 74) of those with dose reductions due to adverse events (including 43 of 54 patients with successful re-escalation). The safety profile of nilotinib was consistent with prior studies. The most common non-haematological adverse events were headache, rash, and nausea; cardiovascular events were reported in 4·5% of patients (grade 3/4, 3·1%). The study was registered at clinicaltrials.gov (NCT01254188).

[Chronic myelogenous leukemia: monitoring and predictors of a favorable response to treatment with imatinib]. / Leucemia mieloide crónica. Monitoreo y factores predictivos de una respuesta favorable en el tratamiento con imatinib.

The expected five-year survival of chronic-phase chronic myeloid leukemia patients treated with tyrosine kinase inhibitors is over 90%. Little data is available regarding the results in the Argentinian population. This information might be of interest as generic imatinib is now available in the region. The aim of this study is to provide information on monitoring and the long-term treatment with imatinib outside of a controlled clinical trial, as well as to analyze the predictive effect of early responses to achieve molecular remission 4.0 (RM 4.0) and the detection of variables that may condition treatment failure. We included 106 patients, who received imatinib 400 mg daily as first-line inhibitor for a median of 8.9 years (IQR 5.8-11.7) between June 2000 and December, 2015. Overall survival was 93%. At latest follow-up 74% of patients continues on initial imatinib. The achievement of response at targeted milestones (6, 12 months) was associated with increased failure-free survival: 87% vs. 56%, p = 0.007; 90% vs. 69% p = 0.01 and was independently associated to RM 4.0: OR 5.6 (95% CI: 1.6-19.0); OR 5.3 (95% CI: 1.4-21.0) p = 0.006. After long-term follow-up, imatinib provided high-rates of response and survival. The prognostic value of response at targeted milestones was confirmed. This study reinforces the importance of molecular monitoring under IS standardization at known timepoints and this must continue to be a target in Argentina.