Phase Chronic Myeloid Leukemia Patients Research Articles

Prospective monitoring of chronic myeloid leukemia patients from the time of TKI discontinuation: the fate of peripheral blood CD26+ leukemia stem cells.

Introduction: In chronic myeloid leukemia (CML), about half of the patients achieving a deep and stable molecular response with tyrosine kinase inhibitors (TKIs) may discontinue TKI treatment without disease recurrence. As such, treatment-free remission (TFR) has become an ambitious goal of treatment. Given the evidence that deepness and duration of molecular response are necessary but not sufficient requisites for a successful TFR, additional biological criteria are needed to identify CML patients suitable for efficacious discontinuation. Leukemia stem cells (LSCs) are supposed to be the reservoir of the disease. Previously, we demonstrated that residual circulating CD34+/CD38-/CD26+ LSCs were still detectable in a consistent number of CML patients during TFR. Methods: CML LSCs could be easily identified by flow-cytometry as they express the CD34+/CD38-/CD26+ phenotype. In this study, we explored the role of these cells and their correlation with molecular response in a cohort of 109 consecutive chronic phase CML patients prospectively monitored from the time of TKI discontinuation. Results: After a median observation time of 33months from TKI discontinuation, 38/109 (35%) patients failed TFR after a median time of 4months, while 71/109 (65%) patients are still in TFR. At TKI discontinuation, peripheral blood CD26+LSCs were undetectable in 48/109 (44%) patients and detectable in 61/109 (56%). No statistically significant correlation between detectable/undetectable CD26+LSCs and the rate of TFR loss was found (p = 0.616). The incidence of TFR loss based on the type of TKI treatment was statistically significant for imatinib treatment compared to that of nilotinib (p = 0.039). Exploring the behavior of CD26+LSCs during TFR, we observed fluctuating values that were very variable between patients, and they were not predictive of TFR loss. Discussion: Up to date, our results confirm that CD26+LSCs are detectable at the time of TKI discontinuation and during TFR. Moreover, at least for the observation median time of the study, the persistence of "fluctuating" values of residual CD26+LSCs does not hamper the possibility to maintain a stable TFR. On the contrary, even patients discontinuing TKI with undetectable CD26+LSCs could undergo TFR loss. Our results suggest that factors other than residual LSCs "burden" playing an active role in controlling disease recurrence. Additional studies evaluating CD26+LSCs' ability to modulate the immune system and their interaction in CML patients with very long stable TFR are ongoing.

Long-term outcomes of frontline imatinib therapy for chronic myeloid leukemia in China.

Imatinib is the first-line therapy recommended for chronic myeloid leukemia (CML) patients in China. We reported a long-term follow-up study of patients on imatinib as first-line treatment for chronic phase (CP) CML to provide an important reference for the actual clinical treatment regimen of CML patients in China. We evaluated the long-term efficacy, safety, low-dose attempt after years of treatment, and treatment-free remission (TFR) of 237 CML-CP patients receiving first-line imatinib therapy. The median age was 46 years (interquartile range: 33-55). After a median follow-up of 6.5 years, the cumulative complete cytogenetic response, major molecular response (MMR), and MR4.5 rates were 82.6%, 80.4%, and 69.3%, respectively. The 10-year transformation-free, event-free, and failure-free survival rates were 97.3%, 87.2% and 53.5%, respectively. Fifty-two (21.9%) patients with sustained deep molecular response (DMR) were treated with low-dose imatinib after years of imatinib treatment. No significant differences in the 1-year and 2-year molecular relapse-free survival in MMR and MR4 were observed between the standard-dose and low-dose groups. Twenty-eight (11.8%) patients discontinued imatinib, and the median time to maintain DMR before discontinuation was 8.43 years. Thirteen patients (5.5%) remained in TFR for a median of 43.33 months. No patients transformed to accelerate or blast phase or died. No new, late toxicity was observed, and the most frequent grade 3/4 adverse events were neutropenia (9.3%), anemia (7.6%), thrombocytopenia (6.3%), and rash (4.2%). This study confirmed the long-term efficacy and safety of imatinib for treating Chinese CML patients. Additionally, it demonstrated the feasibility of imatinib dose reduction and TFR attempts in patients with sustained stable DMR after years of imatinib treatment in real-life settings.

Factors influencing severe cytopenia in chronic phase chronic myeloid leukemia patients receiving initial second generation tyrosine kinase inhibitors and its impact on treatment responses and outcomes

Objective: To explore the influencing covariates of severe neutrophils and/or thrombocytopenia and their effect on treatment response and outcome in patients with chronic-phase chronic myeloid leukemia (CP-CML) receiving initial second-generation tyrosine kinase inhibitors (2G-TKI) . Methods: Data from consecutive patients aged ≥18 years with newly diagnosed CP-CML who received initial 2G-TKI at Peking University People's Hospital from September 2008 to November 2021 were interrogated. Binary logistic regression models and Fine-Gray and Cox regression models were applied. Results: Data from 267 patients who received initial 2G-TKI, including nilotinib (n=239, 89.5% ) and dasatinib (n=28, 10.5% ) , were interrogated. The median age was 36 (range, 18-73) years, and 156 (58.4% ) patients were male. At a median treatment period of 1.0 (0.1-3.0) month, 43 (16.1% ) patients developed grade ≥3 neutrophils and/or thrombocytopenia and recovered within 1.0 (0.1-24.6) month. Male (OR=2.9, 95% CI 1.2-6.8; P=0.018) , age of ≥36 years (OR=3.2, 95% CI 1.4-7.2, P=0.005) , a spleen below a costal margin of ≥7 cm (OR=2.8, 95% CI 1.2-6.6, P=0.020) , and a hemoglobin (HGB) level of <100 g/L (OR=2.9, 95% CI 1.3-6.8, P=0.012) at diagnosis were significantly associated with grade ≥ 3 neutrophils and/or thrombocytopenia. Based on their regression coefficients, male, age of ≥36 years, a spleen below a costal margin of ≥7 cm, and an HGB level of <100 g/L were given 1 point to form a predictive system. All patients were divided into three risk subgroups, and the incidence of severe cytopenia significantly differed among the three groups (P < 0.001) . Grade ≥3 neutrophils and/or thrombocytopenia for >2 weeks was significantly associated with lower cumulative incidences of complete cytogenetic response (CCyR, HR=0.5, 95% CI 0.3-0.7, P<0.001) and major molecular response (MMR, HR=0.4, 95% CI 0.3-0.8, P=0.004) and was not significantly associated with failure, progression, and survival. Conclusion: Male, advanced age, a large spleen, and a low HGB level were significantly associated with severe cytopenia. The four covariates were used to establish a prediction model, in which the incidence of severe cytopenia among different risk groups was significantly different. Severe cytopenia for >2 weeks was a negative factor for responses but not for outcomes.

Health-related quality of life of patients with resistant/intolerant chronic phase chronic myeloid leukemia treated with asciminib or bosutinib in the phase 3 ASCEMBL trial

In ASCEMBL, an open-label, randomized Phase 3 study, asciminib demonstrated superior efficacy and better safety profile compared with bosutinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with ≥2 tyrosine kinase inhibitors. Health-related quality of life (HRQOL) reported by patients is key to understanding the benefit and impact of treatment on patients’ lives, and is becoming increasingly important as the life expectancy of CML-CP patients increases and patients require long-term treatment. In ASCEMBL, patients completed questionnaires to assess CML symptoms and interference with daily life (M.D. Anderson Symptom Inventory – CML [MDASI-CML]), general HRQOL (five-level EQ-5D [EQ-5D-5L], Patient Global Impression of Change – CML [PGIC-CML]), and impact of CML on working life and activity (Work Productivity and Activity Impairment questionnaire – CML [WPAI-CML]). Patients’ CML symptoms and HRQOL remained stable during 48 weeks of treatment with asciminib, with a general trend for decreased CML symptom severity, particularly for fatigue, and improvement in HRQOL. A clinically meaningful increase in diarrhea severity was observed in patients treated with bosutinib compared to asciminib. These data provide better understanding of the patient perspective and treatment impact on HRQOL in a later-line setting, where little information has been published to date.

Efficacy and safety of nilotinib in chronic myeloid leukaemia patients who failed to achieve a treatment-free remission period after imatinib discontinuation: Results of the French Nilo post-STIM study.

Molecular recurrence (MRec) occurs in about half of all patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitors (TKI) in sustained deep molecular response. A second TKI discontinuation has been attempted in some patients who regain the discontinuation criteria after resuming treatment. Nilotinib treatment affords faster and deeper molecular responses than imatinib as first-line therapy. We prospectively evaluated the efficacy and safety of nilotinib (300 mg twice daily) in chronic-phase CML patients who experienced MRec, after imatinib discontinuation and analysed the probability of TFR after a new attempt in patients treated for 2 years with sustained MR4.5 for at least 1 year. A total of 31 patients were included in the study between 2013 and 2018. Seven (23%) patients experienced serious adverse events after a median of 2 months of nilotinib treatment leading to discontinuation of treatment. One patient was excluded from the study for convenience. Among the 23 patients treated for 2 years with nilotinib, 22 maintained their molecular response for at least 1 year (median: 22 months) and stopped nilotinib. The TFR rates at 24 and 48 months after nilotinib discontinuation were 59.1% (95% confidence interval [CI]: 41.7%-83.7%) and 42.1% (95% CI: 25%-71%) respectively (NCT #01774630).

Kinetic of liver enzymes and serum electrolytes in HCV, HBV, and HIV negative chronic phase chronic myeloid leukemia patients treated with imatinib or nilotinib

The outcome for chronic phase (CP) chronic myeloid leukemia (CML) patients was changed dramatically since the introduction of tyrosine kinase inhibitor (TKI) therapy. This study intended to evaluate side effects of TK Imatinib or Nilotinib on liver enzymes and serum electrolytes in relation to hematologic and molecular response in HCV-, HBV-, and HIV-, CP-CML patients. The study was a quasi-experimental pre-post single group design, included 38 HCV-, HBV-, and HIV-newly diagnosed Philadelphia positive CP-CML patients with normal hepatic and renal function. They were divided equally into two groups, 19 received Nilotinib, and 19 received Imatinib. Hematologic, BCR-ABL gene expression by RT-PCR, electrolytes and liver enzymes were measured at baseline and after 6 months of treatment. Patients age ranged between 20 and 62 years. Anemic manifestations represented the highest rate (n=23, 60.5%). The mean WBCs count was significantly reduced after treatment (p < 0.001). The WBCs count was significantly reduced in the Nilotinib group than the Imatinib group (97% and 94%, respectively, p=0.049). The mean hemoglobin level was significantly increased after treatment (p=0.010). The mean platelet level did not change over the treatment period. The mean AST, ALT, and ALP levels were significantly increased after treatment, (p=0.014, p=0.002, and p=0.047, respectively). The ALP level was significantly increased in both groups (p=0.001). The mean sodium potassium, phosphorous, and calcium level was not changed over the treatment period. The mean BCR-ABL gene expression was sharply decreased after treatment (p < 0.001). A higher reduction was observed in the Nilotinib group (99%) than the Imatinib group (91.5%) (p=0.025). Imatinib resulted in rise of AST and ALP levels than Nilotinib, while both had the same effect on the ALT level. Higher reduction in BCR-ABL gene expression was achieved by Nilotinib. Nilotinib and Imatinib did not affect serum levels of sodium, potassium, phosphorous, or calcium.

Does platelet aggregation differ among chronic myeloid leukemia-chronic phase (CML-CP) patients on tyrosine kinase inhibitors (TKIs)? A tertiary center experience

Abstract Background Tyrosine kinase inhibitors (TKIs) have improved the prognosis of chronic myeloid leukemia (CML) by inhibiting the BCR-ABL kinase. There are concerns regarding the effect of TKI on hemostasis by inhibiting platelet aggregation; the possible reason for this is yet unclear. Objectives To study platelet aggregation response to different agonists [(adenosine diphosphate (ADP), collagen, and arachidonic acid (AA)] using platelet aggregometry in 75 CML-chronic phase (CML-CP) patients on TKI therapy, in complete hematologic response (CHR). Patients and methods This study included 75 CML patients of both sexes of age 32–66 years. A detailed medical history, clinical examination, and platelet aggregation by PAP-4 platelet aggregometer were done for all patients. Results Imatinib-treated CML patients had a lower platelet aggregation response to AA (less than 50% aggregation) than those on nilotinib either first- or second-line treatment, in a statistically significant manner (P=0.001, P=0.025) for both comparisons. But there was no statistically significant difference in platelet aggregation between patients on nilotinib either first- or second-line therapy (P=0.073). Conclusion Platelet aggregation response to collagen and ADP was normal in all CML-CP patients, but it had an impaired response to AA&lt;AQ: Pls check whether the change is appropriate&gt;. Further studies are needed to establish the particular mechanism of this inhibition.

The interplay between telomeric complex members and BCR::ABL1 oncogenic tyrosine kinase in the maintenance of telomere length in chronic myeloid leukemia

PurposeChronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by recurrent genetic aberration in leukemic stem cells, namely Philadelphia chromosome caused by reciprocal translocation t(9;22)(q34;q11). In our study, we analyzed the telomeric complex expression and function in the molecular pathogenesis of CML.MethodsWe employed CD34+ primary leukemic cells, comprising both leukemic stem and progenitor cell populations, isolated from peripheral blood or bone marrow of CML patients in chronic and blastic phase to analyze the telomere length and telomeric-associated proteins.ResultsThe reduction in telomere length during disease progression was correlated with increased expression of BCR::ABL1 transcript and the dynamic changes were neither associated with the enzymatic activity of telomerase nor with gene copy number and expression of telomerase subunits. Increased expression of BCR::ABL1 was positively correlated with expression of TRF2, RAP1, TPP1, DKC1, TNKS1, and TNKS2 genes.ConclusionsThe dynamics of telomere length changes in CD34+ CML cells is dependent on the expression level of BCR::ABL, which promotes the expression of certain shelterins including RAP1 and TRF2, as well as TNKS, and TNKS2, and results in telomere shortening regardless of telomerase activity. Our results may allow better understanding of the mechanisms responsible for the genomic instability of leukemic cells and CML progression.

Importance of TKI treatment duration in treatment-free remission of chronic myeloid leukemia: results of the D-FREE study

Treatment-free remission (TFR) is a new goal for patients with chronic myeloid leukemia in chronic phase (CML-CP) with a sustained deep molecular response (DMR) to treatment with tyrosine kinase inhibitors (TKIs). However, optimal conditions for successful TFR in patients treated with second-generation (2G)-TKIs are not fully defined. In this D-FREE study, treatment discontinuation was attempted in newly diagnosed CML-CP patients treated with the 2G-TKI dasatinib who achieved BCR-ABL1 levels of ≤ 0.0032% (MR4.5) on the international scale (BCR-ABL1IS) and maintained these levels for exactly 1 year. Of the 173 patients who received dasatinib induction therapy for up to 2 years, 123 completed and 60 (48.8%) reached MR 4.5. Among the first 21 patients who maintained MR4.5 for 1 year and discontinued dasatinib, 17 experienced molecular relapse defined as loss of major molecular response (BCR-ABL1IS > 0.1%) confirmed once, or loss of MR4 (BCR-ABL1IS > 0.01%) confirmed on 2 consecutive assessments. The estimated molecular relapse-free survival rate was 16.7% at 12 months. This study was prematurely terminated according to the protocol’s safety monitoring criteria. The conclusion was that sustained DMR for just 1 year is insufficient for TFR in CML-CP patients receiving dasatinib for less than a total of 3 years of treatment.

Attenuated Dose Dasatinib in Newly Diagnosed Chronic Myeloid Leukemia Chronic Phase Patients in India.

BCR-ABL Tyrosine kinase inhibitors (TKI's) are most successful of targeted therapies and are currently considered the cornerstone in the management of patients with chronic myeloid leukemia (CML). A recent study reported excellent outcomes of Dasatinib 50mg with better sustained response. Therefore, we aim to evaluate the molecular responses and safety of upfront Dasatinib 50mg in Indian CML-Chronic Phase patients. It was an observational single-centre study. CML-CP patients started on Dasatinib 50mg daily were offered to participate in this study. Data of imatinib was collected retrospectively as a comparator group. Between June 2020 to Feb 2022, fifty patients were included in the dasatinib 50mg once daily group. Median age was 40 yrs. ranging from (19 to73) years. At a median follow up of 9.2 months, 49 patients completed three months treatment, out of which 48 patients were evaluated as one patient stopped medication after a month due to financial constraints. The response rate at three months for dasatinib 50mg daily and Imatinib were 68.75% and 69.7% respectively. At 12 months, 68% and 66.6% patients achieved major molecular response [MMR] in dasatinib 50mg and imatinib groups respectively. In conclusion, low dose dasatinib is safe and effective as an upfront therapy in CML-CP. Early molecular response [EMR] rates were comparable in low dose dasatinib and imatinib arm but deep molecular responses were significantly higher in low dose dasatinib arm. Dasatinib, taken daily at a dose of 50mg, may offer a new, alternative choice as generic versions are available now for frontline therapy in CML-CP.

A Systematic Review on Second Treatment-Free Remission (TFR) Attempt in Chronic Myeloid Leukemia (CML): Can it be Applied in Clinical Practice?

The prognosis and life expectancy of chronic myeloid leukemia (CML) patients have improved significantly with the launch of first tyrosine kinase inhibitor (TKI), imatinib. Maintaining at least one major molecular response in CML patients without the use of TKI is known as treatment-free remission (TFR). The safety of the first TFR (TFR1) effort has been reported by numerous studies. However, some patients relapse during TFR1. A second TFR (TFR2) can be tried again in those patients. This systematic review aims to evaluate individual patient characteristics for a TFR2, factors predicting successful TFR2, monitoring, consequences of the cessation of TKI, and studies about TFR2. We identified 5 studies related TFR2. The results showed that the first failed TKI discontinuation attempt is not an indicator of a second TKI discontinuation failure. TKIs could safely and successfully be discontinued for a second time in chronic phase CML patients despite a TFR1 failure. The most important factors for estimating TFR2 success are the speed of molecular relapse and the TKI-free duration after the first TKI discontinuation attempt. New trends in the management of CML patients are reducing the side effects of treatment, lessening the financial burden, and improving the quality of life of patients as CML has developed into a manageable chronic disease rather than an aggressive cancer. Although there are many studies and guidelines on TFR1, there are few studies on TFR2 and predictive factors. More data is still needed regarding TFR2 attempt in patients with CML.

Comparable Outcomes of Pre- Versus Post-Tyrosine Kinase Inhibitor Era Treatment in Chronic Myeloid Leukemia: A Retrospective Cohort Study With Long-term Follow-up

Imatinib, a selective BCR-ABL tyrosine kinase inhibitor (TKI), was introduced after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with chronic myeloid leukemia (CML). However, the long-term effects of allo-HSCT in chronic phase CML patients are mostly unknown. We retrospectively analyzed the outcomes of 204 patients with sibling donors who received peripheral stem cells and underwent allo-HSCT of chronic phase I (CP1) in the pre- and post-TKI era at Shariati Hospital in Tehran, Iran, from 1998 to 2017 and followed up till the end of 2021. The median follow-up time for all patients was 8.7 (SD = 0.54) years. Fifteen-year overall survival (OS), disease-free survival (DFS), graft-versus-host disease-free relapse-free survival (GRFS), relapse, and non-relapse mortality (NRM) incidence were 65.70%, 57.83%, 17.56%, 13.17%, and 28.98%, respectively. Using multivariable analyses, the only risk factor increasing the hazard of death was the time between diagnosis to allo-HSCT greater than 1 year compared to this time less than 1 year by 74% [hazard ratio (HR) = 1.74, P = 0.039]. Also, age is a significant risk factor for DFS (HR = 1.03, P = 0.031). Our findings suggested that allo-HSCT is still an important treatment option for CP1 patients, especially those resistant to TKI treatment. TKI consumption can have a desirable effect on NRM after allo-HSCT for CP1 CML.

Red blood cell distribution width at diagnosis as a predictor factor in chronic phase-chronic myeloid leukemia patients treated with first-generation tyrosine kinase inhibitors

BACKGROUND: Chronic myelogenous leukemia is a hematological disorder of stem cells resulting from uncontrolled and unregulated growth of myeloid cells in the bone marrow. Since the introduction of tyrosine kinase inhibitors (TKIs), therapy has dramatically improved survival in these patients. TKIs treatment targeting BCR-ABL significantly improves the prognosis of patients with chronic myelogenous leukemia. To date, the validity of scoring systems is insufficient for predicting prognosis, and there are few studies of scoring systems for predicting treatment response and clinical efficacy of TKIs. OBJECTIVES: The objective of this study was to evaluate the ability of the red blood cell distribution width (RDW) to predict treatment response in chronic myeloid leukemia-chronic phase (CP) patients treated with first-generation TKI. PATIENTS AND METHODS: A prospective and retroprospective cohort study was conducted on chronic myeloid leukemia-CP patients treated with first-generation TKI at Iraqi Hematological Centers. The collection period was from December 2020 to November 2021. Patients were treated with first-generation TKIs as initial therapy and were followed up to assess the response by polymerase chain reaction (PCR). The assessment of RDW was done at baseline and then at 3, 6, 12, and 18 months after initiation of therapy. RESULTS: There were 150 patients included in this study. The mean age of patients was 43.7 ± 14 years (range: 18–84 years). Males were representing 48.6% and females 51.3%. The classification of baseline RDW showed that the majority of patients (53%) had high RDW. The RDW showed significant change over time, in which, it was significantly decreasing over time (P &lt; 0.05). Association between PCR over time and baseline RDW category showed that the high baseline RDW was associated with higher mean PCR at 3, 6, 12, and 18 months (P &lt; 0.05). The correlation between RDW at baseline and PCR at 3, 6, 12, and 18 months showed that there was a significant positive weak correlation between baseline RDW and PCR at 6, 12, and 18 months. The association between baseline RDW and the response showed that high baseline RDW was associated with higher failure rate at 6 and 12 months (P &lt; 0.05). CONCLUSION: RDW could be used in the prediction of response to treatment. Furthermore, high RDW showed significant association with high disease activity score, high white blood cell count, and lower hemoglobin, in addition to association and correlation with PCR level.

Next-generation DNA sequencing identifies mutated FANCD2 Gene as a novel Biomarker for monitoring early disease progression and timely therapeutic interventions in advanced phase Chronic Myeloid Leukemia patients

Next-generation DNA sequencing identifies mutated FANCD2 Gene as a novel Biomarker for monitoring early disease progression and timely therapeutic interventions in advanced phase Chronic Myeloid Leukemia patients

Feasibility of treatment-free remission with generic imatinib: Results of generic imatinib-free trial-in-chronic myeloid leukaemia-chronic phase study.

Both innovator and generic imatinib are approved for the treatment of Chronic Myeloid Leukaemia-Chronic phase (CML-CP). Currently, there are no studies on the feasibility of treatment-free remission (TFR) with generic imatinib. This study attempted to determine the feasibility and efficacy of TFR in patients on generic Imatinib. In this single-centre prospective Generic Imatinib-Free Trial-in-CML-CP study, twenty six patients on generic imatinib for ≥3 yr and in sustained deep molecular response (BCR ABLIS ≤0.01% for more than two years) were included. After treatment discontinuation, patients were monitored with complete blood count and BCR ABLIS by real-time quantitative PCR monthly for one year and three monthly thereafter. Generic imatinib was restarted at single documented loss of major molecular response (BCR ABLIS>0.1%). At a median follow up of 33 months (interquartile range 18.7-35), 42.3 per cent patients (n=11) continued to be in TFR. Estimated TFR at one year was 44 per cent. All patients restarted on generic imatinib regained major molecular response. On multivariate analysis, attainment of molecularly undetectable leukaemia (>MR5) prior to TFR was predictive of TFR [P=0.022, HR 0.284 (0.096-0.837)]. The study adds to the growing literature that generic imatinib is effective and can be safely discontinued in CML-CP patients who are in deep molecular remission.

Therapy for patients with chronic phase-chronic myeloid leukemia previously treated with ⩾2 tyrosine kinase inhibitors: a systematic literature review.

ATP-competitive tyrosine kinase inhibitors (TKIs) are the current standard of care for patients with chronic phase-chronic myeloid leukemia (CP-CML) in the first-line and second-line (2 L) setting. Treatment after 2 L is not clearly established. The objective of this study was to summarize the available evidence to compare the efficacy and safety of interventions in the treatment of CP-CML patients who had received ⩾2 prior TKIs. A systematic literature review was performed. A systematic literature review (SLR) of studies published until May 2021, reporting clinical outcomes in adult patients with CP-CML who had received ⩾ 2 prior TKIs was performed. Studies were identified through the database searches via Ovid platform (Embase, MEDLINE Epub Ahead of Print, In-Process and Other Non-Indexed Citations, and Cochrane Central Register of Controlled Trials), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), bibliographic search of relevant reviews, and proceedings from the previous 3 years of the key conferences in the field of oncology. Our search identified 38 relevant studies. Among the identified studies of the current third-line treatments, the major molecular response (MMR) rate for ponatinib was 19.0-66.7%, 23.3-25.5% for asciminib, 19.2% for omacetaxine, and 13.2% for bosutinib at 6 months. The complete cytogenetic response (CCyR) rate was 21.4-64.8% for ponatinib, 38.7-40.8% for asciminib, 18-24.2% for bosutinib, and 16.1% for omacetaxine at 6 months. The findings from current SLR demonstrated the lack of data for patients with CML treated with ⩾2 TKIs. TKIs such as asciminib, ponatinib, and bosutinib are valid options for those patients. Further research is needed to identify the best treatment option for patients with CML receiving later lines of therapy.

Targeting BCR-ABL1-positive leukaemias: a review article.

Treatment and understanding of BCR::ABL1-positive leukaemias is a precision medicine success story. Our appreciation of the BCR::ABL1 gene and resulting BCR::ABL1 oncoprotein in chronic myeloid leukaemia (CML) and Philadelphia chromosome-positive (Ph+) acute leukaemias, has led to treatment advances associated with exceptional improvements in patient outcomes with normal life expectancy for many patients with chronic phase (CP-)CML. However, despite these major therapeutic advances, the management of Ph+ leukaemias remains complex, with development of specific resistance mutations on treatment, as well as the need for lifelong therapy in most patients due to the persistence of CML stem cells despite prolonged tyrosine kinase inhibitors (TKIs) treatment. BCR::ABL1-specific TKIs are associated with chronic toxicities affecting quality-of-life in many patients but can also result in more serious pulmonary and cardiovascular complications. Dose optimisation is increasingly being used to manage side effects and maintain molecular response in CML patients. Here, we review the development of BCR::ABL1-specific TKIs from the discovery of imatinib in 1996 to the more recent second- and third-generation TKIs and emerging specifically targeting the ABL myristoyl pocket (STAMP) inhibitors. We will also evaluate the current evidence for treatment of BCR::ABL1-positive leukaemias, including TKI discontinuation in optimally responding CP-CML patients.

The Role of Bosutinib in Chronic Myeloid Leukemia: An Indian Perspective

AbstractManagement of chronic myeloid leukemia (CML) has been transformed by the use of tyrosine kinase inhibitors (TKIs). Presently in India, five TKIs are approved for the management of CML with distinct safety profiles. The selection of TKIs for chronic phase (CP)-CML patients is based on treatment goals, underlying comorbidities, and specific TKI toxicity profiles. Bosutinib is one of five TKIs indicated for the first-line treatment of CP-CML and patients with intolerance or resistance to prior TKI therapy. It possesses a distinct safety profile among other TKIs, with less cardiovascular adverse events (AEs), albeit the liver-related and gastrointestinal AEs have higher occurrence. The safety and efficacy of bosutinib have been examined in clinical trials; however, there is a paucity of data from Asia. A virtual expert panel meeting was convened to gather expert opinion from India on the selection of bosutinib as a treatment choice for patients with CP-CML. This is a white paper document drafted with the help of an expert panel of 14 oncologists and hematooncologists from India on bosutinib use in CP-CML. The experts concurred that bosutinib has proven efficacy for CP-CML in global randomized clinical trials and is well suited for CP-CML patients with existing cardiovascular comorbidities. However, it was not recommended for patients with gastrointestinal, pancreatic, or renal abnormalities. This review aims to put forth expert opinion and guidance document on key considerations for CP-CML clinical decision-making in India.

Clinical outcomes of second-generation tyrosine kinase inhibitors versus imatinib in older patients with CML.

Age and comorbidities are important factors to be considered in the selection of tyrosine kinase inhibitors (TKIs) for first-line treatment in patients with chronic myeloid leukemia in chronic phase (CML-CP). However, it is yet unclear whether TKI selection, particularly, imatinib versus second-generation TKIs (2GTKIs), impacts treatment outcomes in the clinical practice. To address this, we compared the clinical outcomes of prospectively registered 452 patients with CML-CP treated with imatinib and 2GTKIs, taking into consideration their age and/or comorbidities. A total of 136 patients (30.1%) were classified into an older cohort (≥65 years) and 316 (69.9%) into a younger cohort (18-64 years). The TKI selection did not vary based on age (70.6% received 2GTKIs in the younger cohort and 66.2% in the older cohort). The median follow-up period was 5.4 years. Treatment responses including the cumulative incidence of deep molecular response (BCR-ABL1 international scale ≤0.0032%) at any time were similar between the two age cohorts regardless of the type of TKI. The 5-year overall survival (OS) in the older cohort was lower than that in the younger cohort (95.9% vs 83.8%; p < 0.0001), whereas the 5-year OS in patients treated with 2GTKIs was not influenced by age factors and comorbidities. Therefore, our results suggest that the selection of 2GTKIs as first-line treatment is an effective option for both younger and older CML-CP patients with or without comorbidities. This trial was registered at UMIN-CTR as 00003581.

Discontinuation of Tyrosine Kinase Inhibitor Therapy and Treatment-Free Remission in Chronic-Phase Chronic Myeloid Leukemia: An Observational Retrospective Multi-Center Study

Introduction: Discontinuation of tyrosine kinase inhibitor (TKI) therapy and achievement of treatment-free remission (TFR) in chronic-phase chronic myeloid leukemia (CP-CML) patients is feasible and can be implemented in clinical practice. We conducted a retrospective study at 3 tertiary care centers in Riyadh, Saudi Arabia of all CP-CML patients who discontinued TKI therapy. Methods: All CP-CML patients being followed at participating centers who discontinued TKI, were eligible. TKI discontinuation was carried out as per clinical practice guidelines. Criterion to restart TKI therapy in relapsed patients was loss of major molecular response (MMR; BCR-ABL > 0.1). We collected data on gender, age, prognostic risk-score, type(s) of TKI therapy, type and duration of last TKI before discontinuation, total duration of TKI therapy and response, time to achieve MMR, relapse data including time to relapse and response to re-initiation of TKI therapy, and analyzed the risk factors for relapse. Study was approved by the institutional review boards of all participating centers. Results: Fifty-five patients (35 females) with a median age of 40 years (range 16-74) were included in the study. Median age at TKI stop was 48 years (range 21-80). Majority of the patients (48; 87.27%) received imatinib as first line therapy; 29 (53.74) patients were receiving imatinib at TKI-stop, and 26 (47.27) a second-generation TKI (dasatinib or nilotinib). Fifty-two (94.5%) patients discontinued TKI as per clinical practice (shared decision between treating physician and the patient), and 3 (5.5%) stopped because of pregnancy; 2 patients fulfilled the criteria to stop post-delivery as they remained in deep MR, they were offered to continue stopping. One patient refused to restart TKI (dasatinib) after delivery although she had only 24 months of deep response but continues to have deep remission after 91 months of follow up. Median time to achieve MMR after diagnosis was 12 (range 2-164) months. All the patients had achieved MR4.5 or better (complete molecular response) before stop. Median time from diagnosis to TKI stop was 86 months (IQR 60;132) and median time of last TKI before stop was 66 months (IQR 47;114). After a median follow up of 42 months (IQR 12.5;69) post TKI-discontinuation, 15 (28%) patients relapsed. Median time to relapse was 5 months (range 3-38). Most of the relapses occurred during the first 6 months, except 3 patients who relapsed after 10, 11, and 38 months. Most of the relapsed patients had intermediate or high risk Sokal score. All the relapsed patients achieved MMR after a median of 3 months (range 2-6) after restarting TKI. None of the patients progressed to advanced phase. Conclusion: In real-life practice, TKI discontinuation was possible without relapse for CP-CML patients in deep molecular response, with over two-third of patients continuing in TFR. Majority of the relapsed patients belonged to the intermediate/high-risk score Sokal category at diagnosis. Although this study has the limitation of a retrospective study, our experience in this population confirms that discontinuation of TKI therapy in CP-CML patients is feasible and safe in clinical practice.