Management Of Chronic Myeloid Leukemia Research Articles

Computer-aided drug discovery of c-Abl kinase inhibitors from plant compounds against chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a hematological malignancy characterized by the neoplastic transformation of hematopoietic stem cells, driven by the Philadelphia (Ph) chromosome resulting from a translocation between chromosomes 9 and 22. This Ph chromosome harbors the breakpoint cluster region (BCR) and the Abelson (ABL) oncogene (BCR-ABL1) which have a constitutive tyrosine kinase activity. However, the tyrosine kinase activity of BCR-ABL1 have been identified as a key player in CML initiation and maintenance through c-Abl kinase. Despite advancements in tyrosine kinase inhibitors, challenges such as efficacy, safety concerns, and recurring drug resistance persist. This study aims to discover potential c-Abl kinase inhibitors from plant compounds with anti-leukemic properties, employing drug-likeness assessment, molecular docking, in silico pharmacokinetics (ADMET) screening, density function theory (DFT), and molecular dynamics simulations (MDS). Out of 58 screened compounds for drug-likeness, 44 were docked against c-Abl kinase. The top hit compound (isovitexin) and nilotinib (control drug) were subjected to rigorous analyses, including ADMET profiling, DFT evaluation, and MDS for 100 ns. Isovitexin demonstrated a notable binding affinity (-15.492 kcal/mol), closely comparable to nilotinib (-16.826 kcal/mol), showcasing a similar binding pose and superior structural stability and reactivity. While these findings suggest isovitexin as a potential c-Abl kinase inhibitor, further validation through urgent in vitro and in vivo experiments is imperative. This research holds promise for providing an alternative avenue to address existing CML treatment and management challenges. Communicated by Ramaswamy H. Sarma

Comorbidities and outcomes of patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a real-world, nationwide, retrospective study from Hungary.

Purpose: This study aimed to provide real-world evidence on the characteristics, treatment patterns, and outcomes of patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitor (TKI) treatment in Hungary between 2011 and 2019. Patients and methods: This nationwide, retrospective study included patients who were newly diagnosed with CML in Hungarian clinical practice between January 2011 and December 2019. The analysis was based on the reimbursed prescription claims for imatinib, bosutinib, dasatinib, nilotinib, or ponatinib with the ICD-10 code C9210 in a public pharmacy between January 2009 and December 2019 using data from the National Health Insurance Fund (NHIF) of Hungary. CML incidence and prevalence, TKI treatment patterns, comorbidities, and overall survival (OS) were examined. Results: Between 2011 and 2019, altogether 1,407 patients were diagnosed with CML, with an annual average of 156 patients. The number of patients newly initiating first-line TKI therapy for CML significantly increased between 2011 and 2019 (2011: n = 136 vs. 2019: n = 191; p = 0.0043). Nilotinib was typically prescribed for younger patients (≤64years), while older patients (≥65years) mostly received imatinib. The most common comorbidity of CML patients was hypertension, and the proportion of patients with other malignancies was relatively high in all treatment groups. 5-year OS was 77.1% during the whole study period. Patients initiating first-line TKI treatment for CML in 2015 had significantly better 4-year OS compared to those starting treatment in 2011 (82.4% vs. 73.5%, respectively, (HR 0.53 (95%CI 0.32-0.87) p = 0.0118). Conclusion: This study is the first to provide insights into the characteristics, treatment patterns, and outcomes of CML patients treated with TKIs in Hungarian clinical practice between 2011 and 2019. We found slightly lower OS rates compared to other European countries, however, there was a statistically significant improvement in 4-year OS during the study period. The management of CML was in line with international guidelines and recommendations.

Male Fertility and Fatherhood in Chronic Myeloid Leukemia: Current Understanding and Future Perspectives.

Chronic myeloid leukemia (CML), while traditionally a disease of the elderly, has recently risen in incidence among younger patients. Hence, fertility concerns have emerged considering the disease process and treatments, especially with the current scarce and conflicting recommendations. This review explores the impact of CML treatments including the first-line tyrosine kinase inhibitors (TKIs) and other treatments on male fertility in chronic myeloid leukemia (CML) patients. The aim of this review was to compile the available evidence on male fertility to ultimately tailor treatment plans for male CML patients for whom fertility and future chances for conception pose a concern. The data available on the conventional and newer TKIs to address fertility concerns were reviewed, particularly the potential long- and short-term effects. Also, the possible side effects on subsequent generations were a crucial focus point of this review to reach a more comprehensive CML management approach. We found and compared the evidence on TKIs approved to treat CML. We also reported the effects of hydroxyurea, interferon, and transplantation, which are considered second-line treatments. Our findings suggest that these drugs might have an undiscovered effect on fertility. More research with larger sample sizes and longer follow-up periods is essential to solidify our understanding of these effects.

Frequencies of BCR::ABL1 Transcripts in Patients with Chronic Myeloid Leukemia: A Meta-Analysis.

Chronic myeloid leukemia (CML) is associated with the Philadelphia chromosome and distinct BCR::ABL1 gene transcripts. We assessed the frequencies of these transcripts in Mexico, Latin America, and worldwide. We determined the prevalence of BCR::ABL1 transcripts in CML patients and intercontinental or regional variations using specialized databases and keywords. We analyzed 34 studies from 20 countries, encompassing 5795 patients. Keyword-based searches in specialized databases guided data collection. ANOVA was employed for transcript distribution analysis. The b3a2 transcript was most prevalent globally, followed by b2a2, with e1a2 being the least frequent. Interestingly, Mexico City exhibited a higher incidence of b2a2, while b3a2 predominated in the remaining country. Overall, no significant intercontinental or regional variations were observed. b3a2 was the most common BCR::ABL1 transcript worldwide, with b2a2 following closely; e1a2 was infrequent. Notably, this trend remained consistent in Mexico. Evaluating transcript frequencies holds clinical relevance for CML management. Understanding the frequency of transcript informs personalized CML treatments.

Beyond BCR::ABL1-The Role of Genomic Analyses in the Management of CML.

Chronic myeloid leukemia (CML) is a model of genomically based diagnosis and management where BCR::ABL1 is successfully targeted by tyrosine kinase inhibitor (TKI) therapy in most patients. The dynamics of BCR::ABL1 transcript decline during therapy is a dependable biomarker of response, relapse, and drug resistance. Missense mutations acquired within the BCR::ABL1 kinase domain that disrupt TKI binding can evolve during therapy and are frequently detected in patients for whom TKI treatment fails. Importantly, specific BCR::ABL1 missense mutations are targetable alterations and direct therapeutic decisions based on the individual mutant TKI sensitivity profile. Nevertheless, BCR::ABL1 mutations are only implicated in approximately half of the cases of acquired resistance. Furthermore, not all patients with a single BCR::ABL1 mutation that is predicted to be sensitive to a specific TKI will experience a response when switched to that TKI. Progression to blast phase heralds independence from BCR::ABL1, and this phase of the disease is notoriously difficult to treat. The independent drivers of resistance and disease progression have long been investigated to both predict progression and to find targets for therapeutic intervention. Recent data reaffirm that drug resistance and disease progression is a mutation-driven process in CML, and somatic variants in genes that are known to drive acute myeloid and lymphoid leukemia have been detected in patients in the advanced phases of CML. Genomic testing over the last few decades for patients with blood cancer has revealed of variety of genomic aberrations that drive disease. Consequently, incorporation of genomic factors into patient management for a range of blood cancers has led to the implementation of high-throughput gene testing to detect clinically actionable variants. Is it time to integrate broader genomic screening into clinical management strategies for patients with CML?

Mechanisms underlying therapeutic resistance of tyrosine kinase inhibitors in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a malignant clonal disease involving hematopoietic stem cells that is characterized by myeloid cell proliferation in bone marrow and peripheral blood, and the presence of the Philadelphia (Ph) chromosome with BCR-ABL fusion gene. Treatment of CML has dramatically improved since the advent of tyrosine kinase inhibitors (TKI). However, there are a small subset of CML patients who develop resistance to TKI. Mutations in the ABL kinase domain (KD) are currently recognized as the leading cause of TKI resistance in CML. In this review, we discuss the concept of resistance and summarize recent advances exploring the mechanisms underlying CML resistance. Overcoming TKI resistance appears to be the most successful approach to reduce the burden of leukemia and enhance cures for CML. Advances in new strategies to combat drug resistance may rapidly change the management of TKI-resistant CML and expand the prospects for available therapies.

Accelerated-phase CML: de novo and transformed.

Despite the dramatic improvements in outcomes for the majority of chronic myeloid leukemia (CML) patients over the past 2 decades, a similar improvement has not been observed in the more advanced stages of the disease. Blast phase CML (BP-CML), although infrequent, remains poorly understood and inadequately treated. Consequently, the key initial goal of therapy in a newly diagnosed patient with chronic phase CML continues to be prevention of disease progression. Advances in genomic investigation in CML, specifically related to BP-CML, clearly demonstrate we have only scratched the surface in our understanding of the disease biology, a prerequisite to devising more targeted and effective therapeutic approaches to prevention and treatment. Importantly, the introduction of the concept of "CML-like" acute lymphoblastic leukemia (ALL) has the potential to simplify the differentiation between BCR::ABL1-positive ALL from de novo lymphoid BP-CML, optimizing monitoring and therapeutics. The development of novel treatment strategies such as the MATCHPOINT approach for BP-CML, utilizing combination chemotherapy with fludarabine, cytarabine, and idarubicin in addition to dose-modified ponatinib, may also be an important step in improving treatment outcomes. However, identifying patients who are high risk of transformation remains a challenge, and the recent 2022 updates to the international guidelines may add further confusion to this area. Further work is required to clarify the identification and treatment strategy for the patients who require a more aggressive approach than standard chronic phase CML management.

3-YEARS and Beyond Study Completion Results of the Otpkima Randomized Clinical Trial in Elderly CML Patients

The goal of Treatment Free Remission (TFR) is achievable in no more than 25-30% of patients with Ph+ Chronic Myeloid Leukemia (CML) treated with Tyrosine Kinase Inhibitors (TKIs). Thus, for the great majority of patients, particularly for the elderly, the options are to continue TKI therapy life-long or to enter an intermittent TKI administration, as previously published ( Russo D et al, Blood 2013; Russo et al Blood Adv 2015). The probability of major molecular response (MMR or MR3.0) maintenance while on intermittent 1 month on/1 month off TKI at 1 year is 80%, as reported recently in the first interime analysis of the Italian prospective randomized OPTkIMA trial (Malagola M et al, Cancer Med 2021). This is the second interim report of OPTkIMA trial, in which elderly patients with Ph+ CML in sustained (≥ 2 years) confirmed major molecular response (MMR or MR3.0) or deep molecular response (MR4.0 or deeper) were randomly assigned to receive a FIXED intermittent schedule (1 month on/1 month off) vs a PROGRESSIVE intermittent schedule (1 month on/1 month off for the 1 st year, 1 month on/2 months off for the 2 nd year, 1 month on/3 months off for the 3 rd year). After the 3 rd year, clinicians were free to decide if maintain the intermittent schedule, discontinue TKI or resume TKI daily ( Malagola M et al, Cancer Med 2021). At last follow up, 203 patients are evaluable after randomization (104 FIXED vs 99 PROGRESSIVE). At 3 rd year (end of study protocol), by intention to treat, 28/104 (27%) and 45/99 (45%) patients discontinued OPTkIMA because of MR3.0 loss in the FIXED vs PROGRESSIVE arm, respectively (p=0.005). The percentages of patients who discontinued OPTkIMA because of MR3.0 loss at 1 st, 2 nd and 3 rd year in the FIXED vs PROGRESSIVE arm were: 24% in both arms (p=0.97), 1% vs 22% (p=0.001) and 3% vs 15% (p=0.01), respectively (Figure 1). The probability of survival without MR3.0 loss at 1, 2 and 3 years in the FIXED vs PROGRESSIVE arm were: 81%, 69% and 66% vs 81%, 59% and 53%, respectively (Figure 2; p=0.13). None of the patients who lost MR3.0 progressed to accelerated or blastic phase (AP/BP) and all of the patients regained the MR3.0 after continuous TKI resumption within 9 months. At the end of the 3 rd year from randomization, 61/104 (59%) and 36/99 (36%) patients were in MR3.0 or deeper response in the FIXED vs PROGRESSIVE arm, respectively (p=0.001). For these patients, comparing the two arms, Clinicians' choice was to maintain the ongoing intermittent schedule in 46% vs 28% of the cases (p=0.01), discontinue TKI with the goal of TFR in 36% vs 58% (p=0.03), and resume the TKI continuously in 18% vs 14% of the patients (p=0.59). The results of the OPTkIMA trial clearly confirm that a policy of intermittent TKI administration in elderly patients with Ph+ CML in MR3.0 or deeper response is safe, as no progression to AP/BP was observed. Furthermore, the great majority of protocol discontinuation for MR3.0 loss were recorded in the 1 st year (one month on and one month off in both arms). Then the cumulative incidence of patients who lost MR3.0 beyond the 1 st year was significantly higher in the PROGRESSIVE arm with a trend towards a higher probability of survival without MR3.0 loss in the FIXED arm (Figure 1). Finally, at the end of the study protocol (3 rd year), patients in MR3.0 or deeper response after a FIXED intermittent schedule were more likely addressed to maintain the same program, whereas patients included in the PROGRESSIVE arm were more frequently discontinued with the goal of TFR. This last observation represents a “real-life” CML management by Clinicians. It suggests that after a PROGRESSIVE intermittent therapy, patients were considered at high probability to safely maintain the TFR.

To Study Outcomes in Young CML Treated with TKI. a Registry Data from Hematological Cancer Consortium (HCC) of India

Background: Chronic Myeloid Leukemia (CML) is a hematological malignancy characterized by the abnormal proliferation of white blood cells. While CML is primarily a disease of middle and old age, a significant proportion of cases are diagnosed in adolescents and young adults. The incidence of CML in India is relatively low (0.53 to 0.71 / 100,000), but the country's large population means that even a small increase in incidence can translate to a significant disease burden. The prognosis of CML has improved dramatically with the advent of tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib, and nilotinib, which have transformed CML from a fatal disease to a chronic, manageable condition. However, the optimal management of CML in adolescents and young adults (AYA) is still a matter of debate, and there is limited data on the outcome of this disease in this age group in India. Hematology Cancer Consortium (HCC) is a group of premier hematology and oncology institutes from India created for collecting and collating data of various hematologic malignancies in a central online data management system. Design and methods: Retrospective data from 01 Jan 2020 to 01 June 2022, of all CML patients treated with TKI at 11 member institutions of HCC were analysed. The cohort was divided into AYA (15 to 29 years) and others ( 30 years or more). The objective of this study was to determine the disease outcome of adolescents and young adults (AYA) with CML in India as measured by event free survival (EFS), overall survival (OS) and transformation free survival (TFS) . Events were defined as death from any cause, progression to accelerated phase (AP) or blast crisis (BC) and change to second generation TKI from imatinib while on therapy. We also compared the outcome of AYA with others. Results: Total of 1070 patients diagnosed with CML were included in the study. The patients of age group 15-29 years were 273/1070 (25.5%). Most were in chronic phase (249/273, 95.04%). The low-risk CML cases by Sokal score were 61 (26.75%) cases in 15-29 years age group in comparison to 69 (11.11%) cases in the older group and the difference was statistically significant (p<0.001).Low-risk cases by ELTS and EUTO score were seen in 32.51% and 61.30% cases in 15-29 years age group and it was comparable to other group (24.9 % and 62.1%). The type of transcript were P210 in 202 (97.58%) cases in AYA group. Spleen size, hemoglobin, WBC, Platelet, blasts (%), quantitative BCR ABL (%) were comparable in both the groups. Imatinib was used as first TKI in 193 (71.75%) cases. Significantly more number of patients in AYA group were treated upfront with second generation TKI (28.2%) in comparison to others (23.3%) (p= 0.02). The median doses missed by patients in 15-29 years group during first 03 months were 5, while in other group it was 13 and it was statistically significant (p=0.002). Median duration of therapy was 13 (0-28) months in AYA and 12 (0-38) months in other group. Progression to blast crisis was seen in 3/273 (0.01%) patients in the AYA group. While OS and transformation free survival were comparable in both groups, event free survival (EFS) was significantly better in AYA group (Fig-1A-B). Conclusion: While the AYA group had a significantly less low risk cases by Sokal score, more numbers were treated upfront with second generation TKI. EFS was significantly better in AYA group. Major shortcoming of this registry data is short follow up duration and very less number of evaluable patients for assessing molecular and cytogenetic response.

Prospective Assessment of Co-Morbidities and Framingham Risk Score in Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients and Its Impact on Clinical Outcomes Following Frontline TKI Therapy: Toronto CML Genomic Alliance in Greater Toronto Area & Ontario (TCGA-GTA)

Introduction Front-line (1L) tyrosine kinase inhibitor (TKI) drug selection is a pearl of clinical practice in CML. It requires consideration of multiple aspects including the goal of therapy, potency of the drug as well as comorbidity of the patient (pt). Contemporary CML practice emphasizes the importance of comorbidity for TKI selection. However, such data is scarce particularly the prevalence of comorbidity and its impact on 1L drug selection. We are developing a shared care model with community hematologists in Greater Toronto Area (TCGA-GTA). Newly diagnosed CML pts in the community will be referred to the study core center for prospective enrolment into the CML registry, informed consenting for genetic testing/future research, and evaluation of baseline comorbidity. Pt will return to referring hematologists for management of CML, including 1L TKI treatment as per standard of care, and is scheduled to visit the study center at 6 and 12 months, then annually for 10 years. It gives us a unique opportunity to evaluate the impact of comorbidity on 1L TKI drug selection. Patients and method Adult pts with newly diagnosed CML of any phase within 2 months of diagnosis are eligible for the study unless they are not able to visit study core center. Comorbidities and Framingham risk score (FRS) were assessed at the time of initial evaluation. Mutation profile testing is done by a bar-coded error-corrected sequencing platform for 40 genes developed at the Ontario Institute for Cancer Research. Cumulative incidence of molecular response with 2 log (MR2), 3 log (MR3), 4 log reduction or deeper (MR4), and treatment failure (TF) were calculated using cumulative incidence method considering competing risk. Event-free survival (EFS) was defined as time from start of TKI until TKI stop/switch, TF or death. Failure-free survival (FFS) was defined as time from start of TKI to TF [primary resistance, loss of complete cytogenetic response, new additional cytogenetic abnormalities (ACAs), and progression to accelerated or blasts phase (AP/BP)] or death. Results From November 2020 until June 31, 2023 (data cutoff), a total of 77 pts were enrolled in the study. The median follow-up time was 12 months. The frequency of 1L TKI selection was as follows: IMATINIB (IM) (n=23, 30%), DASATINIB (n=25, 32%), NILOTINIB (n=22, 29%), BOSUTINIB (n=1, 1%), ASCIMINIB (n=6, 8%). Majority of the pts were male (n=51, 66%). Ninety-three percent of pts were in chronic phase at diagnosis, while 4% and 3% were in AP and BP, respectively. Presence of ACAs was detected in 18 pts (23%), 10 of which were high risk, while 6% (n=5) were not evaluable. The baseline clinical and disease characteristics of pts on 1L IM vs other TKIs (2G-TKI) are summarised in Table 1. Of note, pts on IM were significantly older with higher FRS and comorbidities, including coronary artery disease, diabetes mellitus, and hypertension. The OS of all pts at 1 year was 98.5% (95% confidence interval 90%-99.8%). At 1 year, pts with intermediate to high risk FRS had lower FFS (73.2% vs 86.5%, p=0.037) while history of hyperlipidemia was associated with lower EFS (59.3% vs 81.5%, p=0.023) and 6 times more likely to stop or switch therapy due to intolerance or resistance (HR 5.9, p=0.002). Baseline comorbidities did not demonstrate signifincant impact on MR2 and MR3 at 1 year but pts with low FRS were more likely to achieve MR4 within 1 year (22.3% vs 0%, p=0.023). Age did not affect any of the clinical and molecular endpoints. Compared to 2G-TKI, IM had worse EFS (HR 3.93, p=0.003), FFS (HR 5.66, p=0.011), and MR2 (47.3% vs 84.4%, p=0.003) at 1 year. Further, IM pts experienced higher rate of any side effects compared to those on 2G-TKI (69.6% vs 31.5%, p=0.003). Conclusion The TCGA-GTA study provides valuable insights into the impact of comorbidity on selection of 1L TKI and its outcome in a real-world setting. Pts who are older and with higher FRS and comorbidities tend to receive 1L IM. However, pts on 1L 2G TKIs are more likely to reach treatment goals faster with lower probability of TF. The present study did not reach a clear conclusion whether the worse outcomes in the pts receiving IM are from IM treatment or concurrent risk factors such as age and comorbidities, thus further study with an expanded cohort and longer follow-up is required. Elderly pts or those with comorbidities would need alternative treatment with better efficacy and tolerability, such as Asciminib, that can overcome comorbidity issues in the future.

On the Children Side. Overview of 194 Outcomes from Gimema Registry of Conception/Pregnancy in Chronic Myeloid Leukemia (CML)

Pregnancy in patients with chronic myeloid leukemia (CML) is no longer precluded. The literature published to date has mainly evaluated the management of CML and pregnancy with little mention of follow-up of children. This work aims to focus on the effects of the disease and of the drugs taken before conception and/or during pregnancy on fertility, gestation, pre-natal development of the fetus, and the growth of the child. GIMEMA has promoted an observational retrospective/prospective study to harvest and study detailed information on both pregnancies in female CML patients and pregnancies of partners of male patients followed at participating centers. The information requested addressed information on demographic, CML- related (CML therapy before/during/after pregnancy; transcript kinetics; outcome post delivery), pregnancy-related (type of conception; abortion rate; pregnancy progression, delivery, breastfeeding), and baby-related (birth, physical, intellectual, emotional, behavioral, social and sexual development) Data from 83 male patients (109 pregnancies) and 74 female patients (84 pregnancies) were evaluated for a total of 193 pregnancies at term. Fourteen (7 female and 7 male) conceptions were medically assisted, all the others spontaneous. One hundred ninety-four children were born (a twin pregnancy), 15 abortions were registered, 12 spontaneous and 3 voluntary all within the first trimester, while one pregnancy is still in progress. Eleven patients (1 male, 10 female) were diagnosed as having CML during pregnancy. Three patients interrupted pregnancy (2 electives). All male patients, with the exception of two (one undergoing assisted reproduction and one in TFR), conceived during treatment. TKI used were Imatinib (71%), Nilotinib (22%), Dasatinib (2%), Bosutinib (4%) and Ponatinib (1%). The pregnancies carried out by the partners of the male patients did not show any problems, neither pre-conception, nor during gestation, nor at birth. An initial speech delay in a child was reported, with recovery after speech therapy. Most pregnancies result in spontaneous delivery around the 39th week of gestation. Ninety-two/109 babies were breastfed (84%) The last TKI used in the female CML group was imatinib (43%), nilotinib (33%), dasatinib (22%), and Ponatinib (2%). Most patients stopped TKI at the FPT “first pregnancy test” (3-5 weeks). Cesarean deliveries amounted to 41%, just above the national average of 30%, with a mean of 38 weeks of gestation. Of the 84 babies born to women diagnosed with CML, only 20 were breastfed (23%). Three patients treated with IFN at the time of delivery breastfed for about a month, while one breastfed for 9 months and did not resume TKI as she was well-controlled by IFN and eager to start a new pregnancy. The lack of assimilation of IFN through breast milk orally does not contraindicate breastfeeding. In female patients, out of 84 pregnancies, and 1 in progress, 15 required antileukemic therapy during pregnancy. IFN was administered in 13 gestations, and also during organogenesis. In one case the patient introduced IFN at 7 weeks, then stopped due to poor disease control and started Nilotinib at 21 weeks, after placenta formation. In 2 gestations (including the one mentioned above) the patients took nilotinib (starting at 21 and 23 week of gestation). One patient was treated with imatinib at 20 week. The evaluation of the pediatric population under examination was divided into four age groups: 0-3 years for the evaluation of birth and psycho-physical development; 3-6 years for cognitive development; >6 years for socialization and interaction with the surrounding environment, including school performance; >12 years for sexual and hormonal development. Five infants were small for date. Of those, only one was exposed to imatinib from the 20th week of gestation. (Table 1). All children presented a rapid recovery after birth and their development is comparable to that of children belonging to the same age group. The oldest child is 15 years old, and was born at 39 weeks to a father on TFR after suspension of imatinib therapy; the youngest is a 15 days old girl, born at 38 week to a mother treated with IFN during pregnancy. From the results obtained from the study, children born to parents diagnosed with CML do not appear to show any difference compared to their peers in the general population, even if exposed to therapy in the prenatal period.

The Success of Treatment Free Remission in Chronic Myeloid Leukaemia in Clinical Practice: A Single-Centre Retrospective Experience from South Africa.

Chronic myeloid leukaemia (CML) management has evolved from a disease once considered to be incurable just over 2 decades ago to that of one of a "functional cure" as defined by the sustained molecular response on stopping tyrosine kinase inhibitor(TKI) therapy. The next goal of CML management has been treatment-free remission (TFR). The past 4 years have seen much international data on TFR attempts in CML in clinical practice. However, Africa as a continent has lagged behind the rest of the world, in keeping up with the latest trends in CML management, and so this study aims to address this gap by assessing the outcome of TFR in CML in a single centre in South Africa (SA). We conducted a retrospective cohort study in 12 CML patients in the chronic phase to assess the success of TKI discontinuation. The patients were treated in King Edward VIII Hospital (KEH), a tertiary, academic hospital in KwaZulu-Natal, South Africa, and the study period was from June 2020 to May 2022. Patients included had to have been on TKI therapy for a minimum of 5 years and achieved a deep molecular response (DMR) for a minimum period of 3 years. The overall TFR cohort showed a success rate of 75% at a median follow-up of 12 months. All patients who failed TFR, defined as a loss of major molecular remission (MMR), failed within 6 months of stopping TKI therapy. All patients who failed TFR regained DMR after retreatment with TKI, with no disease progression reported. The only factor influencing the success of TFR was the total period of TKI therapy. Despite our study having a small cohort of patients, this study demonstrated that TFR in CML is an attainable goal, even in a resource-limited setting.

Summary of Tyrosine Kinase STI-571 in the Treatment of Chronic Myeloid Leukemia

Chronic Myeloid Leukemia (CML) is a hematological malignancy characterized by the presence of the Philadelphia chromosome, which results in the formation of the BCR-ABL fusion protein with constitutive tyrosine kinase activity. The discovery and development of targeted therapies, such as the tyrosine kinase inhibitor STI-571 (Imatinib), revolutionized the treatment of CML by specifically inhibiting the BCR-ABL kinase activity. This abstract provides a summary of the therapeutic efficacy and clinical impact of STI-571 in the management of CML.Sti-571, a specific tyrosine kinase inhibitor, is a novel antitumor drug that has entered clinical trials and can effectively treat chronic myeloid leukemia caused by abnormal proliferation of hematopoietic stem cells. In this paper, the mechanism of action and regulation of cell cycle of this drug were summarized, and the problems of drug resistance were explored in depth and the development prospects of this drug were briefly introduced. The introduction of STI-571 has dramatically changed the management of CML, leading to a paradigm shift from conventional chemotherapy and allogeneic stem cell transplantation as the primary treatment options. The drug has shown superior efficacy compared to interferon-alpha therapy, the standard treatment before its introduction. STI-571 is generally well-tolerated, with fewer severe adverse effects, making it an attractive option for long-term therapy. Resistance to STI-571 has been observed in a subset of patients, primarily due to the emergence of BCR-ABL kinase domain mutations. However, the development of second-generation tyrosine kinase inhibitors, such as dasatinib and nilotinib, has provided alternative treatment options for patients who fail to respond to or develop resistance to STI-571.

Real-world Management of CML: Outcomes and Treatment Patterns.

Chronic myeloid leukemia (CML) is a disease that previously signified a poor prognosis, but treatment options and outcomes have improved over the last several decades. Despite this, challenges remain in optimal management in clinical practice, as the characteristics in trial populations differ from patients who are treated in a real-world setting. This review describes recent updates in real-world treatment patterns and outcomes in patients with CML. Several analyses describing real-world practice patterns show that tyrosine kinase inhibitors (TKIs) are the most commonly prescribed agents in multiple lines of therapy. First-generation (1G) and second-generation (2G) TKIs are the most commonly prescribed, even in the third line and beyond. Third-generation (3G) TKIs are typically utilized in patients with resistant disease who are younger with fewer comorbidities. Hematopoietic stem cell transplant (HSCT) is utilized significantly less, given other treatment options available. The goals of treatment with CML have shifted to quality of life, cost savings, and treatment-free response (TFR). Despite clear guidelines for attempting TFR, discontinuation practice patterns remain inconsistent. TKIs are the mainstay of CML treatment, including those in later lines of therapy. In real-world practice, several challenges still remain with regard to optimal management. Specifically, ideal sequencing of treatments, side effect profiles of tyrosine kinase inhibitors (TKIs), current role and timing of transplant, and adherence to recommendations for attempting to achieve a treatment-free response (TFR). A national registry could characterize these practice patterns in order to find ways to optimize care for CML patients.

Older patients with chronic myeloid leukemia face suboptimal molecular testing and tyrosine kinase inhibitor adherence.

Tyrosine kinase inhibitor (TKI) use is critical in the care of patients with chronic myeloid leukemia (CML). Quantitative polymerase chain reaction (qPCR) testing for BCR-ABL1 every 3months during the first year of TKI treatment is recommended to assure achievement of milestone response goals. Real-world evidence for the patterns of qPCR monitoring and TKI adherence in the older patient population is lacking. Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified 1192 patients aged ≥66 years (median age, 74 years) with newly diagnosed CML who were followed up for ≥13months from TKI initiation. In total, 965 patients (81.0%) had ≥1 test, with 425 (35.7%) and 540 (45.3%) of the patients tested during 1, 2, and ≥3 quarters (optimal monitoring) of the first year from TKI initiation, respectively. In multivariable analysis, diagnosis in later years and influenza vaccination before diagnosis, a proxy for health care access, were associated with optimal qPCR monitoring. Use of low-income subsidy and residing in census tracts with the lowest socioeconomic status were associated with less optimal monitoring. Patients with optimal monitoring were 60% more likely to be TKI adherent (odds ratio, 1.60; 95%CI, 1.11-2.31; P= .01) and had improved 5-year survival (hazard ratio, 0.66; 95%CI, 0.49-0.90; P< .01) than those without such monitoring. In this large, real-world study of CML management patterns, many older patients had suboptimal molecular monitoring, which was associated with decreased TKI adherence and worse survival.

Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights.

The introduction of tyrosine kinase inhibitors (TKIs) has changed the treatment paradigm of chronic myeloid leukemia (CML), leading to a dramatic improvement of the outcome of CML patients, who now have a nearly normal life expectancy and, in some selected cases, the possibility of aiming for the more ambitious goal of treatment-free remission (TFR). However, the minority of patients who fail treatment and progress from chronic phase (CP) to accelerated phase (AP) and blast phase (BP) still have a relatively poor prognosis. The identification of predictive elements enabling a prompt recognition of patients at higher risk of progression still remains among the priorities in the field of CML management. Currently, the baseline risk is assessed using simple clinical and hematologic parameters, other than evaluating the presence of additional chromosomal abnormalities (ACAs), especially those at "high-risk". Beyond the onset, a re-evaluation of the risk status is mandatory, monitoring the response to TKI treatment. Moreover, novel critical insights are emerging into the role of genomic factors, present at diagnosis or evolving on therapy. This review presents the current knowledge regarding prognostic factors in CML and their potential role for an improved risk classification and a subsequent enhancement of therapeutic decisions and disease management.

Fertility and pregnancy in chronic myeloid leukemia: real-world experience from an Indian tertiary care institution.

Chronic myeloid leukemia (CML) management during pregnancy is challenging. In this retrospective study, hospital records of CML patients treated between 2000 and 2021 were screened to identify patients who tried to conceive/got pregnant (planned and unplanned) on TKIs (tyrosine kinase inhibitors)/were pregnant at CML onset/fathered a child. We found ninety-three pregnancies involving thirty-three women and thirty-eight men, and they were analyzed for the pregnancy outcomes and the strategies utilized for CML management during pregnancy and the pre-conception period. There were two women and four men with primary infertility and five women with secondary infertility. TKIs were discontinued before conception in four planned pregnancies and at the time of recognition of pregnancy in unplanned pregnancies (n = 21). Unplanned pregnancy outcomes were two miscarriages, eight elective terminations, and eleven live births. Planned pregnancies led to four healthy babies. Outcomes of pregnancies at CML onset (n = 17) were six live births, one stillbirth, five elective terminations, and five abortions. Except for one child with congenital micro-ophthalmia, no other child born to thewomen on TKI had any malformations. Thirty-eight men fathered 51 healthy children. All but two patients (one planned and one unplannedpregnancy) lost theirhematological responses during pregnancy and gained their previous best response after restarting TKI. In women who were pregnant at CML onset, complete cytological remission (CCYR) was achieved between 7 and 24months (median:14months) after starting TKI. During pregnancy, intermittent hydroxyurea ± TKI (in the second and third trimesters) was used to keep WBCs less than 30,000/mm3. Outcomes of pregnancies in CML patients can be optimized with our approach. TKIs(Imatinib and Nilotinib) can be safely used in the second and third trimesters. Delayed initiation or interruption of TKI during pregnancy does not negatively affect response to TKIs.

Evaluation of physician guideline adherence and areas for improvement in managing patients with chronic myeloid leukemia: a cross-sectional survey

The experience of a physician at a clinical center is among the critical factors in managing chronic myeloid leukemia (CML) during its treatment with tyrosine kinase inhibitors (TKIs). The authors conducted a cross-sectional questionnaire to investigate barriers to physician use of published evidence-based guidelines in CML management in a real-world setting. Among the participating physicians (N = 407), 99.8% of physicians reported that CML guidelines were useful; however, only 62.9% of physicians reported that they follow guidelines in real-time. Although 90.7% of physicians prefer second-generation TKIs as the first-line treatment, imatinib (88.2%) remains the most widely administered TKI in the first-line setting. Only 50.6% of physicians switched the treatment when patients failed to achieve early molecular response (at 3 months), whereas 70.3% of physicians switched the treatment when patients’ response to TKI was inadequate at 6 months and/or 12 months. Moreover, only 43.5% of physicians considered treatment-free remission (TFR) as one of the top 3 goals for their patients. The major concern to obtain TFR was patients’ adherence. This study demonstrated that CML management was generally in line with the current guidelines, but some of the details at the point of care are needed to be improved in CML.

Association of pre-treatment bone marrow morphology and achievement of BCR-ABL1 transcript milestones in CML

Chronic myeloid leukemia (CML) is characterized by the fusion gene BCR-ABL1 which encodes aberrantly functioning tyrosine kinase. Treatment with tyrosine kinase inhibitors (TKI) is a landmark of CML management and the main goal is to achieve major molecular response (MMR) which is defined as BCR-ABL1IS ≤ 0.1 % at 12 months of therapy. The aim of this study is to analyze histologic features of bone marrow (BM) in CML patients at the time of diagnosis and compare it to the level of BCR-ABL1IS transcript at 3 (BCR-ABL1IS ≤10 % early molecular response; EMR) and 12 months (MMR) as well as to so called molecularly undetectable leukemia (MUL) to see weather bone marrow morphology can be of value in predicting achievement molecular response milestones. Thirty-two bone marrow biopsies of CML patients, prior TKI therapy, were re-evaluated and CD34 immunohistochemistry was performed to examine microvessel density (MVD) and microvessel area (MVA) and subsequently compared it to the level of BCR-ABL1IS transcript. This study showed statistically significant association between BM hypercellularity and EMR (p = 0.048) and MUL (p = 0.034), peri-trabecular adipocyte distribution and EMR and MUL (p = 0.027 and p = 0.011, respectively), MMR and bone marrow fibrosis (p = 0.029), loose megakaryocyte clustering and EMR and MUL (p = 0.004 and p = 0.018, respectively), absence of naked nuclei and MUL (p = 0.033) but there was no statistically significant association with vascular parameters. These results suggest that some bone marrow morphologic features prior TKI therapy might be indicators of favorable molecular response.

Cardiovascular risk in chronic myeloid leukaemia: A multidisciplinary consensus on screening and management.

Tyrosine kinase inhibitors (TKIs) have become the mainstay of treatment for chronic myeloid leukaemia (CML), but cardiovascular (CV) risk and exacerbation of underlying risk factors associated with TKIs have become widely debated. Real-world evidence reveals little application of CV risk factor screening or continued monitoring within UK CML management. This consensus paper presents practical recommendations to assist healthcare professionals in conducting CV screening/comorbidity management for patients receiving TKIs. We conducted a multidisciplinary panel meeting and two iterative surveys involving 10 CML specialists: five haematologists, two cardio-oncologists, one vascular surgeon, one haemato-oncology pharmacist and one specialist nurse practitioner. The panel recommended that patients commencing second-/third-generation TKIs undergo formal CV risk assessment at baseline, with additional investigations and involvement of cardiologists/vascular surgeons for those with high CV risk. During treatment, patients should undergo CV monitoring, with the nature and frequency of testing dependent on TKI and baseline CV risk. For patients who develop CV adverse events, decision-making around TKI interruption, cessation or change should be multidisciplinary and balance CV and haematological risk. The panel anticipates these recommendations will support healthcare professionals in implementing CV risk screening and monitoring, broadly and consistently, and thereby help optimise TKI treatment for CML.