Chronic Phase CML Research Articles

An Overview of Myeloid Blast-Phase Chronic Myeloid Leukemia

Myeloid blast-phase chronic myeloid leukemia (MBP-CML) is a rare disease with a dismal prognosis. It is twice as common as lymphoid blast-phase CML, and its prognosis is poorer. Despite the success with tyrosine kinase inhibitors in the treatment of chronic-phase CML, the same does not hold true for MBP-CML. In addition to the Philadelphia chromosome, other chromosomal and molecular changes characterize rapid progression. Although some progress in elucidating the biology of MBP-CML has been made, there is need to discover more in order to develop more satisfactory treatment options. Currently, most common treatment options include tyrosine kinase inhibitors (TKIs) as monotherapy or in combination with acute myeloid leukemia-based intensive chemotherapy regimens. Some patients may develop resistance to TKIs via BCR-ABL1-dependent or BCR-ABL1-independent mechanisms. In this paper, we provide an overview of the biology of MBP-CML, the current treatment approaches, and mechanisms of resistance to TKIs. In order to improve treatment responses in these patients, more emphasis should be placed on understanding the biology of myeloid blastic transformation in CML and mechanisms of resistance to TKIs. Although patient numbers are small, randomized clinical trials should be considered.

The utility of Insulin Like Growth Factor Binding Proteins (IGFBPs-1, 2, 3) with genes expression in resistance to Imatinib and Nilotinib in chronic myeloid leukemia: a pilot study from Delta Egypt

Introduction: Resistance to tyrosine kinase inhibitors (TKIs) is an obstacle facing CML patients in spite of the high cure rate. In this context, a study association between IGFBP (1, 2, 3) genes expression and their proteins in CML with the response to TKI has been implicated. Patients and methods: 115 newly diagnosed CML in chronic phase (CP) followed up over 12 months under TKI. 116 apparently healthy individuals were used as a control. RT-qPCR amplification was used for detecting IGFBPs genes expression, and ELISA technique was used for measuring serum IGFBPs. Results: IGFBP-1 and IGFBP-3 genes expression, as well as their serum levels, were significantly higher in CML patients, whereas IGFBP-2 gene expression was not. Interestingly, IGFBP-1 gene expression and IGFBP-1 serum levels were significantly higher in resistant patients compared to responder patients. However, the expression of IGFBP-2, 3 genes and their serum were insignificant. Conclusion: IGFBP-1 gene expression and its serum were significantly correlated with resistance. It is currently recommended that IGF-receptor inhibitors be developed and utilized. We are hoping to optimize the cure rate for CML treated with TKIs. Keywords: IGFBP-1-3; Gene expression; CML; Imatinib; Nilotinib.

CML-137 With the Financial Toxicity and Other Adverse Events of 2G TKI, Is Imatinib Still a Valid Option in Higher-Risk Young Patients with Newly Diagnosed Chronic-Phase CML?

CML-137 With the Financial Toxicity and Other Adverse Events of 2G TKI, Is Imatinib Still a Valid Option in Higher-Risk Young Patients with Newly Diagnosed Chronic-Phase CML?

With the Financial Toxicity and Other Adverse Events of 2G TKI, Is Imatinib Still a Valid Option in Higher-Risk Young Patients with Newly Diagnosed Chronic-Phase CML?

With the Financial Toxicity and Other Adverse Events of 2G TKI, Is Imatinib Still a Valid Option in Higher-Risk Young Patients with Newly Diagnosed Chronic-Phase CML?

FDA Approval Summary: Asciminib for Ph+ CML in Chronic Phase Treated with Two or More Tyrosine Kinase Inhibitors and for the T315I Mutation.

On October 29, 2021, FDA granted accelerated approval to asciminib (SCEMBLIX; Novartis), a tyrosine kinase inhibitor (TKI), for the treatment of adult patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP), previously treated with two or more TKIs, and granted traditional approval to asciminib for adult patients with Ph+ CML in CP with the T315I mutation. The first indication was approved based on major molecular response (MMR) at 24 weeks in the ASCEMBL study, a randomized trial comparing asciminib with bosutinib in patients who had failed two or more TKIs. This indication was ultimately granted traditional approval on October 12, 2022, based on safety data and MMR rate at 96 weeks of 38% [95% confidence interval (CI), 30-46] in the asciminib arm versus 16% (95% CI, 8-26) in the bosutinib arm (P value: 0.001). The second indication was approved based on MMR rate by 96 weeks of 49% (95% CI, 34-64) in the single-arm CABL001X2101 study. The most common (≥20%) adverse reactions included upper respiratory tract infections, musculoskeletal pain, headache, fatigue, nausea, rash, and diarrhea. The most common (≥20%) laboratory abnormalities were thrombocytopenia, neutropenia, anemia, lymphopenia, hypertriglyceridemia, hyperuricemia, and increases in creatine kinase, alanine aminotransferase, aspartate aminotransferase, lipase, and amylase. This manuscript describes the basis for approval of these indications.

Discontinuation of Tyrosine Kinase Inhibitor Therapy and Treatment Free Remission (TFR) in Chronic Myeloid Leukemia: Successful Achievement of TFR in More Than Two-Third of Patients in a Real-World Practice

BackgroundDiscontinuation of TKI therapy and treatment-free remission (TFR) have become new goals for chronic-phase chronic myeloid leukemia (CP-CML). The aim of this study was to estimate the TFR post discontinuation of TKI therapy at 3 tertiary-care centers. Patients and MethodsCP-CML patients aged ≥16 years who had an attempt to discontinue TKI therapy till June 2022, were eligible. The collected data included patients’ demographics, prognostic score, type and duration of TKI therapy, response dates, relapse dates, response to re-initiation of TKI therapy, and risk factors for relapse. ResultsFifty-five patients (35, 63.6% females) with a median age of 40 (range 16-74) years at diagnosis discontinued therapy. Forty-eight (87.3%) patients received imatinib as first line therapy. Twenty-nine (52.7%) patients were receiving imatinib at the time of TKI-discontinuation. Median time from diagnosis to TKI discontinuation was 86 months (IQR 60;132) and median duration of TKI therapy after achieving DMR was 66 months (IQR 47;114). After a median follow up of 34 (IQR 12;68) months, 15 (27.3%) patients relapsed. Median time to relapse was 5 months (range 2-38). Most of the relapses occurred during the first 6 months except 3 (20%) patients. All the relapsed patients achieved MMR after a median of 3 (range 2-6) months after restarting TKI therapy. None of the patients progressed to advanced-phase. ConclusionOur experience confirms that discontinuation of TKI therapy in CP-CML patients is feasible and safe in routine clinical practice, and can achieve TFR in more than two-third of carefully selected patients.

Kinetics of BCR::ABL1 transcript levels and molecular relapse after tyrosine kinase inhibitors discontinuation in chronic myeloid leukemia patients: preliminary results from the DES-CML study.

Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of patients with chronic myeloid leukemia. Patients who achieve sustained deep molecular response are eligible for treatment discontinuation. DES-CML is an ongoing, phase 2 multicentric discontinuation trial. Adult patients with CML in chronic phase with typical BCR::ABL1 transcripts, stable deep molecular response (MR4.5 IS) for two years, and no previous resistance were eligible. Patients underwent a phase of TKI dose de-escalation for six months before discontinuation. TKI was reintroduced at the previous dose if the patient lost major molecular response (MMR) at any time. This study aimed to assess the impact of BCR-ABL transcript kinetics during TKI de-escalation and discontinuation phases on treatment-free survival. So far, the study recruited 41 patients, and 38 patients discontinued therapy (4 were in the second discontinuation attempt). Eleven patients lost MMR, one during the de-escalation phase and ten after discontinuation. 24-month treatment-free survival was 66% (95% CI: 48-84%) in a median follow-up of 7 (1-30) months. No patient lost hematological response or had disease progression. A higher rate of molecular relapses occurred in patients with fluctuating BCR::ABL1 levels after the discontinuation phase (with loss of MR4.5, but no loss of MMR) (P=0.04, HR-4.86 (1.03-22.9) but not confirmed in the multivariate analysis. The longer duration of TKI treatment (P=0.03, HR-1.02, 95%CI - 1.00-1.04) and MMR (P=0.004, HR-0.95, 95%CI - 0.92-098) were independent factors of a lower relapse rate.

Frequency of Hematological Response in Patients with Chronic Myeloid Leukemia (Chronic Phase) with Imatinib After Three Months Presenting to CMH Rawalpindi

Objective: To find the frequency of haematological response in patients of chronic myeloid leukaemia (Chronic Phase) after three months of Imatinib Mesylate therapy, presenting to CMH Rawalpindi Study Design: Cross-sectional study. Place and Duration of Study: Department of Oncology Combined Military Hospital, Rawalpindi Pakistan, from Jan to Jun 2020. Methodology: Forty-six patients aged 18 and above within the chronic phase of CML were included. Patients underwent detailed clinical history, examination, baseline investigations, and bone marrow studies at presentation. Enrolled patients were given 400mg of Imatinib, and a complete haematological response was noted at the end of 3 months of therapy. Results: In our study, the age of patients ranged from 18 to 67 years, with a mean age of 47.2+10.6 years. 33(71.7%)were male, and 13(28.3%) were female. 42(91.3%) patients achieved complete haematological response to Imatinib at three months of therapy. Adverse drug reactions exhibited were oedema 18(39.1%), gastrointestinal disturbance 12(26.1%), anaemia 05(10.9%), and skin reactions 03(6.5%). Conclusion: This study has concluded that Imatinib Mesylate is highly effective in treating chronic phase CML at the haematological level and can be considered the drug of first choice in CML-CP.

Incidence of pleural effusion with dasatinib and the effect of switching therapy to a different TKI in patients with chronic phase CML

Dasatinib is one of the second generation tyrosine kinase inhibitors (TKI) which is approved for the treatment of patients with chronic phase CML (CP-CML) both in the front line and in the second line setting. Pleural effusion (PE) is a unique toxicity associated with dasatinib use. Our aim was to study the incidence of pleural effusion in our cohort of patients who were treated with dasatinib for CP-CML and the safety upon TKI switch. A total of 390 patients were treated with dasatinib during their course of treatment for CP-CML. A total of 69 patients (17.6%) developed any grade of PE. About 33 (48%) patients developed CTCAE grade 2 PE, 34 (49%) grade 3 and only 1 patient developed grade 4 PE. Recurrence of PE was observed in 34 (49%) patients. While only 12 patients (17.3%) continued using dasatinib after development of PE, dasatinib was discontinued in the other 57 patients. Therapy was switched to bosutinib in 13 patients out of which 6 (46%) patients re-developed PE. While only 12.5% patients developed re-accumulation of pleural fluid in patients switched to imatinib, none of the patients switched to nilotinib re-developed PE. A change in TKI to bosutinib was associated with a 46% risk of recurrence of PE in patients who develop PE on dasatinib for the treatment of CP-CML. The incidence of recurrent PE was markedly lower in patient switched to imatinib or nilotinib.

The Effect and Safety of Flumatinib in Patients with Chronic Myelogenous Leukemia Failed First-and Second-line Treatment

To analyze the efficacy and safety of flumatinib, a second-generation tyrosine kinase inhibitor (TKI) independently developed in China, in patients with chronic myelogenous leukemia in chronic phase (CML-CP) who falied first-line and second-line treatment. The clinical data of 30 CML-CP patients treated with flumatinib in Lianyungang First People's Hospital from January 2020 to September 2022 were collected retrospectively. Among them, 15 patients who received imatinib first-line treatment but failed treatment were included in the second-line group, and the other 15 patients who failed second-line treatment with nilotinib or dasatinib were included in the third-line group. The hematological and molecular responses of the patients in the two groups at 3, 6 and 12 months of treatment, and the event-free survival (EFS) and adverse reactions of patients at the end of follow-up were statistical analyzed. At 3, 6, and 12 months of treatment, 10, 11, and 12 patients in the second line group achieved major molecular response (MMR), which was higher than that of 3, 4, and 5 patients in the third line group (P =0.010, P =0.011, P =0.010). At 3 months of treatment, 12 and 13 patients achieved complete hematological response (CHR) and early molecular response (EMR) in the second-line group, which was higher than that of 9 and 13 patients in the third-line group, but the difference between the two groups was not statistically significant (P =0.232, P =1.000); At 6 and 12 months of treatment, 6 and 7 patients in the second-line group achieved MR4.5, which were higher than of 3 and 2 cases in the third-line group, but the difference was not statistically significant (P =0.427, P =0.713). The hematological adverse reactions of patients in the second-line group during treatment the period were mainly grade 1-2 thrombocytopenia and anemia, and no grade 3-4 of adverse reactions occurred. In the third-line group, there were 2 cases of grade 1-2 thrombocytopenia, grade 1-2 anemia and white blood cell 3 cases were reduced each, 1 case of grade 3-4 anemia, 2 cases of grade 3-4 neutropenia. The non-hematological adverse reactions in the second-line group were rash (2 cases), headache (1 case), diarrhea (1 case), fatigue (1 case), limb pain (1 case). There were 1 cases of diarrhea, 1 cases of nausea, and 1 cases of edema in the third-line group. There was no statistical significance in hematological and non-hematological adverse reactions between the two groups of patients (P >0.05). At the end of follow-up, the EFS rate of patients in the second-line group was higher than that in the third-line group (100% vs 93.3%), but the difference was not statistically significant (P =0.317). The second-generation TKI flumatinib independently developed in China, has good curative effect and safety for CML-CP patients who failed first-line and second-line treatment.

Comparison of the Efficacy Among Nilotinib, Dasatinib, Flumatinib and Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients: A Real-World Multi-Center Retrospective Study

BackgroundThere are limited data comprehensively comparing therapy responses and outcomes among nilotinib, dasatinib, flumatinib and imatinib for newly diagnosed chronic-phase chronic myeloid leukemia in a real-world setting. Patients and MethodsData from patients with chronic-phase CML receiving initial a second-generation tyrosine-kinase inhibitor (2G-TKI, nilotinib, dasatinib or flumatinib) or imatinib therapy from 77 Chinese centers were retrospectively interrogated. Propensity-score matching (PSM) analyses were performed to to compare therapy responses and outcomes among these 4 TKIs. Results2,496 patients receiving initial nilotinib (n = 512), dasatinib (n = 134), flumatinib (n = 411) or imatinib (n = 1,439) therapy were retrospectively interrogated in this study. PSM analyses indicated that patients receiving initial nilotinib, dasatinib or flumatinib therapy had comparable cytogenetic and molecular responses (p = .28-.91) and survival outcomes including failure-free survival (FFS, p = .28-.43), progression-free survival (PFS, p = .19-.93) and overall survival (OS) (p values = .76-.78) but had significantly higher cumulative incidences of cytogenetic and molecular responses (all p values < .001) and higher probabilities of FFS (p < .001-.01) than those receiving imatinib therapy, despite comparable PFS (p = .18-.89) and OS (p = .23-.30). ConclusionNilotinib, dasatinib and flumatinib had comparable efficacy, and significantly higher therapy responses and higher FFS rates than imatinib in newly diagnosed CML patients. However, there were no significant differences in PFS and OS among these 4 TKIs. These real-world data may provide additional evidence for routine clinical assessments to identify more appropriate therapies.

BCR/ABL-Positive Chronic Myeloid Leukemia in Children: Current Treatment Approach.

The purpose of this review is to summarize the most updated treatment recommendations for pediatric CML, and to discuss current areas of investigation. There is new phase 1 data to support the safety of the non-ATP competitive tyrosine kinase inhibitor (TKI) asciminib in the pediatric cohort. Ongoing studies are investigating the role of treatment-free remission in children. Chronic phase CML in children is managed with lifelong TKI therapy; however, evidence of deeper remissions sustained with second-generation TKIs may permit shorter treatment courses. Use of more specific TKIs may mitigate some of the side effects specific to the pediatric cohort. Children with advanced phase CML should achieve a complete hematologic remission with use of a second-generation TKI prior to transplant to achieve the best outcome.

Chronic Myeloid Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase-CML. The primary goal of TKI therapy in patients with chronic phase-CML is to prevent disease progression to accelerated phase-CML or blast phase-CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase-CML.

Navigating the Management of Chronic Phase CML in the Era of Generic BCR::ABL1 Tyrosine Kinase Inhibitors.

Over the past several years, advances in research, treatment, and market dynamics have impacted treatment strategies in chronic myeloid leukemia in chronic phase (CML-CP). They include the broader availability of cost-effective generic imatinib, and soon other generic second-generation tyrosine kinase inhibitors (TKIs). Access to affordable generics means that all patients with CML-CP should have access to safe and highly effective lifelong therapies. When overall survival is the treatment endpoint, imatinib provides a good treatment value. Second-generation TKIs may be the best frontline strategy when treatment-free remission is the goal. Recent studies have shown maintained efficacy and reduced toxicity when TKIs are used at reduced dosing. Reduced-dose schedules of second-generation TKIs (which are less toxic and induce faster deep molecular responses) may render generic second-generation TKIs a more attractive treatment option. Adjusting the dose of TKI in the presence of mild-to-moderate, or even severe but reversible, adverse events may be preferable to switching to a different TKI. The selection of second-line and beyond therapies depends on the evolving patterns observed with frontline treatment. Dose-adjusted ponatinib schedules have demonstrated improved efficacy and safety in patients resistant to second-generation TKIs or those with T315I-mutated disease. For asciminib, longer-term follow-up is needed to better evaluate its safety and efficacy compared with ponatinib. Allogeneic stem cell transplantation represents a valid alternative to newer-generation TKIs, with a better treatment value when TKIs are priced at >$40,000/year.

HJKC3-0006: Outcome of Patients with CML Treated on Second Line or Later Therapy in Routine Clinical Practice

Background: First-line therapies for chronic-phase (CP) CML include the tyrosine kinase inhibitors(TKIs) dasatinib, nilotinib, bosutinib or imatinib, while ponatinib and asciminib are indicated only in later lines. There are typically high response rates to first-line therapy in CP-CML, with responses to second- and third-line therapy lower and highly dependent on the specific TKI. Our goal in this study is to evaluate the role of ponatinib in the treatment of patients with CML using data from routine clinical practice. Study design and methods: Data will come from the H. Jean Khoury Cure CML Consortium (HJKC3) CML registry, a North American multi-site research database. Participating sites include the HJKC3 members (curecml.org). Patient inclusion criteria include a diagnosis CML in chronic phase, receiving second line therapy after initial therapy with a second generation TKI (dasatinib, nilotinib, or bosutinib) or receiving third or later line TKI therapy for CML. Participating patients provide consent to collect their data both retrospectively and prospectively for 1 year. Clinical data, including toxicities and complications of TKI therapy, are abstracted from the electronic health record. Participating patients are invited to complete a questionnaire to assess health-related quality of life. Data are managed using REDCap, a secure web application. Study Objectives: The primary objective is to compare the outcome of patients treated with ponatinib vs. other TKIs as second or later line therapy. Secondary objectives are to evaluate patient-reported outcomes (PRO) for CML treated with second or later line therapy and to determine if there are any patient or disease characteristics that can predict outcomes. Statistical plan for clinical outcomes: Descriptive statistics will be used to compare baseline demographic characteristics. Categorical variables will be compared using the Chi-square test. Continuous variables will be compared using ANOVA. Overall survival will be calculated from the time of diagnosis to death from any cause and patients will be censored if they were alive at the last follow-up. Survival probabilities will be computed using the Kaplan-Meier method and compared with the log-ranktest. Cox regression analyses will be used to determine significant factors that influence survival, and hazard ratios with 95% confidence intervals will be presented. Event free survival (EFS) and transformation free survival (TFS) will be calculated for patients. For EFS, loss of complete hematologic remission, loss of major cytogenetic response, progression to accelerated or blast phase, or death from any cause at any time will be considered an event. For TFS, transformation to accelerated or blast phase while on therapy or death on study will be considered an event. Statistical plan for PRO: Different PRO domains will be analyzed separately (for example, depression separate from fatigue, etc.). Descriptive statistics for each PRO measure will be reported and compared to previously published studies. Differences by treatment type will be evaluated.

Whole Genome and Transcriptome Sequencing of 21 Paired Chronic and Blast Phase CML Cases: Acquisition of Genomic Alterations, Changes in the Transcriptomic Profiles and Occurrence of B-Cell Receptor Rearrangements

Background: Since the introduction of tyrosine kinase inhibitor therapy survival has substantially improved in CML. However, a subset of patients become resistant and progress to blast phase. Still the underlying genomic changes are not completely understood. Cohort &amp; Methods: We studied 21 CML patients with paired sample material available from diagnosis in chronic phase (CP) and from blast phase (BP). All patients received a tyrosine kinase inhibitor starting at diagnosis of CML CP. Samples were analyzed by cytomorphology, chromosome banding analysis, WGS (100x, 2x151bp) and WTS (50 Mio reads, 2x101bp). B-cell receptor (BCR) rearrangements were analyzed with MiXCR software. The transcriptomic phenotype (TP) of each CP and BP sample was estimated by mapping their profiles to representative cases diagnosed with B-ALL, T-ALL, MDS, CMML, AML and CML CP. Results: The median time between diagnosis of CP and BP was 14.7 months (range: 4.7 - 137 months). While 18/21 CML in CP showed a TP corresponding to CML CP, one case each showed a TP corresponding to CMML, AML and B-ALL, respectively, although bone marrow blast counts were 6.5%, 5.5% and 5.5%, respectively. Of note, the case with the CMML-TP harbored a p190 BCR:: ABL1 isoform and also resembled CMML in bone marrow morphology. These three cases progressed to BP after 5.8, 5.3, and 8.9 months. The TP in BP corresponded to B-ALL in 13 cases, while 4, 3, and 1 case showed an AML-, CML CP- and MDS-TP, respectively (figure). In CP recurrent genomic alterations in addition to the BCR:: ABL1 fusion were mutations in ASXL1 (n=5), DNMT3A, TET2, RUNX1, and MGA (2 cases each). In BP the genomic landscape was more complex. Additional genetic alterations compared to CP were detected in all cases. Recurrently gained mutations in BP were mutations in WT1, BCOR, and SETD2 (2 cases each). The gain of copy number alterations (CNA) was more frequent. Recurrent CNA were: loss 9p (n=6), gain Ph-chromosome (n=4), loss 7q (n=3), gain 21q (n=3), gain 1q, loss 3q, gain 8q, loss 12p, and loss 13q in 2 patients each. Only three balanced structural variants were gained: a MECOM-, a NUP98:: HHEX- and a KMT2A:: MLLT3-rearrangement. Further, in 11/21 BP resistance mutations within the BCR:: ABL1 kinase domain were detected. The variant allele frequency (VAF) of RUNX1 mutations increased in BP in both cases with RUNX1 mutation present in CP (5% to 42%, time to BP: 4.7 months; 8% to 59%, time to BP: 11.7 months). DNMT3A and MGA mutations were about stable (VAF CP/BP: DNMT3A: 48%/37%, 33%/46%; MGA: 52%/36%, 40%/52%), while TET2 mutations were stable in one case (46%/49%) and decreased in the second (57%/27%). ASXL1 mutations were stable in 2 cases with an AML-TP in BP and lost in 3/5 cases with a B-ALL-TP in BP. BP with a lymphoid TP differed substantially with respect to the genomic profile from BP with myeloid TP. WTS data revealed a clonal BCR rearrangement in 8/13 BP with B-ALL-TP, of which 4 rearrangements are predicted to be productive. Further, CDKN2A/B deletions, IKZF1 deletions, and SETD2 mutations were only found in BP with B-ALL-TP. Thus, CML in BP with a B-ALL-TP showed a genomic landscape similar to B-ALL with BCR:: ABL1-rearrangement. In contrast CML BP cases with an AML-TP (n=4) had gained either rearrangements typically found in AML such as a KMT2A:: MLLT3 rearrangement and a MECOM rearrangement or acquired mutations in RUNX1, BCOR and WT1, or a CN-LOH 11p in combination with a WT1 VAF increase from 51% to 94%. Cases showing still a CML CP-TP (n=3) in BP acquired rather few additional genetic abnormalities (mutations in BCOR, WT1, CTCF; NUP98:: HHEX-rearrangement, gain of Ph-chromosome, loss of 11p, 17q), which were more myeloid in appearance. Conclusions: 1) Extensive genetic profiling indicated a substantial clonal evolution in the progression from CP to BP CML including loss of ASXL1 mutations, expansion of RUNX1 mutated clones, multiple CNA, and the frequent acquisition of a BCR rearrangement in BP with a transcriptomic phenotype resembling B-ALL. 2) A subset of CML cases in CP already showed a transcriptomic phenotype resembling acute leukemia indicating a rapid progression to BP. 3) The presence of a RUNX1 mutated subclone or a clonal BCR rearrangement seem to represent a warning signal in CML CP. 4) The prognostic validity of an extended genetic profiling including ASXL1, RUNX1, BCR rearrangement, and transcriptional signature in CML CP needs to be assessed in forthcoming prospective studies.

Treatment Free Remission (TFR) “for” Pregnancy. Overview and Outcome of Pregnancies Reported in the Italy-Tfr Registry

TFR is a consolidated practice and the goal to be reached for all CML patients. In Italy only a few centers participate in TFR clinical trials, while, in clinical practice, many patients discontinue TKIs for intolerance, pregnancy, or other reasons. A cohort of 467 Italian patients who underwent discontinuation outside of clinical trials were collected in the Italy TFR registry. This cohort showed a mean TFR rate of 73% at 12 months. Italy-TFR is an observational study, both retrospective and prospective, with the purpose of collecting data on patients with Ph+, chronic phase CML who discontinue TKIs in an off-protocol setting. Eligibility criteria include patients treated with TKI monotherapy or in association with other drugs (IFN, BCR:;ABL1 peptidic vaccine, and others) and those who discontinued therapy for any reason. Deep Molecular Response (DMR) defined as MR4 (BCR::ABL ratio ≤ 0.01% IS), MR4.5 (≤ 0.0032%) or MR5 (≤ 0.001%) was confirmed at least three times before TKI discontinuation. Data from patients discontinuing in less than DMR were collected and analyzed separately. Molecular responses were assessed by qPCR; tests were performed by the GIMEMA Laboratories Network (LabNet). TFR was assessed using the Kaplan-Meier method and 95% confidence interval, from the date of TKI discontinuation to the date when therapy was reinitiated. Patients discontinuing for pregnancy were analyzed in this sub-analysis. Thirty patients and 33 pregnancies (3 patients had 2 pregnancies) were entered from 8/32 participating centers. Main data are reported in Table 1. Median age at diagnosis was 28 years (range 19-36), and 35 years at pregnancy (range 29-41). Fifteen patients switched from 1st to 2 ndG TKI before pregnancy due to intolerance or resistance/unsatisfactory responses. Only one patient switched to another TKI to deepen the response before attempting a second pregnancy (imatinib to nilotinib). Not all patients at TKI interruption were in DMR, however, they were all treated with the last TKI for a median of 60 months (range 18-151), and exposed to any TKI for a median of 89 months (range 44-186). Specifically, 9/33 pregnancies started in MMR (≤0.1% transcript), 13 in MR4, 6 in MR4.5, and 5 in MR5. Three patients stopped TKI therapy before conception, two at 5 months and 1.5 months, respectively, before pregnancy. The third patient, in TFR after the first pregnancy, conceived a second child while still in TFR. These 3 patients were in TFR for 9, 9 and 5 years after treatment stoppage. During pregnancy 4 patients were treated after losing MMR. One patient, in MR5 with imatinib for 4 years rapidly lost MMR and was treated with a peptidic vaccine, maintaining complete cytogenetic remission until delivery; 2 patients were treated with IFN, and 1 restarted nilotinib at 23 weeks. All 33 pregnancies were carried to term, with unremarkable outcomes for mothers and babies. No CML progression was recorded. Breastfeeding was allowed for patients with stable transcript levels. With a median follow-up of 40 months, 11 patients were still in TFR (33%; 48% at 12 months), with no differences for patients treated with imatinib or a 2 ndG TKI. The lower number of patients maintaining TFR compared with the general population of patients studied can be explained by 3 main considerations. First, 9/33 pregnancies started in MMR, which is not a criteria that allows for discontinuation, the kinetics of transcript rise are often not correlated with molecular remission. Second, the biological clock in women can rush conception attempts before the appearance of a consolidated response (also resistant patients). Third, as demonstrated in the main study, older age is the only statistically significant positive prognostic factor, with a higher risk of relapse for younger patients. Indeed, all patients restarting treatment regained at least MMR within 3 months. Except for the patient described earlier, and a patient who had a suboptimal response to the 2nd line and switched to bosutinib 3rd line, patients recommenced the same TKI discontinued before pregnancy. There was no significant difference in TFR between patients who discontinued imatinib 1 st versus 2 nd lines (Fig.1) and also in patients who discontinued 2 ndG TKI frontline versus 2 nd line for intolerance/resistance unsatisfactory response. The Italy-TFR protocol is still enrolling in the prospective cohort and updating. We plan to include more cases and present an exhaustive analysis.

Biological Factors Associated with Treatment-Free Remission in Clinical Practice: Data from the Canarian Registry of CML

Introduction: The probability of maintaining treatment-free remission (TFR) after the discontinuation of tyrosine kinase inhibitors (TKI) is affected by clinical factors such as length of TKI treatment and the depth of molecular response. However, some individuals with similar treatment duration and response remain in TFR while others relapse. Thus, patient-specific factors must also play a role. Biological factors suggested to influence TFR include BCR::ABL1 transcript type, blasts at diagnosis, halving time (HT, first 3 months), BCR::ABL1 positivity at stop, and presence of somatic mutations. The aim of this study was to evaluate the biological factors associated with TFR in the clinical practice, using data from the Canarian CML Registry. Methods: The OMOP-standardized data of adult patients with chronic phase CML who discontinued TKI treatment included in the Canarian CML Registry (https://rclmc.es/rclmc/) were reviewed. Criteria to discontinue included TKI treatment ≥5 years and MR4.5 or better ≥3 years. TFR was defined as major molecular response (MMR), or deeper after stop. Molecular relapse was defined as loss of MMR in two consecutive tests. NGS was performed with the 30-gene panel Myeloid Solution (SOPHiA) on the MiSeq (Illumina) platform using 200 ng genomic DNA extracted from peripheral blood at diagnosis. Results: A total of 109 patients were included, with an average age of 50.5 years; 54 were male (49.5%). Median follow-up was 3.3 years. 86 patients discontinued from first-line, 21 from second- and 2 from third-line. 51% of patients (n=56) discontinued from imatinib, 31% from nilotinib (n=34), 16% from dasatinib (n=17), and 1% from bosutinib and ponatinib (1 patient each). The median TFR was 101 months ( Figure 1A; range 1.02-148.4 months). Thirty-two patients had molecular relapse and re-started TKI treatment: 36.7% with imatinib or dasatinib, 26.7% with nilotinib. Median time to regain MMR was 101 days (range 25-276). No difference was observed in the time to regain MMR for imatinib vs. 2G-TKI (106 vs. 144, p=0.419). No patients progressed to an accelerated phase. Differences were observed in duration of MR4 and MR4.5 prior to stop comparing the TFR vs. relapse groups (88.3 vs. 69.9 months, p=0.044; 74.2 vs. 58.6 months, p=0.079), but not total time on TKI (172.6 vs. 102.1, p=0.310), respectively. In terms of biological factors at diagnosis, 44 patients had blasts, 66.7% had a low Sokal risk. 23.9% expressed transcript e13a2 and 76.1% had e14a2. No differences in TFR were observed when blasts, Sokal or transcript were considered in chi-squared analyses. A long HT (&amp;gt;21.9 days, Shanmuganathan et al. Blood 2021;137) was of marginal significance for molecular relapse (p=0.076, OR 3.2) but no difference was found for short HT (&amp;lt;9.4 days). By Kaplan-Meier analysis, an MR3, 4, or 4.5 at stop was predictive of molecular relapse (n=42; Figure 1B) vs. an MR5 or undetectable (limit of detection 0.0001%). In multivariable analysis, only an MR5 or deeper at stop and withdrawal syndrome were predictive for TFR (p=0.003, HR 4.3; p=0.049, HR 0.20, respectively). NGS data was available for 47 patients. Myeloid mutations were detected in 21 patients (44.7%) at diagnosis, of these 11 had an epigenetic mutation (23.9%; in ASXL1, DNMT3A, TET2 or EZH2). 11 patients (23.9%) had a variant that was potentially germline (VAF 40-60%). By chi-squared and Kaplan-Meier analysis, no differences were observed between the median TFR for patients with or without a pathogenic somatic, epigenetic, ASXL1 or germline mutation. However, a greater separation of the curves was observed when considering TFR at 36 months for somatic (p=0.101) but not germline mutation. Conclusions: We confirmed previous observations that the biological factors BCR::ABL1 positivity at stop and longer HT were associated with molecular relapse although no difference was found for short HT. The impact of clinical factors on TFR, including duration of MR4 and MR4.5 prior to stop, were also confirmed in our real-life series with a long follow-up, while total TKI duration was not prognostic. Adnan Awad et al. associated the presence of epigenetic mutations at diagnosis with shorter TFR and higher relapse probability (Blood Cancer J. 2022;12). Here, a significant difference in TFR was not observed for epigenetic mutation at diagnosis; however, a tendency was observed between a pathogenic somatic but not a germline myeloid mutation and TFR at 36 months.

Real-Life Data of Bosutinib Treatment for Chronic Myeloid Leukemia: The Multi-Center Experience of the Gruppo Di Miglioramento Sicilia-Calabria

Background and rationale: Bosutinib is a second generation tyrosine kinase inhibitor (TKI), which has been indicated in Italy in the second line of CML treatment, since 2014. Thanks to its safety profile, bosutinib is frequently chosen as an advanced line of treatment in fragile patients. We collected retrospective data from patients treated with bosutinib in any line of TKI therapy, in order to study the role that this drug has in real-life, compared to clinical trials in terms of treatment line, dosage, toxicity and efficacy. Patients and methods: We collected data from65 chronic phase CML patients treated with bosutinib between 2015-08-18 and 2023-04-27, followed at 12 Haematology centers in Sicily and Calabria. Of these patients, 42 (64.6%) were male, and had a median follow-up of 29 months (range 1-96). Mean age at diagnosis was 62, and mean age at bosutinib start was 67. Median therapies prior bosutinib treatment was 2. Fourtyfour patients (67.7%) had cardiovascular comorbidities (CV) at diagnosis: 37 patients (55%) had at least one cardiovascular risk factor: in particular, arterial hypertension in 31 patients (70.4%), dyslipidaemia in 10 patients (22.7%), diabetes mellitus in 14 patients (31.8%), obesity (grade 3) in 2 patients (4.5%); 7 patients (10.7%) had already experienced an acute cardiovascular or cerebrovascular event. Finally, only 12 patients (18.4%) had no comorbidity at diagnosis. Mean age at the start of bosutinib for CV-risk patients was 70 years. Among 44 patients with CV risk before starting bosutinib, 38 patients were still alive (86.4%) at last follow-up. Fifteen patients with CV risk discontinued bosutinib (34%), while none presented new CV events during treatment. In terms of efficacy, however, in patients with CV risk, the median molecular response, at the last follow-up, is MR2. Results: Thirty-eight patients (58.5%) discontinued bosutinib, while 27 (41.5%) were still on treatment at the time of the last follow-up. Of the 38 patients who discontinued bosutinib, 5 discontinued due to resistance (13.8%) and 19 due to intolerance (50%). Of these 19 intolerant patients, only 1 patient discontinued bosutinib due to CV event (heart failure) and only 1 patient discontinued due to gastrointestinal toxicity (grade 3 diarrhea). Most reported toxicities were as follows: Skin Toxicity 3 pt 5%Perpheral edema 2 pt 3%Hepatototoxicity 2 pt 3% In the efficacy evaluation, early-suspenders (bosutinib treatment duration &amp;lt; 6 months) were, therefore, cut out, 55 patients (84.6%) were evaluated in this sub-analysis, 34 (61.8%) male and 21 (38.2%) female. Median age in this subanalysis is 67 years. Bosutinib was second-line treatment in 35 cases (63.6%), third-line therapy in 15 cases (27.3%), fourth-line therapy in 4 cases (7.3%). Overall, 35 patients assumed bosutinib as a second-line TKI: 22 of them were from the 1L-imatinib group (62.9%), while 13 were from the 2nd generation TKI-1L group (37.1%). Of the 22 1L-imatinib and 2L-bosutinib patients, 56.1% reached MR3 or deeper during bosutinib treatment and 38.1% reached MR4.5 or deeper. Of the 13 patients in 1L-2genTKI 2L-bosutinib group, 61.5% reached at least MR3, while 15.4% reached MR4.5 or MR5. Drop-out rate was similar between the two groups. Conclusion Bosutinib revealed to be safe in patients with CML in 2 nd and further lines of treatment, especially in terms of cardiotoxicity, even in subjects with a high CV risk at treatment initiation. Furthermore, our data revealed as most patients are currently treated with a lower dose of bosutinib than standard (median dosage 302 vs 500 mg a day), obtaining good response rates in 2 nd and further lines. Subsequent eventual dose increase is evaluated on the basis of the molecular response.

Cytogenetic and Molecular Remission in Chronic Myeloid Leukemia in Togo

The availability of tyrosine kinase inhibitors (TKIs) in Togo through the GIPAP program has revolutionized the management of chronic myeloid leukemia and increased patient life expectancy. However, diagnosis and molecular monitoring of therapeutic efficacy remain a real challenge due to the inaccessibility of cytogenetic and molecular biology tools. We’ve conducted, a cross-sectional, descriptive study that ran from December 21, 2022, to January 20, 2023, with the aim to evaluate the cytogenetic and molecular remission in CML patients followed at the CHU Campus de Lomé in Togo. Patients diagnosed with chronic-phase CML who had been treated for at least three months with imatinib or dasatinib and had achieved complete hematological remission were included. Dosage of BCR-ABL transcript levels was performed by RQ-PCR in Seattle, USA, using Dried Blood Spot. The transcript detection limit was 0.003% i.e., MR4. A total of 38 patients were included, 68.4% of them were treated with imatinib and 31.6% with dasatinib. In terms of remission, 28.9% had not achieve a partial cytogenetic remission while 15.8% of patients had achieved a MR4 remission and 7.9% a major molecular remission. Major molecular remission was achieved at a mean follow-up time of 95 months for patients taking imatinib and 22 months for those taking dasatinib. Patients in MR4 were on imatinib after a mean of 68 months. All in one, our study showed a high rate of treatment failure. Better access to cytogenetic and molecular biology tools is needed to improve management.