Phase Chronic Myeloid Leukemia Patients Research Articles

Response and Outcomes of Third-Line Tyrosine Kinase Inhibitor Therapy on Patients with Chronic Phase Chronic Myeloid Leukemia

Response and Outcomes of Third-Line Tyrosine Kinase Inhibitor Therapy on Patients with Chronic Phase Chronic Myeloid Leukemia

Addressing Challenges in Chronic Phase Chronic Myeloid Leukemia: Impact of Education on Practice Behaviors and Knowledge

Background: Optimal outcomes for patients with chronic-phase chronic myeloid leukemia (CML) require both rigorous patient adherence to oral tyrosine kinase inhibitor (TKI) therapy and regular monitoring of treatment response by clinicians. Clinicians caring for patients with CML face a number of challenges with respect to management including selecting initial therapy, monitoring for treatment resistance and failure, and determining when to switch therapy. As a result of barriers including lack of time to search guidelines and lack of experience with CML, analyses have demonstrated that adherence to management guidelines, such as those of the European LeukemiaNet and National Comprehensive Cancer Network, is poor (Goldberg SL, et al. J Oncol Pract. 2015;11:e398-e404; Guérin A, et al. Curr Med Res Opin . 2014;30:1345-1352). To address these challenges, we created an education activity focused on molecular profiling, treatment selection, and management of treatment outcomes. Learner responses were evaluated to assess the influence of education.Methods: A live-online 1-hour video continuing medical education activity with slides, polling and live questions was launched on October 27, 2016 and made available on-demand at www.OMedLive.com through October 27, 2017. CME test questions were administered at 3 time points (pre-activity, immediate post-activity, and after 8-weeks). Data from these test questions, live polling responses, and questions that learners posed during live Q&A were analyzed to determine engagement, lessons learned, and continuing education gaps. Tests of statistical significance were conducted using the McNemar test for matched pairs (learners who completed both pre/post & pre/survey, respectively). Effect size was computed using Cohen's d (for all significant findings).Results: Forty-five of 149 (30%) registered learners completed all pre-, post-, and 8-week follow-up surveys, of whom, 71% reported the educational activity positively influenced patient experience or outcome, and 76% reported it positively altered their clinical practice. Learners reported improvements in their ability to assess the relative safety, efficacy and tolerability profiles of TKIs used to treat CML (69%), manage potential adverse events that may be associated with TKI therapies in patients with CML (67%), educate patients on the recent improvements and benefits of existing therapies with respect to survival outcomes (60%), and follow recommendations from clinical practice guidelines on CML (64%). As the result of education, 95 of 149 (64%) of learners reported commitments to change in regards to: medical/practice knowledge (88%), care attitudes (84%), practice behavior (84%) and patient clinical outcomes (79%). Learners demonstrated improved competence via a case scenario which required identifying the optimal next step for a 61-year old patient with CML who was not meeting treatment milestones. They also showed improved knowledge on the efficacy of specific TKIs in newly diagnosed CML patients, the definition of a complete cytogenetic response, and use of molecular profiling and influence of molecular response on prognosis. Although this study is limited by lack of access to practice data, outcomes results and participant questions indicate clinicians may benefit from continuing education on CML.Conclusions: Ongoing education on CML can yield immediate and sustained gains in knowledge, competence, and performance, which may improve adherence to guidelines and outcomes for patients. DisclosuresSteensma:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; H3 Biosciences: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy, Research Funding; Incyte: Equity Ownership; Onconova: Consultancy.

Altered Expression of Pdgfrα and Its Downstream Signalling Components May be Causal in the Development of Imatinib Induced Thrombocytopenia in CML Patients Receiving Imatinib Treatment

Background:The main regulators of most of the cellular signalling pathways are protein kinases. Among these the receptor tyrosine kinases (RTKs) play important roles in cellular growth and proliferation by transmitting extracellular messages to intracellular signalling circuits. An important component of the intracellular circuits is the (PDGFR/PI3K/Akt/mTOR) pathway. Aberrant functioning of this pathway is known to occur in a number of diseases through various mechanisms. We report here that expression of PDGFRα gene and its downstream signalling components viz. PI3K and AKT is down regulated after imatinib treatment in some CML patients on imatinib therapy and may be a causal in the development of imatinib induced thrombocytopenia in these patients.Methods:A cohort of 100 chronic phase CML patients admitted to the Lok Nayak Hospital, New Delhi, India were included in this study. After initiation of imatinib treatment, haematological response of CML patients was monitored regularly for two years, in which development of thrombocytopenia was the primary end point.Total RNA, from blood samples of CML patients, was extracted using Trizol method. RNA concentration was determined by measuring absorbance at 260 nm. A cDNA synthesis kit (ThermoFisher Scientific, USA) was used for cDNA synthesis according to the manufacturer's instructions. The mRNA expression of all the genes was evaluated by quantitative SYBR Green based real time polymerase chain reaction (qRT-PCR) and results were expressed as fold change (2-∆∆ct). Results:Expression of PDGFRα, PI3K and AKT1 genes was significantly downregulated after imatinib treatment with a fold change (Mean + SD) of (2.12 + 0.41, 2.38 + 0.53 and 4.78 + 0.38 respectively) in CML patients receiving imatinib therapy (p < 0.0001). Further, we analysed the expression of PDGFRα, PI3K and AKT1 genes in two groups of CML patients- one that developed thrombocytopenia after imatinib treatment and the other that did not. We observed that there was a differential expression of PDGFRα and AKT1genes in thrombocytopenic and nonthrombocytopenic CML patients. Thrombocytopenic CML patients had a lower expression of PDGFRα and AKT1 genes in comparison to non-thrombocytopenic CML patients and this difference reached a statistical significance with a p-value of 0.02 and 0.04 respectively. Moreover, the expression of PI3K gene was also slightly downregulated in thrombocytopenic CML patients (fold change = 2.21+ 0.47 ) compared to nonthrombocytopenic ones (fold change = -2.55 + 0.57) but this difference did not reach a statistical significance (p=0.14). DisclosuresNo relevant conflicts of interest to declare.

Pilot Study of Imatinib Discontinuation in Patients with Chronic Myeloid Leukemia with Deep Molecular Response (EDI-PIO) — Evaluation of Pioglitazone in Treatment-Free Remission

Introduction: Successful TKI discontinuation is feasible in approximately 40-60% of CML patients with stable and deep molecular response, but the persistence of quiescent CML stem cells (LSC) may be responsible for relapse. Pioglitazone, a PPARgamma agonist may reduce STAT5 activity and cause an erosion of CML LSC.Objectives: to evaluate safety and efficacy of pioglitazone in treatment-free remission (TFR) after imatinib discontinuation in patients with CML treated with pioglitazone for 3 months before imatinib discontinuation.Patients and methods: prospective, phase II trial. Inclusion criteria: CML in chronic phase, treated with imatinib for at least 3 years, with CCyR and stable deep molecular response (MR4.5) for at least 2 years. Patients received pioglitazone 30 mg/day, orally, for 3 months before imatinib discontinuation. BCR-ABL levels were measured by real-time quantitative PCR monthly for 12 months, every two months for 12 months, and then every 3 months during the subsequent follow-up. Imatinib was reinitiated at molecular relapse, defined as any single sample with a value of >0.1% (loss of major molecular response - MMR) or two consecutive positive samples with a value >0.01% (loss of MR4.0). Treatment-free remission (TFR) was calculated from imatinib discontinuation until molecular relapse, resumption of imatinib by any cause, progression to advanced phases or death to any cause.Results: Recruitment is ongoing. Between June 2016 and July 2017, 21 chronic phase CML patients were included. Median age was 48 years (23-65) at CML diagnosis and 56 years (29-76) at trial initiation; 52.4% male; Sokal: 62.5% low risk, 25% intermediate, 12.5% high risk; 14% treated previously with IFN. Two patients had diabetes and were using hypoglycemic drugs. The median time between diagnosis and imatinib start was 2 months (1-39); the median duration of imatinib treatment was 8.2 years (4-12). Nineteen patients received pioglitazone for 3 months and discontinued imatinib and two are still using both. There were no grade 2 or 3 adverse events related to pioglitazone; one patient did not complete the first month of pioglitazone treatment due to worsening of edema and went to discontinuation phase. The median follow-up of the 20 patients that discontinued imatinib was seven months (0-11). One patient dropped out of the trial and was censured in the analysis. Seven/18 patients (38%) presented newly or worsening musculoskeletal pain or arthralgia grades 1-2 occurring within 1-6 months after imatinib discontinuation. The two diabetic patients presented increase in glucose levels (grade 2 and 3), seven and eight months after imatinib discontinuation. There was no loss of hematological response or transformation to advanced phases. However, 4/18 (22%) patients (all male) reinitiated imatinib after molecular relapse: 1 lost MMR and CCyR response; 2 lost MMR, one had confirmed loss of MR4. Two of them recovered RM4.0 in 2 and 3 months after imatinib reintroduction. TFR was 74% (95% CI: 52-96%) in 9 months. TFR was higher in female patients (100% vs. 45%, P=0.019).Conclusion: Pioglitazone was well tolerated in the majority of the patients. The rate of withdraw syndrome was similar to the reported in other discontinuation trials. Increase in glucose levels was observed in two patients with diabetes after imatinib discontinuation. TFR was higher in female patients. A longer follow-up is necessary to evaluate the duration of TFR.This trial is registered in ClinicalTrials.gov (NCT02852486) DisclosuresPagnano:Bristol-Meirs Squibb: Consultancy, Speakers Bureau; Roche: Speakers Bureau; Amgen: Consultancy; Novartis: Consultancy.

Outcomes after Sequential Tyrosine Kinase Inhibitors Treatment in Chronic Phase Chronic Myeloid Leukemia

Introduction: Tyrosine kinase inhibitors (TKIs) made great success in chronic myeloid leukemia (CML) treatment. However, TKIs often need to be changed due to not only adverse events but also suboptimal response or treatment failure. Currently, 5 TKIs, imatinib (IM), dasatinib (DAS), nilotinib (NIL), bosutinib (BOS), and ponatinib (PON) are approved for CML, and the sequential TKI treatment outcomes has not been well studied. Thus, we sought to evaluate outcomes of CP CML in an era where several TKIs are available.Method: Record of CP-CML who were referred to Winship Cancer Center between January 2005 and April 2016 were reviewed. We excluded patients who did not initiate TKI as first-line within 6 months after diagnosis.Results: A total 206 patients were included and followed up median 48.8 (1.4-190.1) months. Clinical characteristics were summarized in table 1. Age at diagnosis was 50 (11-88), and male/female was 105/101. Risk scores was calculated in 110 patients (53.4%), and low/(intermediate)/high of Sokal, Hasford, and EUTOS were 64/27/19, 66/38/6, and 95/15, respectively. Four-teen patients (6.8%) showed additional chromosomal abnormality at initial diagnosis. A total 76 patients (36.9%) were treated with one TKI, 73 (35.4%) were 2 TKIs and rest of them (27.7%), more than 3 TKIs (3 TKIs, n=33; 4 TKIs, n=17; 5 TKIs, n=7). Eight-teen patients (8.7%) reused same TKIs in different treatment lines. IM was the most frequently used in 1st line treatment (n=145, 70.4%), DAS in 2nd line treatment (n=68, 52.3%), NIL in 3rd line treatment (n=21, 32.3%), and PON in 4th and 5th line treatment (n=11, 36.7%, and n=4, 40%), respectively. Reason for switching TKIs or discontinuation included resistant (49.8%), intolerance or adverse event (43.5%), and others (insurance, clinical trial, or reason are not available, 6.7%). ABL domain mutation were tested in 71 (34%) patients, and mutations were detected in 25 patients (35%). Nine patients had more than one mutation, and T315I were detected in 36% of them (n=9).Median 39.0 (3.8-119.8) months after diagnosis, 19 (9.2%) were progressed to advanced phase (AP, n=6; myeloid BC (MBP), n=4; lymphoid BP (LBP), n=9). Eight patients underwent allogeneic HSCT due to TKI failure (n=2), presence of T315I mutation (n=1), persistent neutropenia after imatinib (n=1), and progression to LBP (n=3) and AP (n=1), and 1 did autologous HSCT due to progression to MBP with CSF involvement. Ten patients were expired because of complication of allogenic HSCT (n=3), refractory disease (n=6) and acute myocardial infarction (n=1).Estimated cumulative PFS at 5- and 10-year were 92% and 81%, and OS at 5- and 10-year were 94% and 87% respectively. Fifteen patients of progressed patients were treated with median 1.5 (1-3) more TKIs after disease progression, number of used TKIs for PFS and for OS are not same. According to number of used TKI, PFS rates were not different between groups (Figure 1A, p=0.051), but OS rate were different (Figure 1B, p=0.002). OS at 10 years of 1 TKI was 100% (n=76), 2TKI, 82% (n=73), 3TKIs, 87% (n=33), 4 TKIs, 75% (n=16), and 5TKIs, 55% (n=7), respectively. In univariate analysis, female (p=0.008), ABL kinase mutation (p<0.001), optimal response at 3, 6, and 12 months were related PFS (p<0.001, p=0.002, and 0.037, respectively) (Figure 2 A, C, and E), and Hasford (p<0.001), EUTOS (p=0.047), optimal response at 3 and 6 months (p=0.002 and 0.013) predicted OS. (Figure 2 B and D). Age, race, Sokal score, additional chromosomal abnormality, and 1st line TKI (IM vs newer generation TKIs) did affect neither PFS nor OS.Conclusion: In the era of multiple TKIs, 63% of CP-CML patients were treated more than one TKIs. The best OS was observed in patients tolerating and responding to first and second-line TKI, but OS of 5 TKIs treated patients at 10 years were still 55%, showing potential for long term survival. PFS and OS can be predicted by early molecular response. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Characteristics of BCR-ABL gene variants in patients of chronic myeloid leukemia.

BackgroundDepending on breakpoints of rearrangement different types of BCR–ABL fusion protein can be generated in patients of chronic myeloid leukemia (CML). The aim of this study is to observe frequencies of major transcripts in CML patients by reverse transcriptase polymerase chain reaction (RT-PCR) and their hematological features at the time of presentation.Materials and methodsThis cross sectional study was performed at Molecular Lab of Riphah International University, Islamabad from January to June 2019. Consecutive peripheral blood samples of 70 newly diagnosed CML patients in chronic phase were analyzed by RT-PCR to detect different BCR–ABL transcripts. Routine blood cell counts were assessed by an automated hematology analyzer.ResultsAll samples expressed typical BCR–ABL rearrangement. Expression of either e14a2 or e13a2 transcript was detected in 38 (54%) and 30 (43%) patients, respectively. Coexpression of e13a2 + e14a2 was found in 2 (3%) patients. The mean total leukocyte count was higher in group expressing e13a2 (P = 0.01). Higher mean platelet count was noted in patients with e14a2 transcript, but this difference was statistically insignificant (P = 0.1). The association of male gender was observed with the group exhibiting e14a2 (P = 0.01). There was no statistically significant association between transcript type and different ranges of age, hemoglobin levels, and platelet and total leukocyte counts (P > 0.05).Conclusione14a2 transcript was most common transcript in CML patients. Patients exhibiting e13a2 subgroup presented with significantly higher mean white blood cell count at the time of presentation. Significantly higher proportion of male patients was found to express e14a2 transcript over e13a2.

English

BACKGROUND Chronic myeloid leukemia (CML) accounts for 15 - 20 % of leukemia in adults worldwide. At present, the three tyrosine kinase inhibitors (TKI) imatinib, dasatinib, or nilotinib are accepted as the standard first-line treatment in chronic phase (CP). Nilotinib is a second generation TKI having faster and deeper response compared to imatinib. We wanted to see if the response achieved with nilotinib in the first three months could be translated into long term benefits when imatinib was given after 3 months. METHODS Newly diagnosed CML-CP patients were randomized into two arms. The patients on the first arm were given imatinib and in the second arm nilotinib was given for first 3 months. After three months nilotinib was switched over to imatinib. The molecular response was assessed in both arms at 3 months and 6 months. RESULTS Twenty-six patients in each arm were analysed. The optimal molecular response (QPCR &lt;10 %) after 3 months was significantly higher in patients receiving nilotinib than imatinib (96.1 % vs 65.38 %; P &lt; 0.0048). The optimal response after 6 months (QPCR &lt; 1 %) was found to be more in the initial nilotinib arm than the initial imatinib arm (76.9 % vs 65.3 %; P - value = 0.35). CONCLUSIONS Patients on nilotinib arm did well even after switching to imatinib. It gives us an important platform for an economically backward country like India where the therapy with more potent drug like nilotinib is given in the initial three months or even six months. KEYWORDS Chronic Myeloid Leukaemia, Imatinib, Nilotinib, Optimal Response, Major Molecular Response

Relevance of treatment-free remission recommendations in chronic phase chronic leukemia patients treated with frontline tyrosine kinase inhibitors.

BackgroundTyrosine kinase inhibitors (TKI) can be safely discontinued in chronic phase chronic myeloid leukemia (CP‐CML) patients who had achieved a sustained deep molecular response. Based on the results of discontinuation trials, recommendations regarding patient selection for a treatment‐free remission (TFR) attempt had been proposed. The aims of this study were to evaluate the rate of patients eligible for TKI discontinuation and molecular recurrence‐free survival (MRFS) after stop according to recommendations.MethodsOver a 10‐year period, newly diagnosed CP‐CML patients and treated with first‐line TKI in the nine French participating centers were included. Eligibility to treatment discontinuation and MRFS were analyzed and compared according to selection criteria defined by recommendations and first‐line treatments.ResultsFrom January 2006 to December 2015, 398 patients were considered. Among them, 73% and 27% of patients received imatinib or either second or third generation tyrosine kinase inhibitors as frontline treatment, respectively. Considering the selection criteria defined by recommendations, up to 55% of the patients were selected as optimal candidates for treatment discontinuation. Overall 95/398 (24%) discontinued treatment. MRFS was 51.8% [95% CI 41.41–62.19] at 2 years and 43.8% [31.45–56.15] at 5 years. Patients receiving frontline second‐generation TKI and fulfilling the eligibility criteria suggested by recommendations had the lowest probability of molecular relapse after TKI stop when compare to others.ConclusionOne third of CP‐CML patients treated with TKI frontline fulfilled the selection criteria suggested by European LeukemiaNet TFR recommendations. Meeting selection criteria and second‐generation TKI frontline were associated with the highest MRFS.

Assessment of molecular response after tyrosine kinase inhibitors & serum granulocyte-macrophage colony-stimulating factor levels in Egyptian patients with chronic myelogenous leukemia in chronic phase

BackgroundIn chronic myelogenous leukemia (CML), one of the most important & documented benefits of the profitable use of tyrosine kinase inhibitors (TKIs) is achieving major molecular response (MMR) & undoubtedly raising the life expectancy. We evaluate the molecular response after one year of 32 newly diagnosed Egyptian CML patients in chronic phase receiving TKIs (imatinib vs nilotinib). Quantitative assessment of BCR-ABL1 mRNA transcripts using real-time reverse transcription polymerase chain reaction was done. Also, baseline quantitative detection of serum GM-CSF level was done using enzyme linked immunosorbent assays technique together with correlation to molecular response. ResultsThirty-two patients were included in the study, but the molecular response was assessed in only 17 patients; 6 patients were under imatinib treatment and 11 patients received nilotinib. Overall within 1 year, 7/17 (41.2%) patients achieved major molecular response (MMR) with median BCR-ABL1 level of 0.06% on the international scale (IS). Five patients (29.4%) reached MR4 with median BCR-ABL1 level 0.007% on IS. Regarding TKIs therapy, each MMR and MR4 was noticed in 2/6 (33.3%) patients who received imatinib treatment with median BCR-ABL1 level of 0.01% & 0.005% on the IS, respectively. However, MMR and MR4 were detected in 5/11 (45.4%) & 3/11 (27.3%) patients who received nilotinib treatment, respectively with median BCR-ABL1 level 0.06% & 0.008% on the IS, respectively. Median serum GM-CSF level was higher in patients who reached MR4 than patients who achieved MMR but it did not reach significant difference (p value = 0.7). ConclusionThis study demonstrates the molecular profile of Egyptian CML patients after TKIs treatment. Also, it assesses the baseline serum GM-CSF levels to predict therapeutic outcome in CML patients.

When to Stop TKIs in Patients with Chronic Myeloid Leukemia and How to Follow Them Subsequently.

ABL1 tyrosine kinase inhibitors (TKI) have dramatically improved the outcome for CML (chronic myeloid leukemia) patients. When TKI therapy is addressed appropriately, it can lead to an optimal molecular response in the majority of CML patients and a life expectancy that approaches that of the general population. However, lifelong TKI therapy may have consequences, including chronic, mostly low-grade, adverse events that can substantially impact patients' quality of life, adherence to therapy and, consequently, success of treatment. In the last few years, several groups have demonstrated that approximately 50% of chronic phase CML patients (CP-CML) who have achieved a stable deep molecular response (DMR) can stop therapy without suffering molecular relapse. Nowadays, treatment-free remission (TFR) has a significant role in the management of CML and should be considered in selected motivated patients that fulfill well-defined requirements to maximize the probability of successful discontinuation of TKI therapy.

Meta-Analysis of Gastrointestinal Adverse Events from Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia.

Simple SummaryPhiladelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs) often suffer from adverse events that negatively impact quality of life and patient therapy compliance. The purpose of this meta-analysis was to assess and compare the incidence of gastrointestinal adverse events (GI AEs), particularly in second-generation TKIs, in a very large, heterogeneous CML population. Results illustrate significant differences in GI AE profiles between different TKIs but minimal differences in patient survival. TKI AE profile should be a primary consideration when choosing an optimal, personalized TKI therapy for chronic phase CML patients without resistant mutations.Tyrosine kinase inhibitors (TKIs) are the frontline therapy for BCR-ABL (Ph+) chronic myeloid leukemia (CML). A systematic meta-analysis of 43 peer-reviewed studies with 10,769 CML patients compared the incidence of gastrointestinal adverse events (GI AEs) in a large heterogeneous CML population as a function of TKI type. Incidence and severity of nausea, vomiting, and diarrhea were assessed for imatinib, dasatinib, bosutinib, and nilotinib. Examination of combined TKI average GI AE incidence found diarrhea most prevalent (22.5%), followed by nausea (20.6%), and vomiting (12.9%). Other TKI GI AEs included constipation (9.2%), abdominal pain (7.6%), gastrointestinal hemorrhage (3.5%), and pancreatitis (2.2%). Mean GI AE incidence was significantly different between TKIs (p < 0.001): bosutinib (52.9%), imatinib (24.2%), dasatinib (20.4%), and nilotinib (9.1%). Diarrhea was the most prevalent GI AE with bosutinib (79.2%) and dasatinib (28.1%), whereas nausea was most prevalent with imatinib (33.0%) and nilotinib (13.2%). Incidence of grade 3 or 4 severe GI AEs was ≤3% except severe diarrhea with bosutinib (9.5%). Unsupervised clustering revealed treatment efficacy measured by the complete cytogenetic response, major molecular response, and overall survival is driven most by disease severity, not TKI type. For patients with chronic phase CML without resistance, optimal TKI selection should consider TKI AE profile, comorbidities, and lifestyle.

Therapeutic Effect of Imatinib Made in Real World to Newly Diagnosed Chronic Myeloid Leukemia

To evaluate the clinical efficacy and safety of domestic imatinib (made in China) in patients with newly diagnosed chronic myeloid leukemia chronic phase(CML-CP). Fifty-seven newly diagnosed CML-CP patients who did not receive any other anti-CML treatment were treated by domestic imatinib 400 mg once a day. The hematological, cytogenetic and molecular reactions and safety were observed and evaluated after 3, 6 and 12 months of treatment. Fifty-six patients were treated for ≥3 and 6 months, among which 50 patients were treated for ≥12 months. After 3 months of treatment, 49 patients underwent hematological examination, 47 patients (95.9%) achieved complete hematological response (CHR), 49 patients underwent cytogenetic examination, 39 patients (79.6%) achieved major cytogenetic response (MCyR), and 12 patients (24.5%) achieved complete cytogenetic response (CCyR). 49 patients underwent the level of BCR-ABL test, including 41 patients (83.7%) with BCR-ABLIS≤10%, and 5 patients (10.2%) with major molecular response (MMR: BCR-ABLIS ≤ 0.1%). After 6 months of treatment, 49 patients underwent hematological examination, and 49 patients (100%) all achieved CHR. 49 patients underwent cytogenetic examined, of which 41 cases (83.7%) obtained MCyR and 31 cases (65.3%) obtained CCyR. 49 patients underwent the level of BCR-ABL test, among which 33 patients (67.4%) showed BCR-ABLIS≤1%, and 15 patients(30.6%) reached MMR. After 12 months of treatment, 45 patients underwent hematological examination, and all the patients (100%) got CHR. 45 patients underwent cytogenetic examined, of which 41 cases (91.1%) obtained MCyR and 35 cases (77.8%) obtained CCyR. 45 cases were tested for BCR-ABL level, and 24 cases (55.3%) reached MMR. The incidence of grade Ⅲ leukopenia, thrombocytopenia and anemia were 14.0%, 8.7% and 10.5%, respectively. Non-hematological adverse reactions were edema (64.9%), nausea (50.9%), vomiting (35.1%), rash (24.5%), fever (15.8%), bone and joint muscle pain (38.6%), diarrhea(17.6%) and liver function damage (3.5%). There were no grade IV hematological and non-hematological adverse reactions. In the real world, Domestics imatinib mesylate is effective and safe in the treatment of newly diagnosed CML-CP patients, but long-term follow-up data are still necessary to verify its long-term efficacy.

MiR-181d/RBP2/NF-κB p65 Feedback Regulation Promotes Chronic Myeloid Leukemia Blast Crisis

BackgroundChronic myeloid leukemia (CML) is a malignant clonal proliferative disease. Once it progresses into the phase of blast crisis (CML-BP), the curative effect is poor, and the fatality rate is extremely high. Therefore, it is urgent to explore the molecular mechanisms of blast crisis and identify new therapeutic targets.MethodsThe expression levels of miR-181d, RBP2 and NF-κB p65 were assessed in 42 newly diagnosed CML-CP patients and 15 CML-BP patients. Quantitative real-time PCR, Western blots, and cell proliferation assay were used to characterize the changes induced by overexpression or inhibition of miR-181d, RBP2 or p65. Luciferase reporter assay and ChIP assay was conducted to establish functional association between miR-181d, RBP2 and p65. Inhibition of miR-181d expression and its consequences in tumor growth was demonstrated in vivo models.ResultsWe found that miR-181d was overexpressed in CML-BP, which promoted leukemia cell proliferation. Histone demethylase RBP2 was identified as a direct target of miR-181d which downregulated RBP2 expression. Moreover, RBP2 inhibited transcriptional expression of NF-κB subunit, p65 by binding to its promoter and demethylating the tri/dimethylated H3K4 region in the p65 promoter locus. In turn, p65 directly bound to miR-181d promoter and upregulated its expression. Therefore, RBP2 inhibition resulting from miR-181d overexpression led to p65 upregulation which further forwarded miR-181d expression. This miR-181d/RBP2/p65 feedback regulation caused sustained NF-κB activation, which contributed to the development of CML-BP.ConclusionsTaken together, the miR-181d/RBP2/p65 feedback regulation promoted CML-BP and miR-181d may serve as a potential therapeutic target of CML-BP.

Dosing Strategies for Improving the Risk-Benefit Profile of Ponatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase.

The treatment of chronic myeloid leukemia (CML) has been advanced by the development of small-molecule tyrosine kinase inhibitors (TKIs), which target the fusion protein BCR-ABL1 expressed by the Philadelphia chromosome. Ponatinib is a 3rd generation TKI that binds BCR-ABL1 with high affinity and inhibits most BCR-ABL1 mutants, including the T315I mutation. The approved starting dose of ponatinib is 45 mg once daily (full dose), however, the need for a full dose, especially in patients with dose adjustments due to tolerability problems, remains undemonstrated. Lower starting doses of ponatinib (30 mg or 15 mg once daily) for patients “with lesser degrees of resistance or multiple intolerances, especially those with an increased cardiovascular risk profile” has been recommended by the 2020 European LeukemiaNet. However, the available literature and guidance on the use of ponatinib at low dosage are limited. The objective of this paper is to describe how we select ponatinib dosage for CML patients in chronic phase in our clinical practice based on the available evidence and our clinical experience. We propose dosing regimens for the optimal starting dose for six generic cases of CML patients in chronic phase eligible for the switch to ponatinib and provide an algorithm to guide ponatinib dosing during treatment.

Long-term follow-up of late chronic phase chronic myeloid leukemia patients treated with imatinib after interferon failure: a single center experience

We report the long-term outcome of 139 patients treated with imatinib in late chronic phase after IFN failure. Median follow-up was 16.6 years and the estimated 18-year OS was 64.8%. 18-year EFS and PFS were 69% and 64.4%, respectively. Fifty (36%) patients stopped imatinib, 72% received a second line. b2a2 transcript was associated with a significantly inferior 18-year OS (p = 0.008), FFS (p = 0.036), PFS (p = 0.013) compared to the b3a2 type, whilst the type of transcript did not influence the time to response achievement. Failure to achieve MMR at 12 months significantly reduced the chance of reaching a DMR (p = 0.001). Imatinib discontinuation after achieving a sustained deep molecular response was attempted in 14 patients; 12 (86%) are still in treatment-free remission (TFR) at the last follow-up. Our experience confirms the long-term efficacy of imatinib after IFNα failure in real-life setting and documents the possibility of attempting a TFR in this subset of patients.

MiR-486-5p: A Prognostic Biomarker for Chronic Myeloid Leukemia.

MicroRNA miR-486-5p has been reported as a potential biomarker for diagnosis, prognosis, and as a therapeutic target in various cancers. In this study, we analyzed alterations in the expression of miR-486-5p in chronic Myeloid Leukemia (CML) patients. Initially, the expression of miR-486-5p was studied in the BCR-ABL1+ve CML K562 cell line by quantitative real-time polymerase chain reaction (qRT-PCR). The results indicated that the miR-486-5p expression was significantly upregulated in K562 cells after imatinib exposure, as compared to untreated K562 cells (p-value = 0.047). These observations were corroborated by a hospital-based study of the miR-486-5p expression in peripheral blood leucocytes of 36 CML patients in the chronic phase (CP) and compared with age and sex-matched healthy volunteers as control subjects. qRT-PCR-based quantification revealed significant downregulation of the miR-486-5p expression in newly diagnosed untreated CP-CML patients’ samples (2–ΔCt = 13.19 ± 14.41) as compared to control samples (2–ΔCt = 254.5 ± 274.8) (p-value < 0.0001). Levels of miR-486-5p were found to be distinctly elevated in the post-imatinib treatment samples of CML patients (2–ΔCt = 469.7 ± 312.9) as compared to pre-treatment samples (p-value < 0.0001). CML patients’ clinical and hematological responses to imatinib therapy (oral dose of 400 mg OD) were monitored for 12 months. The correlation of pre-treatment miR-486-5p levels with Sokal score indicated that patients with a higher expression of miR-486-5p had better prognoses. Patients with higher pre-imatinib miR-486-5p levels also showed a major hematologic response to imatinib in a shorter time and vice versa. To the best of our knowledge, this is the first report of alterations in the miR-486-5p expression in peripheral blood leucocytes of CML patients. Our observations support a tumor suppressor role of miR-486-5p in CML. The downregulation of the miR-486-5p expression may be critically important in the disease progression of CML patients. The upregulation of the miR-486-5p expression in post-imatinib exposure K562 cells and CML patients after 12 months of imatinib treatment suggests an onco-suppressor effector role of miR-486-5p in the BCR-ABL downstream signaling pathway. miR-486-5p can be explored as a novel biomarker for the early detection of CML.

Bosutinib in the real-life treatment of chronic myeloid leukemia patients aged >65years resistant/intolerant to previous tyrosine-kinase inhibitors.

To evaluate the role of bosutinib in elderly patients aged>65years with chronic myeloid leukemia (CML), a real-life cohort of 101 chronic-phase CML patients followed up in 23 Italian centers and treated with bosutinib in second or a subsequent line was retrospectively evaluated. Starting dose of bosutinib was 500mg/day in 25 patients (24.8%), 400mg/day in 7 patients (6.9%), 300mg/day in 33 patients (32.7%), 200mg/day in 34 patients (33.6%), and 100 mg/day in 2 patients (2.0%). Grade 3/4 hematological toxicity occurred in 7/101 patients (6.9%) and grade 3/4 extra-hematological toxicity in 19/101 patients (18.8%). Permanent bosutinib discontinuation due to toxicity was needed in 12 patients (11.9%). Among the 96 patients evaluable for response, 74 (77.0%) achieved a complete cytogenetic response (CCyR), while 64 of these 74 patients in CCyR (66.6% of all 96 evaluable patients) also achieved a molecular response (MR) (major MR [MR 3.0] in 21 [21.8%], deep MR [MR 4.0/4.5] in 43 [44.8%]). The 3-year event-free survival and overall survival of the whole patients' cohort from bosutinib start were 60.9% (CI 95% 49.3-72.5) and 86.4% (CI 95% 77.2-95.6), respectively. Our real-life data show that bosutinib is effective, with a favorable safety profile, also in elderly patients with important comorbidities and resistance and/or intolerance to previous tyrosine-kinase inhibitor treatments. As a consequence, it could play a significant role in current clinical practice for frail patients.

Higher red blood cell distribution width at diagnose is a simple negative prognostic factor in chronic phase-chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: A retrospective study.

The aim of this study was to evaluate the ability of the red blood cell distribution width (RDW) to predict prognosis and treatment response in chronic myeloid leukemia (CML)-chronic phase (CP) patients treated with tyrosine kinase inhibitor (TKIs).We retrospectively enrolled 93 newly diagnosed CML-CP patients treated with TKIs from 2009 to 2018 at the First Hospital of Lanzhou University. Patients were divided into 2 groups using an RDW of 18.65% determined by receiver operating characteristic curve analysis. We analyzed the correlation of treatment responses and the RDW compared to common scoring systems, as well as the correlation of the RDW with disease outcome, including overall survival (OS) and progression-free survival (PFS), and demographic and laboratory factors affecting outcome. Univariate analysis and Cox regression analysis were used.The median age of patients was 40 years, and 51 patients (54.8%) were men. A high RDW could predict treatment response at 3 months (P = .03) and 6 months (P = .02). The RDW was significantly lower in patients who achieved molecular response by 3 months (P < .001) and complete cytogenetic response by 6 months (P = .001) than in those who did not respond. Patients with a high RDW (>18.65%, n = 35) had significantly worse 5-year OS (77.1% vs 96.6%; P = .008) and PFS (80.0% vs 98.3%; P = .002) than those with a low RDW (≤18.65%, n = 58). Multivariate analysis demonstrated that a high RDW was an adverse predictor of OS (P = .005, HR (hazard ratio) = 9.741) and PFS (P = .009, HR = 16.735).The RDW is a readily available prognostic marker of outcome in patients with CML-CP and can predict treatment response to TKIs. Further larger and prospective studies are required.

Loss of expression of both miR-15/16 loci in CML transition to blast crisis

Despite advances that have improved the treatment of chronic myeloid leukemia (CML) patients in chronic phase, the mechanisms of the transition from chronic phase CML to blast crisis (BC) are not fully understood. Considering the key role of miR-15/16 loci in the pathogenesis of myeloid and lymphocytic leukemia, here we aimed to correlate the expression of miR-15a/16 and miR-15b/16 to progression of CML from chronic phase to BC. We analyzed the expression of the two miR-15/16 clusters in 17 CML patients in chronic phase and 22 patients in BC and in 11 paired chronic phase and BC CML patients. BC CMLs show a significant reduction of the expression of miR-15a/-15b/16 compared to CMLs in chronic phase. Moreover, BC CMLs showed an overexpression of miR-15/16 direct targets such as Bmi-1, ROR1, and Bcl-2 compared to CMLs in chronic phase. This study highlights the loss of both miR-15/16 clusters as a potential oncogenic driver in the transition from chronic phase to BC in CML patients.

Early BCR-ABL1 kinetics are predictive of subsequent achievement of treatment-free remission in chronic myeloid leukemia

With treatment-free remission (TFR) rapidly becoming the ultimate goal of therapy in chronic myeloid leukemia (CML), there is a need to develop strategies to maximize sustained TFR by improving our understanding of its key determinants. Chronic-phase CML patients attempting TFR were evaluated to identify the impact of multiple variables on the probability of sustained TFR. Early molecular response dynamics were included as a predictive variable, assessed by calculating the patient-specific halving time of BCR-ABL1 after commencing tyrosine kinase inhibitor (TKI) therapy. Overall, 115 patients attempted TFR and had ≥12 months of follow-up. The probability of sustained TFR, defined as remaining in major molecular response off TKI therapy for 12 months, was 55%. The time taken for the BCR-ABL1 value to halve was the strongest independent predictor of sustained TFR: 80% in patients with a halving time of <9.35 days (first quartile) compared with only 4% if the halving time was >21.85 days (last quartile) (P < .001). The e14a2 BCR-ABL1 transcript type and duration of TKI exposure before attempting TFR were also independent predictors of sustained TFR. However, the BCR-ABL1 value measured at 3 months of TKI was not an independent predictor of sustained TFR. A more rapid initial BCR-ABL1 decline after commencing TKI also correlated with an increased likelihood of achieving TFR eligibility. The association between sustained TFR and the time taken for BCR-ABL1 to halve after commencing TKI was validated using an independent dataset. These data support the critical importance of the initial kinetics of BCR-ABL1 decline for long-term outcomes.