Phase Chronic Myelogenous Leukemia Research Articles

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.

Long-term results of therapy for chronic myeloid leukemia: a 20-year analysis of the use of tyrosine kinase inhibitors in Russia

Introduction. In Russia, within the framework of the GIPAP program, in the period from 2001 to 2007 at the National Medical Research Center for Hematology, imatinib therapy was initiated in 235 patients in the chronic phase of chronic myelogenous leukemia (CML).Aim: to analyze the long-term results of therapy in patients with CML who started imatinib therapy as part of the GIPAP program.Methods. A retrospective analysis of the results of therapy was performed in 235 patients with СР CML, who received imatinib under the GIPAP program from 2001 to 2007 at the National Medical Research Center for Hematology. The protocols for therapy and monitoring of the residual disease of patients at various time intervals were determined by the clinical recommendations relevant at that time in the conditions of real clinical practice and the possibilities of the patient’s region of residence. Overall survival and survival without discontinuation of imatinib therapy, univariate and multivariate analysis of overall survival were performed. The cumulative incidence of responses was calculated. An analysis of response factors, the probability of death from concomitant diseases and death from CML was carried out.Results. The median follow-up of living patients at the time of analysis was 17.3 years (IQR 15.5–18.5). 70 (30 %) patients died, with the median time to death from the start of therapy being 7.8 years (IQR 3.7–13.6). The overall 10-year, 15-year and 20-year survival rates were 82 %, 74 % and 62 %. The cause of death in 43 cases (61%) was the progression of CML to the phase of acceleration or blast crisis and death out of remission for an unspecifi ed cause. 27 (39%) patients died from causes not related to CML. Patient age at initiation of imatinib therapy, length of time from diagnosis to initiation of imatinib therapy, and Sokal and ELTS risk groups at disease onset were identifi ed as signifi cant for survival by univariate analysis. Multivariate analysis showed independent predictive value for overall survival for age at initiation of imatinib therapy, length of illness before imatinib treatment, and ELTS risk group at disease onset. Among patients who died from CML progression, the proportion of patients who did not achieve CCyR for the entire period of therapy before death was 83% (35/42), while among patients who died from concomitant diseases, the proportion of patients without CCyR for the entire period of therapy was 11 % (p < 0.0001). The median duration of imatinib therapy was 11.4 years (0.8–21 years). 40 people died during imatinib therapy, 103 patients are alive and continue therapy with imatinib, 92 patients received at least one second-generation of Tyrosine kinase inhibitors (TKI) (TKI2), of which 62 people are alive and continue treatment with TKI. No more than two lines of TKI therapy were received by 49 (21 %) patients, and three or more lines were prescribed to 43 (18 %) patients. The median duration of therapy after switching to TKI2 was 7.8 years (0.1–15.6 years). Overall 15-year survival after switching to TKI2 was 59 %. On therapy with imatinib, during the entire observation period, complete cytogenetic response (CCyR) was achieved in 171 patients (73 %), another 18 patients (8 %) achieved CCyR for the fi rst time after switching to TKI2. Major (MMR) and deep molecular response (DMR) were achieved with imatinib in 129 (56 %) and 124 (53 %) patients, with TKI2 TKI2 therapy in 38 (16 %) and 33 (14 %) patients, respectively. Multivariate analysis showed an independent predictive value of only the time period from diagnosis to the start of imatinib treatment for achieving molecular responses to TKI therapy.Conclusion. After 20 years of monitoring patients on TKI therapy, we still cannot say that survival in CML is comparable to the survival of normal population. Long-term follow-up confi rms the fact that tumor reduction to at least the level of CCyR is the most signifi cant surrogate marker associated with a reduced risk of death from CML. Timely diagnosis of the disease, rapid initiation of targeted therapy and the fastest possible induction of cytogenetic and molecular responses is a very important mechanism for reducing the risk of resistant course and progression of CML.

POSTER: CML-590 ASC4START: A Phase 3b, Open-Label, Randomized Study of Asciminib vs Nilotinib in Patients With Newly Diagnosed Ph+ Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

POSTER: CML-590 ASC4START: A Phase 3b, Open-Label, Randomized Study of Asciminib vs Nilotinib in Patients With Newly Diagnosed Ph+ Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

CML-590 ASC4START: A Phase 3b, Open-Label, Randomized Study of Asciminib vs Nilotinib in Patients With Newly Diagnosed Ph+ Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

CML-590 ASC4START: A Phase 3b, Open-Label, Randomized Study of Asciminib vs Nilotinib in Patients With Newly Diagnosed Ph+ Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

An AI-Aided Diagnostic Framework for Hematologic Neoplasms Based on Morphologic Features and Medical Expertise

A morphologic examination is essential for the diagnosis of hematological diseases. However, its conventional manual operation is time-consuming and laborious. Herein, we attempt to establish an artificial intelligence (AI)-aided diagnostic framework integrating medical expertise. This framework acts as a virtual hematological morphologist (VHM) for diagnosing hematological neoplasms. Two datasets were established as follows: An image dataset was used to train the Faster Region-based Convolutional Neural Network to develop an image-based morphologic feature extraction model. A case dataset containing retrospective morphologic diagnostic data was used to train a support vector machine algorithm to develop a feature-based case identification model based on diagnostic criteria. Integrating these 2 models established a whole-process AI-aided diagnostic framework, namely, VHM, and a 2-stage strategy was applied to practice case diagnosis. The recall and precision of VHM in bone marrow cell classification were 94.65% and 93.95%, respectively. The balanced accuracy, sensitivity, and specificity of VHM were 97.16%, 99.09%, and 92%, respectively, in the differential diagnosis of normal and abnormal cases, and 99.23%, 97.96%, and 100%, respectively, in the precise diagnosis of chronic myelogenous leukemia in chronic phase. This work represents the first attempt, to our knowledge, to extract multimodal morphologic features and to integrate a feature-based case diagnosis model for designing a comprehensive AI-aided morphologic diagnostic framework. The performance of our knowledge-based framework was superior to that of the widely used end-to-end AI-based diagnostic framework in terms of testing accuracy (96.88% vs 68.75%) or generalization ability (97.11% vs 68.75%) in differentiating normal and abnormal cases. The remarkable advantage of VHM is that it follows the logic of clinical diagnostic procedures, making it a reliable and interpretable hematological diagnostic tool.

ASC4START: A Phase IIIb, Open-Label, Randomized Study of Tolerability and Efficacy of Asciminib Versus Nilotinib in Patients with Newly Diagnosed Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia in Chronic Phase

Objectives: Tyrosine kinase inhibitors (TKIs) have greatly improved treatment outcomes for patients with newly diagnosed chronic myelogenous leukemia in chronic phase (CML-CP), transforming it into a chronic disease requiring long-term treatment. This emphasizes the need for treatments that combine high efficacy with a favorable safety profile, improving over currently available options. Asciminib is a first-in-class BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket (STAMP) which has been approved by the FDA with subsequent approvals worldwide for patients with Philadelphia chromosome-positive (Ph+) CML-CP, previously treated with ≥2 prior TKIs based on the results of the ASCEMBL (NCT03106779) trial. The ABL specificity of asciminib compared with the selectivity of second-generation (2G) TKIs can reduce off-target effects and improve tolerability while maintaining efficacy and reducing the probability of developing resistance. The ongoing ASC4FIRST (NCT04971226) study will evaluate the efficacy and safety of asciminib vs investigator-selected TKI in patients with newly diagnosed Ph+ CML-CP. Additional data on asciminib in newly diagnosed Ph+ CML-CP may help to address patient-centric objectives, in particular the ability of patients to remain on treatment without having to permanently discontinue due to adverse events (AEs). The ASC4START study (NCT05456191) will primarily evaluate the tolerability of asciminib vs the 2G TKI nilotinib in adult patients with newly diagnosed Ph+ CML-CP, as measured by the time to study treatment discontinuation due to adverse event (TTDAE). The study will also report on further safety, efficacy and quality of life (QoL) outcomes. Methods: This is a phase IIIb, multi-center, open-label, randomized study in patients ≥18 years of age with newly diagnosed Ph+ CML-CP. The trial will enroll approximately 541 patients with CML-CP diagnosed within 3 months of study entry and an Eastern Cooperative Oncology Group (ECOG) performance status ≤1. Patients cannot be included if they have received previous treatment for CML with any other anticancer agents (except hydroxyurea and/or anagrelide), have confirmed central nervous system infiltration, or present impaired cardiac function or abnormalities in cardiac repolarization. Patients will be randomized 1:1 to receive asciminib 80 mg once daily or nilotinib 300 mg twice daily, both administered orally under fasting conditions; randomization will be stratified based on European Treatment Outcome Study long-term survival (ELTS) score at diagnosis (high vs intermediate vs low) to help achieve balance between the treatment arms (Figure). The primary endpoint is TTDAE, defined as the time from the date of the first dose of study treatment to the date of discontinuation of study treatment due to an AE. Secondary endpoints include type, frequency and severity of AEs; dose modifications due to AE; changes in laboratory values that fall outside pre-determined ranges; clinically notable ECG changes; time to discontinuation due to selected reasons (lack of efficacy/treatment failure/disease progression/suboptimal response/death); major molecular response (MMR), MR4, MR4.5, complete hematological response (CHR), and BCR::ABL1 ≤1% at and by all scheduled data collection time points; duration of and time to first MMR, MR4 and MR4.5; time to treatment failure; event-free survival, progression-free survival and overall survival. Secondary endpoints related to QoL include change from baseline in overall scores and individual scales of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires QLQ-C30 and QLQ-CML24. Participants will be treated in the study until approximately 64 discontinuations due to AEs are met; treatment duration for an individual patient is expected to be 2‒4.5 years. Current status: The study is recruiting as of October 2022. This study was sponsored by Novartis Pharmaceuticals. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ASC4OPT: A Phase 3b Open-Label Optimization Study of Oral Asciminib in Chronic Myelogenous Leukemia in Chronic Phase Previously Treated with 2 or More Tyrosine Kinase Inhibitors

Introduction Tyrosine kinase inhibitors (TKIs) are the standard of care in the treatment of chronic myeloid leukemia (CML). However, patients (pts) may experience resistance or intolerance to successive lines of TKI therapy. Asciminib is the first BCR::ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP). It is approved in the United States for the treatment of adults with Philadelphia chromosome-positive (Ph+) CML in chronic phase (CP) previously treated with ≥2 TKIs (at 40 mg twice daily [BID] or 80 mg once daily [QD]), and also Ph+ CML-CP with the T315I mutation (at 200 mg BID). This was based on the Phase 3 ASCEMBL trial (Rea et al. Blood 2021) and a Phase 1 study (Cortes et al. ASH 2020). The ASC4OPT (NCT04948333) trial was initiated to investigate the potential optimization of treatment with asciminib in adult pts with CML-CP previously treated with ≥2 TKIs (≥3rd-line). ASC4OPT will explore 3 aspects of treatment optimization: 1. Pt population, ASCEMBL inclusion criteria were based on the European LeukemiaNet (ELN) treatment recommendations from 2013. ASC4OPT will re-evaluate asciminib in an expanded ≥3rd-line population using the ELN 2020 treatment recommendations for warning and failure criteria. 2. Simplified posology, asciminib dosing in ASCEMBL was 40 mg BID. BID dosing may affect optimal compliance for pts and ASC4OPT will investigate both asciminib 40 mg BID and 80 mg QD. 3. Dose escalation, with limited treatment options in the ≥3rd-line setting, ASC4OPT will explore whether pts not in major molecular response (MMR) at ≥48 weeks (wks) could benefit from a potential dose escalation to 200 mg QD. Methods ASC4OPT is an international, multi-center, non-comparative, Phase 3b study in pts aged ≥18 years with CML-CP previously treated with ≥2 TKIs. The trial will enroll approximately 156 pts who are in treatment failure or warning (ELN 2020) or intolerant to the last prior TKI and not in MMR at baseline. Up to 30 additional pts in MMR at baseline and intolerant to their most recent TKI treatment will also be enrolled; these pts will not be included in the primary endpoint analysis, however all assessments will be performed. Pts are excluded if they have had previous or planned hematopoietic stem cell transplantation, second CP after previous progression to accelerated phase/blast crisis, or known presence of the BCR::ABL1 T315I mutation at any time prior to study entry. Pts will be randomized 1:1 to receive asciminib 40 mg BID or 80 mg QD. In pts not achieving MMR at 48 wks or losing response after wk 48 and up to wk 108, asciminib dose may be escalated to 200 mg QD if in the investigator's opinion the pt may benefit from the escalation. In addition, for dose escalation there must not be any grade 3 or 4 toxicity while on therapy, or persistent grade 2 toxicity, possibly related to asciminib and unresponsive to optimal management (Figure). The primary endpoint is MMR rate (BCR::ABL1IS ≤0.1%) at wk 48 in pts not in MMR at baseline. Secondary endpoints include MMR rate at wks 12, 24, 36, 72, 96 and 144 in pts not in MMR at baseline, MMR rate at wk 48 for pts in MMR at baseline, time to MMR, rate of early responses of BCR::ABL1IS ≤10% and ≤1% at wks 12, 24, 36 and 48, deep molecular responses (rates of MR4.0 [BCR::ABL1IS ≤0.01%] and MR4.5 [BCR::ABL1IS ≤0.0032%] at wks 12, 24, 36, 48, 72, 96 and 144), rate of cytogenetic response at wk 48 and at end of treatment (up to 144 wks), and patient-reported outcomes and quality of life. Current status As of July 2022, 77 patients have been enrolled in the study. This study is sponsored by Novartis Pharmaceuticals. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Primary Chronic Myelogenous Leukemia Blast Crisis with Precursor B Lymphoblastic Leukemia, a Case Report

Abstract Introduction/Objective Primary chronic myelogenous leukemia (CML) blast crisis at the initial disease presentation is rare. Most CML blast crisis cases present with increased myeloblasts with a minority of patients showing lymphoblastic leukemia. Differentiating primary CML lymphoblast crisis from de novo acute lymphoblastic leukemia may represent a diagnostic challenge to both pathologists and treating clinicians. This distinction is important as it has significant implications on patient management. Methods/Case Report A 15-year-old male patient was admitted to our University Hospital for hyperleukocytosis. Patient reportedly had weight loss with occasional sweats and cervical lymphadenopathy. She was found to have massive splenomegaly. Peripheral blood showed hyperleukocytosis with predominance of granulocytes at all maturation stages ranging from blast to segmented neutrophils with increased blasts. Subsequent bone marrow findings were consistent with extensive involvement by B-lymphoblastic leukemia. Ten-color Flow cytometry showed approximately 30% blasts with rare lymphocytes and monocytes. The blasts revealed precursor B-lymphoblastic immunophenotypic expression of CD45, CD10, CD19, CD20, CD22, CD34, CD38, CD200, HLA-DR and TdT expression. The results were similar to that of peripheral blood. Granulocytes showed abnormal maturation pattern with increased immature precursors and partial expression of CD4 and CD56 with no abnormalities detected in lymphocytes. In this case, while the bone marrow findings are consistent with B-lymphoblastic leukemia, the peripheral blood findings are consistent with blast phase of chronic myeloid leukemia. Further evaluation by cytogenetic and molecular studies confirmed the presence of Philadelphia chromosome, p210 transcripts, and rearrangement of BCR-ABL1, which supported the impression of precursor B-lymphoblastic leukemia in primary blast phase of CML. The patient was treated with tyrosine kinase inhibitor combined chemotherapy and went into remission. She has been followed up without significant complications for a year. Results (if a Case Study enter NA) NA. Conclusion The diagnosis of CML in primary lymphoblastic crisis is rare and needs to be systemically excluded before giving the diagnosis of de novo BCR-ABL1-positive acute lymphoblastic leukemia. If the patient does not have splenomegaly or previous leukocytosis, it needs cytological examination and extensive molecular analyses.

Relapse with BCR-ABL1 Elevation in Chronic Myeloid Leukemia after Progression to Multiple Myeloma from Monoclonal Gammopathy of Undetermined Significance with a Persistent KMT2D Mutation

Chronic myeloid leukemia (CML) and monoclonal gammopathy of undetermined significance (MGUS) are two different hematologic malignancies, the former arising from the myeloid cell lineage, and the latter arising from plasma cells. The concurrent diagnosis of CML and MGUS progression to multiple myeloma (MM) in one patient is an extremely rare event.A 59-year-old male was diagnosed with CML and MGUS with no discomfort in August 2012. Bone marrow (BM) aspiration suggested chronic myelogenous leukemia in chronic phase and perhaps myeloproliferative with 6.5% mature plasma cells (Figure 1A). FISH analysis detected that the BCR-ABL1 expression was 130%. And Next-generation sequencing (NGS) of BM showed: ASXL1 , KMT2D , SPEN , BRINP3 , ANKRD26 , PLCG1 , CUX1 were mutated (Figure 2I). The patient started oral imatinib 400 mg per day and achieved a complete cytogenetic response at 3 months. In September 2019, his IgG levels were 2,790 mg/dl (Figure 2J and serum immunofixation electrophoresis revealed monoclonal (M) protein of IgG-Lambda type (Figure 1E). BM aspiration revealed 9.5% plasma cell infiltration, including 6% mature plasma cells and 3.5% proplasmacyte (Figure 1C and 2H). Flow cytometry in BM showed 6.3% plasmacytoma and abnormal cell expressing CD38+CD138+CD56+CD117+clambda+ (Figure 1F). BM biopsy showed hematopoietic hyperplasia with abnormal growth of immature cells (Figure 1B). Fluorescent in situ hybridization (FISH) was negative. Mutations of KMT2D, SPEN, BRINP3, ANKRD26, PLCG1, CUX1, and ZMYM3 still existed(Figure 2I). In January 2020, examination of a new BM aspiration revealed that mature plasma cells were 3% and plasmablast and proplasmacyte were 4.5% (Figure 2H). In February 2020, he stopped IM therapy with undetectable BCR-ABL1 copies because he met the requirement of stopping TKI therapy . In March 2020, IgG levels were 3520 mg/dl and serum immunofixation electrophoresis still revealed monoclonal (M) protein of IgG-Lambda type. His BM aspiration demonstrated 13.5% plasma cells in April 2020 (Figure 2B and 2H). Flow cytometry in BM showed 6.44% (Figure 2F). BM biopsy showed extremely increased proliferation with abnormal growth of abnormal cells (Figure 2A). FISH demonstrated the presence of t(4;14)(p16;q32)(IGH/FGFR3) , 13q14 deletion（RB-1） and 13q14.3 （D13S319） (Figure 2C, 2D and 2E). The patient was diagnosed as MM (IgGλ type, D-S stage IA; ISS stage II) . BCR-ABL1 copies were still not detected at this point (Figure 2G). The patient continued his follow-up treatment of MM without chemotherapy.However, in June 2020, he was considered to have a molecular relapse with 0.2013% BCR-ABL1 copies in the peripheral blood (Figure 2G). NGS showed that the variant allele fractions of KMT2D, SPEN, BRINP3, ANKRD26, PLCG1, CUX1, and ZMYM3 mutations were similar to former . He restarted 400 mg daily IM therapy and BCR-ABL1 copies were undetectable againafter one month therapy (Figure 2G). BM aspiration revealed that the percentage of plasma cells increased to 25.5% in August 2020 (Figure 2H). Then the patient was started on treatment for ISS stage II standard risk myeloma with ID regimen: ixazomib 4 mg on days 1, 8 , 15 and dexamethasone 20 mg on days 1, 8, 15 , 22 in 28-day cycles. After 6 cycles , the patient got VGPR. BM aspiration demonstrated 13% plasma cells (Figure 2H). And he continued to receive myeloma treatment and imatinib . BCR-ABL1 were <MR4.5 (Figure 2G).Our research indicated that KMT2D mutation may make MGUS progress to MM with NK cells functional defects and then promote the recurrence of BCR-ABL1. Co-existence of these two diseases is rare, therefore, additional investigations are warranted.Acknowledgment:The research was supported by the Public Technology Application Research Program of Zhejiang, China (LGF21H080003), the Key Project of Jinhua Science and Technology Plan, China (2020XG-29 and 2020-3-011), the Academician Workstation of the Fourth Affiliated Hospital of the Zhejiang University School of Medicine (2019-2024), the Key Medical Discipline of Yiwu, China (Hematology, 2018-2020) and the Key Medical Discipline of Jinhua, China (Hematology, 2019-2021). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Which Tyrosine Kinase Inhibitors Should Be Selected as the First-Line Treatment for Chronic Myelogenous Leukemia in Chronic Phase?

Simple SummaryThis review discusses the optimal selection of BCR-ABL1 tyrosine kinase inhibitors (TKIs) as the first-line treatment for newly diagnosed chronic myelogenous leukemia in chronic phase (CML-CP). With the advent of TKIs, the treatment goals for CML-CP patients have changed from “simply survival” to “survival with adequate quality of life”, hence the number of CML-CP patients aiming to achieve treatment-free remission has increased, irrespective of age or comorbidities. Therefore, optimal selection of TKIs for maximizing the number of patients to achieve treatment-free remission is an important factor for consideration in future studies. To this end, we must understand the advantages and disadvantages of each TKI in terms of treatment response, disease risk at diagnosis, comorbidities, and medical expenses, and use of effective 2GTKIs based on patient background. This review provides insights into “shared decision-making” in individual cases, including the elderly population.With the use of tyrosine kinase inhibitors (TKIs), chronic myelogenous leukemia in chronic phase (CML-CP) has been transformed into a non-fatal chronic disease. Hence, “treatment-free remission (TFR)” has become a possible treatment goal of patients with CML-CP. Currently, four types of TKIs (imatinib, nilotinib, dasatinib, and bosutinib) are used as the first-line treatment for newly diagnosed CML-CP. However, the second-generation TKI (2GTKI), the treatment response of which is faster and deeper than that of imatinib, is not always recommended as the first-line treatment for CML-CP. Factors involved in TKI selection in the first-line treatment of CML-CP include not only patients’ medical background, but also patients’ choice regarding the desired treatment goal (survival or TFR?). Therefore, it is important that clinicians select an appropriate TKI to successfully achieve the desired treatment goal for each patient, while minimizing the development of adverse events. This review compares the pros and cons of using imatinib and 2GTKI for TKI selection as the first-line treatment for CML-CP, mainly considering treatment outcomes, medical history (i.e., desire for pregnancy, aging factor, and comorbidity), and cost. The optimal use of 2GTKIs is also discussed.

Leukemic retinopathy, a rare entity: A case report

Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate. Consequently, the peripheral blood cell profile shows an increased number of granulocytes and their immature precursors, including occasional blast cells. CML accounts for 20% of all leukemias affecting adults. Retinal lesions are the most common ocular manifestation of leukemia. They are found most often in adults and in patients with myeloid leukemia. Despite the significant efforts made by different groups to optimize treatment and outcome, there are still unmet needs and unanswered questions. Ophthalmologic manifestations are among the therapeutic challenge. Here we present a case of CML (chronic phase) with ophthalmologic manifestations as initial presentation, trying to shed light on this important type of presentation.

CML-417: ASCEMBL Phase 3 Health-Related Quality of Life (HRQL) Comparison of Asciminib and Bosutinib for Patients with Chronic Myelogenous Leukemia in Chronic Phase (CML-CP), Previously Treated with 2 or More Tyrosine Kinase Inhibitors (TKI)

<h3>Context:</h3> Asciminib is a first-in-class potent and specific BCR-ABL1 inhibitor that specifically targets the ABL1 Myristoyl Pocket (STAMP). ASCEMBL, the first controlled study comparing treatments for resistant/intolerant CML-CP, demonstrated that asciminib has a superior efficacy and an improved safety and tolerability profile compared with bosutinib. <h3>Objective:</h3> To evaluate the HRQL impact of asciminib compared with bosutinib at 24 weeks of treatment. <h3>Design:</h3> A phase 3, multi-center, open-label, randomized clinical trial. <h3>Patients:</h3> A total of 157 patients, randomized to asciminib 40 mg twice daily, and 76 patients randomized to bosutinib 500 mg once daily. <h3>Main Outcome Measures:</h3> HRQL was assessed in the intent to treat population with the MD Anderson Symptom Inventory – chronic myeloid leukemia (MDASI-CML), an exploratory endpoint. Additional HRQL measures were included in ASCEMBL and are reported elsewhere. Analyses included mixed model repeated measures (MMRM). <h3>Results:</h3> MMRM analyses on MDASI-CML demonstrated that asciminib patients maintained or improved from baseline on all items (demonstrating improvement on 20 out of 26 items), symptom total score, and symptom distress score. Notable item improvements from baseline included fatigue, mood, and feeling of being upset. HRQL was similar to baseline in the bosutinib arm on symptom total score, symptom distress score, and all items, except for nausea and diarrhea, with treatment differences favoring asciminib. Questionnaire compliance rates at week 24 were high and similar between treatment arms (83.1% <i>vs</i> 82.0%, respectively, for asciminib and bosutinib). <h3>Conclusions:</h3> Asciminib patients showed improvement in treatment-related symptoms and HRQL compared with baseline and relative to bosutinib, within the first 24 weeks of treatment, confirming earlier findings.

Poster: CML-417: ASCEMBL Phase 3 Health-Related Quality of Life (HRQL) Comparison of Asciminib and Bosutinib for Patients with Chronic Myelogenous Leukemia in Chronic Phase (CML-CP), Previously Treated with 2 or More Tyrosine Kinase Inhibitors (TKI)

Poster: CML-417: ASCEMBL Phase 3 Health-Related Quality of Life (HRQL) Comparison of Asciminib and Bosutinib for Patients with Chronic Myelogenous Leukemia in Chronic Phase (CML-CP), Previously Treated with 2 or More Tyrosine Kinase Inhibitors (TKI)

Pre-Transplant Transferrin Saturation Levels As a Predictive Marker for Invasive Fungal Disease Following Allogeneic Hematopoietic Stem Cell Transplantation

▪IntroductionInvasive fungal disease (IFD) following allogeneic hematopoietic stem cell transplantation (allo-HCT) is a well-known, potentially fatal complication. Previous multicenter, prospective observational studies (Girmenia et al., 2014; Sun et al., 2015) have showed that the incidence of IFD after allo-HCT was approximately 9.0%, and risk factors were disease status, development of IFD prior to allo-HCT, alternative donor source (cord blood donor and unrelated donor), diabetes mellitus, prophylaxis of IFD, and acute or chronic graft-versus-host disease (GVHD).Iron has a pivotal role in various types of fungal growth and iron overload impairs the host immune system, leading to IFD. Moreover, some retrospective studies have reported that elevated pre-transplant serum ferritin levels, as a marker of iron overload, might be associated with the development of IFD (Dadwal et al., 2015). Although use of ferritin and transferrin saturation (TSAT) to assess iron status is extremely common, whether pre-transplant TSAT levels might be related to the development of IFD after allo-HCT has not been fully examined.We therefore investigated risk factors of IFD, including iron overload markers such as ferritin and TSAT.Patients and MethodsWe retrospectively analyzed data from consecutive patients undergoing allo-HCT between 1 April 2007 and 31 December 2014. We excluded three patients with active IFD at initiation of the conditioning regimen and two patients undergoing double-cord blood transplantation. Proven or probable IFD cases were defined as IFD. According to our institution guidelines, we administered IFD prophylaxis in all patients. We used Cox proportional hazards models with time-dependent covariates to investigate risk factors for IFD.ResultsA total of 285 patients were eligible. Twenty-one patients developed IFD within 1 year after allo-HCT. Median time to onset was 77 days (range, 8-363 days). Pathogens included Aspergillus (n=12), Candida (n=2), and others (n=7).Notably, none of our participants from HLA-matched or one-antigen mismatched sibling donors developed IFD. The significant univariate risk factors were as follows: disease status (malignancies in complete remission, non-malignancies, and chronic myelogenous leukemia in chronic phase vs. others), donor type (cord blood vs. haploidentical peripheral blood with post-transplant cyclophosphamide (PT-CY) vs. others), GVHD prophylaxis (calcineurin inhibitor (CNI) plus methotrexate (MTX) vs. CNI plus mycophenolate mofetil (MMF) vs. PT-CY vs. others), use of antithymocyte globulin (ATG), TSAT, and hematologic relapse after transplant or refractory at transplant. However, development of IFD prior to allo-HCT, diabetes mellitus, and acute or chronic GVHD were not related to the development of IFD.In the multivariate model considering pre-transplant factors, although use of ATG (hazard ratio (HR) 2.68, 95% confidence interval (CI): 1.07-6.02, P=0.04) was significant, disease status (HR 2.04, 95% CI: 0.78-5.32, P=0.15) and TSAT (HR 1.02, 95% CI: 1.00-1.03, P=0.07) were marginally but significantly associated with development of IFD. Regarding post-transplant factors, in model 2, hematologic relapse after transplant or refractory at transplant (HR 9.63, 95% CI: 3.86-24.02, P<0.01), TSAT (HR 1.02, 95% CI: 1.00-1.04, P=0.03), CNI plus MMF (vs. CNI plus MTX) among GVHD prophylaxis (HR 3.48, 95% CI: 1.07-11.30, P=0.04) were significant. In model 3, hematologic relapse after transplant or refractory at transplant (HR 10.42, 95% CI: 4.21-25.79, P<0.01), TSAT (HR 1.02, 95% CI: 1.00-1.03, P=0.05), and use of ATG (HR 2.72, 95% CI: 1.08-6.82, P=0.03) were significant. Remarkably, 33 of 55 patients who underwent ATG received PT-CY (n=55) to prevent GVHD.ConclusionOur results suggest that pre-transplant TSAT value might be useful for predicting development of IFD. Further investigation might be warranted to validate the generalizability of this marker. DisclosuresHino:Novartis: Research Funding.

Role of Signal Transducing Adaptor Protein (STAP) Family in Chronic Myelogenous Leukemia

Role of Signal Transducing Adaptor Protein (STAP) Family in Chronic Myelogenous Leukemia

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.

Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation

AbstractPeripheral blood cells are increasingly used in place of bone marrow as a source of hematopoietic stem cells for allogeneic transplantation. The relative efficacy of these 2 approaches is unknown. This retrospective multivariate analysis compared results of 288 HLA-identical sibling blood stem cell transplantations with results of 536 HLA-identical sibling bone marrow transplantations. No transplants were T-cell depleted. Median follow-up was 12 months, and analyses focused on 1-year outcomes. Recipients of blood stem cell transplants had more rapid recovery of neutrophils to at least 0.5 × 109/L (median time to recovery, 14 days, compared with 19 days for marrow transplants;P < .001) and of platelets to at least 20 × 109/L (median time, 18 days, compared with 25 days for marrow transplants; P < .001). There was no significant difference in the incidence of grades II to IV acute graft versus host disease (GVHD). The incidence of chronic GVHD was significantly higher after blood stem cell transplantation (1-year probability [95% confidence interval], 65% [56%-72%] compared with 53% [47%-59%]; P = .02) Relapse incidence in the 2 transplant groups did not differ significantly. Treatment-related mortality rates were lower and leukemia-free survival rates were higher with blood stem cell transplants in patients with advanced leukemia (acute leukemia in second remission or chronic myelogenous leukemia in accelerated phase) but not in early leukemia (acute leukemia in first remission or chronic myelogenous leukemia in chronic phase). The median time from transplantation to hospital discharge was 23 days after blood stem cell transplantation and 28 days after bone marrow transplantation (P = .003). Further study with longer follow-up is necessary to definitively establish the role of blood stem cells for allogeneic transplantation, especially in patients with good-risk disease.

NOVEL-1st: A Non-Interventional, Multi-Center Observational Study to Assess the Safety and Efficacy of Nilotinib in Newly Diagnosed Patients with Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) in Taiwan

Background Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), has been approved for the treatment of patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) globally, including Taiwan. However, the real-world evidence regarding the long-term safety (primary) and effectiveness (secondary) of nilotinib in newly diagnosed untreated Ph+ CML-CP is limited in Taiwan. Methods The NOVEL-1st study was a non-interventional, multi-center study. A total of 129 patients with newly diagnosed and previously untreated Ph+ CML-CP were enrolled from 11 centers. The objective was to collect the long-term safety (primary) and effectiveness (secondary) data in patients treated with nilotinib under the real clinical practice for up to three years. Results Of the 129 enrolled patients, 32 patients (24.8%) discontinued the study, predominately due to AEs (n = 8; 6.2%), discontinuing nilotinib or switching to other treatments (n = 7; 5.4%), and death (n = 5; 3.9%). The median age of the study population was 49 years (range, 20 - 53 years), of whom 77 were male (59.7%). At enrollment, the median time from initial CML diagnosis was 22 days (range, 0.0 - 602 days), and three of them had their CML diagnosed for more than one year. Across the 3-year observational period, a total of 1,466 AEs were reported in 127 (98.4%) patients, of which 151 AEs in 44 (34.6%) patients were serious adverse events (SAEs) and 524 AEs in 37 (29.1%) patients were nilotinib-related. The most commonly reported non-hematological AEs (regardless of relationship to nilotinib, incidence ≥ 20 %) were rash (24.8%); while that for hematological AEs were thrombocytopenia (31.0%; Grade 3 or above: 13.2%) (Table 1). Nilotinib discontinuation, and dose reduction or interruptions were only reported in 9 (7.1%) and 11 (8.7%) patients, respectively. Five (3.9%) patients expired, of whom 2 were due to CML progression. Favorable efficacy outcomes were observed in this real-world study. From 3 to 36 months, the rates of clinical response increased over time, from 72.5% to 98.3% for complete hematological response (CHR), from 48.3% to 92.5% for complete cytogenetic response (CCyR), from 16.7% to 85.8% for major molecular response (MMR), from 4.2% to 65.0% for MR4.0 (BCR-ABL ≥ 4 log reduction), and from 3.3% to 45.0% for MR4.5 (BCR-ABL ≥ 4.5 log reduction) (Figure 1). The median time to CHR, CCyR, MMR, and MR4.0 were 4, 5, 9, and 25 months, respectively (not reached for MR4.5). Early molecular response (EMR), defined as BCR-ABL ≤ 10% at Month 3, was seen in 87.6% of patients. Non-hematological and hematological AEs were comparable with previous studies, with no new safety signal detected. This NOVEL-1st study demonstrated a lower percentage of patients withdrawing nilotinib owing to AEs (NOVEL-1st vs. prior: 7.1% vs. 10.0%) and an extremely lower incidence of AEs leading to dose reduction or interruption (8.7% vs. 37 - 55%). It was inferred that the high tolerability and patient adherence further contributed to high treatment response in terms of complete molecular response (CMR [i.e., MR4.5], 45% vs. 32%), molecular response 4.0 (MR4.0, 65% vs. 50%), and major molecular response (MMR, 85.5% vs. 73%) at 3 years. Over the 3 years of follow-up, there was no newly onset of hepatitis or hepatitis B flare. This NOVEL-1st study also reported lower incidence rates of CV events (NOVEL-1st vs. prior: 2.3% vs. 3.5 - 6.0%), diabetes (2.3% vs. 20.2%), and hyperglycemia (3.1% vs. 42.1%) than prior studies. None of them was judged as related to nilotinib treatment (Table 1). Conclusions Across the 3-year observational period, nilotinib demonstrated comparable efficacy and had lower risk of hepatitis flare, CV event, diabetes and hyperglycemia among Ph+CML-CP patients in a real world setting in Taiwan. Long-term good patient adherence and holistic care could contribute to good treatment outcome in this chronic disease under the first-line treatment with nilotinib. Disclosures Chen: Novartis: Current Employment. Lee:Novartis: Current Employment. Ku:Novartis: Current Employment.

Novel Approach for Bone Marrow Transplantation Conditioning in Acute Myelogenous Leukemia not Responding to the Induction Therapy Using Etoposide Carried in Lipid Core Nanoparticles: A Pilot Clinical Study

Allogeneic hematopoietic cell transplantation (HCT) is the treatment of choice for acute myelogenous leukemia (AML) not responding to induction therapy. It is a therapeutic choice for the blast phase of chronic myelogenous leukemia (CML-BP) in patients failing to respond to tyrosine kinase inhibitors (TKIs). Lipid core nanoparticles (LDEs) concentrate severalfold more in blast cells than in corresponding normal cells. Incorporation of anticancer drugs to LDE formulations increases the pharmacologic action and decreases the toxicity. We tested a drug-targeting system, LDE-etoposide plus total body irradiation (TBI; 1200 cGy dose), in 13 patients with AML not responding to the induction therapy and in 2 patients with CML-BP refractory to second-generation TKIs. The mean patient age was 46.7 years (range, 22 to 66 years). The LDE-etoposide dose was escalated at 20, 30, 40, 50, and 60 mg/kg. No patients developed grade 4 or 5 toxicity; however, mucositis grade 3 occurred in 6 patients, 3 patients experienced diarrhea, and 1 patient had an elevated total bilirubin level. No deaths were related to conditioning. All patients were successfully engrafted. The median times to neutrophil and platelet engraftment were 20 ± 5 days and 16 ± 4 days, respectively. Five patients (33.4%) had acute graft-versus-host-disease (GVHD), including 4 grade I, and 1 with grade II, and 8 patients (57.1%) had moderate-to-severe chronic GVHD. This pilot study shows the potential of LDE-etoposide plus TBI as an HCT conditioning regimen in AML patients not responding to the induction and refractory therapies for CML-BP patient. These findings pave the way for subsequent larger clinical trials.

Psychotropic drug initiation in patients diagnosed with chronic myeloid leukemia: a population-based study in France.

Psychotropic drugs (PD) are often used close to a cancer diagnosis and may be considered as a way of coping. We aimed to determine the incidence of anxiolytics, hypnotics, antidepressants, and antipsychotics initiation around a diagnosis of chronic myelogenous leukemia (CML). Population-based cohort: Data were extracted from Systeme National des données de Santé (SNDS, the French health insurance database) at the regional level (Midi-Pyrenees area, 2.9 million inhabitants). All newly diagnosed patients treated by a CML tyrosine kinase inhibitor (TKI) between 10/01/2011 and 04/01/2014 were included. Pre-CML (9months before to 3months before first TKI prescription-F-TKI) and CML (3months before to 9months after F-TKI) phases were defined. The main evaluation criterion was the initiation of PD during CML phase. Determinants associated with this incident PD use were studied through a logistic regression model. We compared pre-CML and CML healthcare consumption. The cohort included 103 patients (mean age of 60.8years). PD initiation rate was 35.9%, anxiolytics being the most initiated PD (59.5%). Advanced age was associated with PDinitiation (adjusted OR=1.029, 95% CI=1.001-1.056). The number of consultations during the pre-CML phase and female gender tended to be associated with increased risk of PD initiation in univariate analysis. For PD initiators, healthcare consumption was greater in CML but not in pre-CML phase. PD initiation is a frequent finding around a CML diagnosis. Its risk increases with age. It could be a way to identify a subgroup with higher healthcare consumption.