Blast Phase Chronic Myeloid Leukemia Research Articles

Chronic myeloid leukemia, tyrosine kinase inhibitors and cardiovascular system.

Cardiovascular system health becomes important with the extended survival of chronic myeloid leukemia (CML) patients. Cardiotoxicities are related to the second- and third-generation tyrosine kinase inhibitors (TKIs). The most frequent and important cardiovascular events are myocardial infarction, stroke and peripheral arterial disease, QT prolongation, pleural effusions, and both systemic and pulmonary hypertension. The aim of this paper is to review the interactions between administrated TKIs and the cardiovascular system during the clinical course of CML. Elucidation of TKI effects on the cardiovascular system is vital since the current goal of CML therapy is a cure that leads to normal age and gender-similar survival with a normal quality of life. Up to August 2022, literature searches were performed via the internet search engines MEDLINE, EMBASE, GOOGLE SCHOLAR: (i) chronic myeloid leukemia; (ii) tyrosine kinase inhibitor; (iii) cardiovascular system. Only articles in English and research including humans were included in the search. Tailored TKI treatment with individual patient characteristics must account for CML disease risk, patient age, patient comorbidities, patient compliance, TKI drug off-target risk profile, accelerated or blastic phase CML disease, pregnancy and allografting in CML. The treatment-free survival, improving quality of life, limiting adverse events of TKIs, and the optimal dose and administration duration of TKIs are still a matter of controversy. Special attention should be paid to the comorbidities of CML patients and clinical TKI effects on CVS since the aim of CML treatment is a cure that leads to normal age and gender-similar survival with a "normal" quality of life. CVS is an important morbidity and mortality cause for adult patients. The discontinuation of TKI treatment in CML and the treatment-free remission of CML patients are very important in order to reduce the risk for cardiovascular adverse effects of TKIs. The frail CML patients and especially the patients who have cardiac comorbidities, should be carefully evaluated for TKI treatment, and hematopoietic stem cell transplantation (HSCT) should be the last choice in these risky CML patients. The current CML treatment target is a cure that leads to normal age and gender-adjusted survival with a "normal" quality of life. Cardiovascular disorders are one of the major obstacles to reaching this target in CML patients. The treatment choices for CML patients must include a cardiovascular perspective.

Treg Cells, FoxP3 and TGF-β Expression and Significance in Chronic Myeloid Leukemia

To investigate the expression and significance of regulatory T cells (Tregs), FoxP3 and transforming growth factor-β (TGF-β) in different phase of chronic myeloid leukemia (CML). Peripheral blood of 73 CML patients in Department of Hematology, Heze Municipal Hospital from March 2018 to March 2021 were collected. According to patient's period in CML, they were divided into ND CML group (newly diagnosed), CP CML group (chronic period), and BP CML group (blast phase). The percentage of Tregs, expression level of FoxP3 mRNA and TGF-β were detected by flow cytometry, RT-qPCR, and ELISA, respecitively. The roles of above indices in clinical pathogenesis of patients with CML were analyzed. The proportion of Treg in the ND CML group was slightly higher than the CP CML group, but the difference was not statistically significant (P =0.695), while the BP CML group was significantly higher than the other two groups (P =0.008, P <0.001). The expression levels of FoxP3 mRNA in ND CML group, CP CML group and BP CML group were 11.61±2.21, 6.46±1.35 and 8.54±2.13, respectively. Significant difference in FoxP3 mRNA levels was observed among patients in different phases of CML (F =55.199, P <0.001). The expression levels of FoxP3 mRNA both in ND CML group and BP CML group were significantly higher than that in CP CML group (P <0.001), and the ND CML group was the highest (P <0.001). However, the expression levels of TGF-β in different phases of CML showed no statistical differences (H =0.634, P =0.728). The abnormal distribution of Treg subset in different phases of CML and the significant increase of the expression level of FoxP3 mRNA in the new onset and blast phase of CML suggest that Tregs may promote the occurrence and progression of CML through immune regulation.

Abstract CT101: Phase I study of the T-cell receptor-like antibody Hu8F4 in patients with advanced hematologic malignancies

Abstract Background: Despite recent advances in the treatment of AML, most approaches are rarely curative and most patients (pts) succumb to relapsed disease. The effectiveness of stem cell transplant and associated graft vs. leukemia effect implies an important role for immune-based therapy in producing long lasting remissions. Traditional approaches using immunotherapy have failed to establish a suitable surface target or treatment paradigm that is effective in myeloid malignancies. Hu8F4 is a humanized T-cell receptor-like monoclonal antibody that binds to the conformational epitope of PR1 bound to HLA-A2, which is highly, differentially expressed on the surface of AML compared to normal progenitors. Methods: We conducted a first in human, phase I dose escalation trial of Hu8F4 in pts with myeloid malignances. Pts with R/R AML, MDS, CMML, and myeloid blast phase of CML with adequate organ function and PS ≤ 2 were eligible. Pts were treated on 7 escalating dose levels, ranging from 0.01 mg/kg to 10 mg/kg IV on D1 &amp; 15. Initial dose levels required 1 pt per dose (0.01, 0.03, 0.1, 0.3, 1), followed by 3 pts per dose (3, 10). Results: 10 pts with R/R AML have been enrolled, with a median age of 65 years (range, 23-77), including 6 females (60%). Pts had received a median of 4 (1-4) prior therapies; 5 pts (50%) had a PS of 2. At enrollment, the median WBC was 1.9 (0.1 - 18.4), median BM blasts were 32% (8 - 76); 9 (90%) pts had complex karyotype and 3 (30%) had a TP53 mutation. All pts had &amp;gt; 98% surface expression of PR1 on the myeloid blasts. Hu8F4 Cmax ranged up to 160,000 ng/mL with t1/2 of 48 hours and clearance of 2.61 hr*ng/mL at the highest dose. Weak anti-drug antibodies were observed after week 4 in 2 of 3 pts treated at 3 mg/kg. With a median follow up of 3.5 months (1.1 - 9.9), pts have received a median of 1 (1-4) cycle of therapy. Two pts had decline in BM blasts and 4 had stable disease. Routine peripheral blood testing revealed sharp decline in peripheral blasts immediately after infusion of Hu8F4 on D1 and 15 with associated elevation in serum LDH in some pts and a rise in normal granulocytes, consistent with on-tumor effects. The pharmacokinetic parameters and transient blast reduction indicated a possible sink effect mediated by high levels of circulating blasts. SAEs documented on study were mostly disease-related and included infections, cytopenias, hemoptysis, pneumonia, and GI bleeding. Treatment related AEs were temporally related to the infusion included hypotension (Grade 2: N=2), rigors (Grade 2: N=2; Grade 1: N=1). All infusion reactions were observed at dose levels of 3 and 10 mg/kg, but were transient, and managed with steroids and antihistamines. All pts proceeded with their next dose without further issues. No cytokine release syndrome or neurologic toxicity was observed. Correlative studies support antibody dependent cellular cytotoxicity and phagocytosis as important mechanisms of anit-AML activity. Conclusion: Hu8F4 was well tolerated with no dose-limiting toxicities observed at the maximum planned dose. On-target peripheral blast reduction temporally related to infusion suggests biological activity. Real-time pharmacokinetic data on study indicate a possible sink effect that may be overcome by a more frequent dosing strategy. Citation Format: Tapan M. Kadia, Hagop Kantarjian, Gheath Alatrash, Anna Sergeeva, Hong He, Lisa St. John, Priya Koppikar, Celine Kerros, Abhishek Maiti, Courtney Dinardo, Elias Jabbour, Serge Vesrstovsek, Naveen Pemmaraju, Nitin Jain, Ghayas Issa, Guillermo Montalban-Bravo, Aditi Shastri, Daniel Couriel, Rhona Pinsoy, Sapna Parshottam, Richard Champlin, Jorge Cortes, Jeffrey Molldrem. Phase I study of the T-cell receptor-like antibody Hu8F4 in patients with advanced hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT101.

The m6A regulator KIAA1429 stabilizes RAB27B mRNA and promotes the progression of chronic myeloid leukemia and resistance to targeted therapy

Chronic myeloid leukemia (CML) is a common adult leukemia. Both the acute phase of the disease and the adverse effects of anti-cancer treatments can lead to a poor prognosis. The N6-methyladenine (m6A) modification plays an important regulatory role in various physiological and pathological processes. KIAA1429 is a known m6A regulator, but the biological role of KIAA1429 in CML is unclear. In this study, we observed that the m6A levels and KIAA1429 expression were significantly up-regulated in patients with blast phase CML. Notably, KIAA1429 regulated the total level of RNA m6A modification in the CML cells and promoted the malignant biological behaviors of CML cells, including proliferation, migration, and imatinib resistance. Inhibiting KIAA1429 in CML cells reduced the stability of RAB27B mRNA through the m6A/YTHDF1 axis, consequently inhibiting CML proliferation and drug efflux, ultimately increasing the sensitivity of CML cells to imatinib. Moreover, the knockdown of RAB27B also inhibited the proliferation and drug resistance of CML cells and promoted their apoptosis. Rucaparib, a recently developed anti-cancer agent, suppressed the expression of KIAA1429 and CML cell proliferation and promoted cell apoptosis. Rucaparib also inhibited the tumorigenesis of CML cells in vivo. The combined use of rucaparib and imatinib enhanced the sensitivity of CML cells to imatinib. Our study provides evidence that elevated KIAA1429 expression in the blast phase of CML enhances the stability of RAB27B mRNA through the m6A/YTHDF1 axis to up-regulate RAB27B expression, thereby promoting CML progression. Rucaparib exerts inhibitory effects on KIAA1429 expression and thus reduces CML progression.

Long-term outcomes of third-line therapy with tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia: A real-life experience.

Tyrosine kinase inhibitor (TKI) therapy has greatly improved the prognosis of patients with chronic myeloid leukemia (CML), improving the survival expectancy of patients with chronic phase (CP) CML to that of the general population. However, despite these advances, nearly 50% of patients with CP CML experience failure to respond to frontline therapy, and most fail to respond to the subsequent second-line TKI. Treatment guidelines for patients failing second-line therapy are lacking. This study aimed to determine the efficacy of TKIs as third-line therapy in a "real-world" clinical practice setting and identify factors favorably influencing the long-term outcomes of therapy. We have retrospectively analyzed the medical records of 100 patients with CP CML. The median age of the patients was 51 (range, 21-88) years, and 36% of the patients were men. The median duration of the third-line TKI therapy was 22 (range, 1- 147) months. Overall, the rate of achieving complete cytogenetic response (CCyR) was 35%. Among the four patient groups with different levels of responses at baseline, the best results were achieved in the groups with any CyR at the baseline of third-line therapy. Thus, СCyR was reached in all 15 and 8/ 16 (50%) patients with partial cytogenetic response (PCyR) or minimal or minor CyR (mmCyR), respectively, whereas CCyR was detected only in 12/69 (17%) patients without any CyR at baseline (p < 0.001). Univariate regression analysis revealed that the factors negatively associated with CCyR achievement in thirdline TKI therapy were the absence of any CyR on first- or second-line TKI therapy (p < 0.001), absence of CHR prior to third-line TKI (p = 0.003), and absence of any CyR prior to third-line TKI (p < 0.001). During the median observation time from treatment initiation to the last visit [56 (4-180) months], 27% of cases progressed into accelerated phase or blast phase CML, and 32% of patients died. Progression-free survival (PFS) and overall survival (OS) were significantly higher in patients with CCyR on third-line than in the group without CCyR on third-line therapy. At the last visit, third-line TKI therapy was ongoing in 18% of patients, with a median time of treatment exposure of 58 (range, 6-140) months; 83% of these patients had stable and durable CCyR, suggesting that patients without CHR at baseline and without CCyR at least by 12 months on third-line TKI should be candidates for allogeneic stem cell transplantation, third-generation TKIs, or experimental therapies.

Effects of miR-144-3p on Proliferation, Cell Cycle and Apoptosis of K562 Cells

To investigate the effects of miR-144-3p on cell proliferation, cell cycle and apoptosis of blast phase chronic myelogenous leukemia (CML) K562 cells. K562 cells were cultured in vitro and mimics negative control, hsa-miR-144-3p mimics, inhibitor negative control and miR-144-3p inhibitor were respectively transfected into K562 cells with transfection reagents. The cells were divided into five groups including blank control, mimics negative control, miR-144-3p mimics, inhibitor negative control and miR-144-3p inhibitor. After transfection, the cell proliferation activity was detected by CCK-8 assay. The cell cycle distribution and apoptosis were detected by flow cytometry. Compared with the blank control and mimics negative control groups, the proliferation rate of miR-144-3p mimics group was significantly decreased (P<0.05), the proportion of S phase cells was markedly increased (P<0.05), while the proportion of G1 phase cells was obviously decreased (P<0.05), and the apoptosis rate was significantly increased (P<0.05). Compared with the blank control and inhibitor negative control groups, the proliferation rate of miR-144-3p inhibitor group was obviously increased (P<0.05), the proportion of S phase cells was markedly decreased (P<0.05), while the proportion of G1 phase cells was obviously increased (P<0.05), and the apoptosis rate was significantly decreased (P<0.05). miR-144-3p can inhibit the proliferation and promote apoptosis of K562 cells, affect the cell cycle, and block K562 cells in S phase, which indicates that miR-144-3p is involved in the cell cycle activity of CML during blastic phase.

Pediatric chronic myeloid leukemia in myeloid blast crisis

Chronic myeloid leukemia (CML) accounts for 2-3% of childhood leukemias. About 5% of cases present in a blastic phase of CML which clinically and morphologically mimics more common acute leukemias of childhood. We report a case of a 3-year-old male who presented with gradual onset swelling of the abdomen and extremities along with generalized weakness. Examination revealed massive splenomegaly, pallor, and pedal edema. Initial workup showed anemia, thrombocytopenia, and leukocytosis (120,000/uL) with a blast percentage of 35%. Blasts were positive for CD13, CD33, CD117, CD34 and HLA-DR, and stained negative for Myeloperoxidase and Periodic Acid Schiff. Fluorescence in situ hybridization was positive for b3a2/e14a2 junction BCR-ABL1 transcript and negative for RUNX1-RUNX1T1/t(8;21), clinching the diagnosis of CML in myeloid blast crisis. The patient expired within 17 days of diagnosis and initiation of therapy.

Hemophagocytic Lymphohistiocytosis Appearing During Blast Phase of Chronic Myeloid Leukemia

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening illness with rapid progression and high mortality and is associated with genetic defects or can be induced by malignancies or severe infections. Most of the hematological malignancy-related HLH reported was accompanied by lymphoid neoplasms. Here, we present an unusual case of HLH with co-existing blast phase of chronic myeloid leukemia (CML-BP). A diagnosis of AML-M5 with most likely concomitant HLH was made based on the clinical features, morphology, flow cytometry immunophenotyping, and genetics. Moreover, clinical characteristics were more suggestive of myeloid blast phase CML than de novo AML with the positive p210 BCR-ABL1. However, disease-causing mutations of HLH were not available, the patient probably had secondary malignancy-associated HLH induced by an acute infection. The case focuses on the contribution of bone marrow morphological examination in getting the first diagnostic clue of CML-BP concomitant with HLH.

Activation-Induced Cytidine Deaminase Expression in Patients with Chronic Myeloid Leukemia

Objective: The findings on chronic myeloid leukemia (CML) patients suggest that clonal tumoral cells tend to have additional mutations besides the formation of the BCR-ABL fusion gene. Previous studies have demonstrated abnormal activation-induced cytidine deaminase (AID) expression in various types of cancer, showing AID transcript levels to be elevated in the CML blast phase. The study aimed to investigate the AID gene expression levels in CML and to investigate the etiopathogenic role of AID, which is not yet fully understood. Materials and Methods: This study analyzed the AID transcript levels of 80 CML patients and 50 controls using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results: The study found the AID transcript levels to be significantly elevated (p &lt; 0.001) in the CML patients compared to the control group, with no significance in AID transcript levels with regard to the patients’ age, gender, clinical characteristics, or laboratory findings. No correlation was found between the AID and BCR-ABL transcript levels, while a positive correlation was present between AID transcript levels and presence of polymorphonuclear leukocytes (PMNL; r = 0.320, p = 0.021). No significant relationship occurred in AID transcription levels with the tyrosine-kinase-inhibitor (TKI) resistant mutation profile or cytogenetic response during TKI therapy. Conclusion: This study found AID expression levels to be significantly elevated in CML patients and AID to be able to contribute to the etiopathogenesis of CML

BH3 mimetics in combination with nilotinib or ponatinib represent a promising therapeutic strategy in blast phase chronic myeloid leukemia

Dysregulation of the BCL-2 family is implicated in protecting chronic myeloid leukemia (CML) cells from intracellular damage and BCR::ABL1-inhibition with tyrosine kinase inhibitors (TKIs) and may be a viable therapeutic target in blast phase (BP-)CML, for which treatment options are limited. BH3 mimetics, a class of small molecule inhibitors with high-specificity against the prosurvival members of the BCL-2 family, have displayed clinical promise in the treatment of chronic lymphocytic and acute myeloid leukemia as single agents and in combination with standard-of-care therapies. Here we present the first comparison of inhibition of BCL-2 prosurvival proteins BCL-2, BCL-xL and MCL-1 in combination with a second or third generation TKI, crucially with comparisons drawn between myeloid and lymphoid BP-CML samples. Co-treatment of four BP-CML cell lines with the TKIs nilotinib or ponatinib and either BCL-2 (venetoclax), MCL-1 (S63845) or BCL-xL (A-1331852) inhibitors resulted in a synergistic reduction in cell viability and increase in phosphatidylserine (PS) presentation. Nilotinib with BH3 mimetic combinations in myeloid BP-CML patient samples triggered increased induction of apoptosis over nilotinib alone, and a reduction in colony-forming capacity and CD34+ fraction, while this was not the case for lymphoid BP-CML samples tested. While some heterogeneity in apoptotic response was observed between cell lines and BP-CML patient samples, the combination of BCL-xL and BCR::ABL1 inhibition was consistently effective in inducing substantial apoptosis. Further, while BH3 mimetics showed little efficacy as single agents, dual-inhibition of BCL-2 prosurvival proteins dramatically induced apoptosis in all cell lines tested and in myeloid BP-CML patient samples compared to healthy donor samples. Gene expression and protein level analysis suggests a protective upregulation of alternative BCL-2 prosurvival proteins in response to BH3 mimetic single-treatment in BP-CML. Our results suggest that BH3 mimetics represent an interesting avenue for further exploration in myeloid BP-CML, for which alternative treatment options are desperately sought.

Single Centre, Retrospective Analysis of Treatment Outcomes and Prognostic Factors in Blastic Phase Chronic Myeloid Leukemia (CML-BP) Following Systemic Therapy

Introduction: Despite the introduction of BCR-ABL1 tyrosine kinase inhibitors (TKI), the prognosis of blastic phase chronic myeloid leukemia (CML-BP) remains dismal. Due to its low incidence, prospective evaluation of outcomes of CML-BP following systemic treatment is challenging. Thus, we aimed to evaluate the outcomes of CML-BP following systemic therapy, and to analyze prognostic factors affecting treatment outcomes. Methods: We retrospectively identified 55 patients with CML-BP per the European LeukaemiaNet 2013 criteria who treated at the Princess Margaret Cancer Centre in Toronto, Canada between 2000 and 2022. Patient and disease characteristics at the time of CML-BP diagnosis are presented in Table 1. Multiparametric flow cytometry data are described below, with percentages reflecting the proportion of positive antigen expression in evaluable patients. Treatment outcomes measured included: complete response (CR), leukaemia-free survival (LFS) and overall survival (OS). Prognostic factors evaluated include: age, transformation from chronic/accelerated phase (CP/AP), clonal evolution (CE), additional cytogenetic abnormalities (ACA), ABL1 KD mutation, extramedullary disease, blast immunophenotype, systemic treatment modality (intensive chemotherapy (IC) +/- TKI vs TKI monotherapy) and allogeneic haematopoietic stem cell transplantation (HCT). Results: Among the 55 patients, the median age at time of CML-BP diagnosis was 45 years (17 - 68) and included 35 (64%) cases of CML in myeloid BP (MBP) and 20 (36%) cases of lymphoid BP (LBP). 40 (72%) patients had transformed from a previous CP/AP with a median time of 2.4 years (0.1 - 19.3) from initial diagnosis to transformation. Extramedullary disease was present in 18/53 (34%) patients. The blast immunophenotype of MBP patients (n=31) was: CD34+ (84%), CD117+ (52%), HLA-DR+ (68%), CD13+ (87%), CD33+ (97%), MPO+ (40%), CD38+ (100%) and CD123+ (50%). Nine MBP patients (36%) had aberrant CD7 expression. Among 17 evaluable LBP patients, the immunophenotypic profile was: CD34+ (94%), HLA-DR+ (76%), CD19+ (94%), CD20+ (41%), CD10+ (94%), TdT (88%), CD38+ (100%) and CD7+ (18%). Nine patients (53%) had aberrant CD13 expression and five (29%) displayed aberrant CD33 expression. At CML-BP diagnosis, 21/42 (50%) had an ACA, of which 11 (26%) patients had high risk ACA, defined as −7/7q, 11q23 or 3q26.2 aberrations, or complex karyotype. Among transformed patients, CE was present in 16/43 (37%) patients. In 18 patients evaluated with Sanger sequencing at time of BP transformation, 9 patients (50%) had an ABL1-KD mutation. 54/55 received systemic therapy: 31 (57%) intensive chemotherapy (IC) + TKI, 7 (13%) IC alone, and 16 (30%) TKI monotherapy. Two patients died before response assessment, one after IC and one after TKI monotherapy. Among 46 patients with available post-treatment bone marrow assessments, CR/CRi rates were similar in those treated with IC+ TKI (29/31; 94%), IC only (5/6; 83%) or TKI only (7/9; 78%). Overall, 40/54 (74%) patients proceeded to allogeneic HCT after achieving CR/CRi or second CP. After a median follow-up of 39 months, the 3-year LFS and OS rates of all patients were 34.9% (20.7-49.6%) and 44.9% (95% CI, 30.4-58.4%), respectively. Patients with CML-LBP had a significantly higher OS compared to those with CML-MBP (p=0.0463), however, no significant difference in LFS was seen (p= 0.0913). Median duration of LFS and OS was 1.56 and 2.51 years, respectively. The following variables were found to be independently prognostic for OS: Transformation from CP/AP (p=0.0489, HR 4.328 [1.007, 18.60]), CD117 expression at time of CML-BP (p=0.0291, HR 2.809 [1.111, 7.102]), and IC + TKI (vs TKI monotherapy) (p=0.0068, HR 0.268 [0.104, 0.689]). CE at BP, transformation from CP/AP and IC +TKI (vs TKI monotherapy) were prognostic for LFS by univariate analysis, however, none was identified as independent risk factors. Conclusion The prognosis of CML-BP remains poor despite systemic therapy. Transformation from CP/AP, CD117 positivity at diagnosis of CML-BP and TKI monotherapy were identified as independent, adverse prognostic risk factors for OS. However, treatment with IC + TKI appeared to improve survival outcomes compared with TKI therapy alone. Therefore, combination therapy with IC + TKI should be considered the optimal strategy in treatment patients with CML-BP. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hematoma or Bleeding As Initial Presentation of Chronic Myeloid Leukemia (CML): Review

Background: Chronic myeloid leukemia (CML) is defined per the WHO 2016 classification as a myeloproliferative neoplasm characterized by the chromosomal translocation t (9; 22) (q34.1; q11.2). Patients with CML can have a very wide range of symptoms at presentation. Most patients presents as an incidental finding on a routine complete blood count (CBC). Symptoms might include B symptoms like fever, loss of weight, and night sweats. While splenomegaly is the most common initial presentation in the chronic phase, in accelerated or blast phase of CML, the presentations might resemble acute leukemia with signs and symptoms of anemia, bleeding, petechiae, and ecchymosis. Bleeding might be the initial presentation of acute leukemia; however, it is scarce for CML, especially the chronic phase, to present initially with spontaneous bleeding without coagulopathy and thrombocytopenia. The mechanism behind this rare perennation is not known up to the moment. Methods: A literature search was performed for English language articles using Medline data through PubMed, Scopus, and Google Scholar, for any date up to June 2022. The following keywords were used "CML," "spontaneous bleeding," "bleeding," and "hematoma.". We did not find any retrospective, prospective or clinical trials or reviews on this rare topic. We decided to review all the case reports and case series published in the literature and collect all the general characteristics, common findings, treatment, and outcomes Results: Thirty articles with 30 patients were included. Most of them were males, 23 (76.7%) with a median age was 40 years, and the majority were of Asian origin 13 out of 17 (76.4%). Hematoma sites were different; intracranial was most affected in 11 (36.6%) patients, followed by intraabdominal and musculoskeletal (MSK) bleeding in 9 (30%) patients each. One case was reported as an intrathoracic bleed. All the patients diagnosed with CML chronic phase except one patient in accelerated phase without thrombocytopenia and one presented with blast crisis. Coagulopathy was reported in 2 patients only. The average duration of symptoms was around 6 days, and the median white blood cell count on presentation was 232,000, while 192,000 for platelets and 8.5 gm/dL for hemoglobin. The sequel reported were bilateral deafness in 1 patient, unilateral blindness in 1 patient, and one admission to the intensive care unit. Sixteen (53%) patients received imatinib 400 mg daily. Surgery was done in 12 (40%) patients, and a similar number were treated conservatively. Documented recovery was reported in 10 (33%) patients. Overall survival was reported in 26 patients. 20 (66.6%) were alive, while 6 (33.3%) were dead. The cause of death was reported to be intracranial hemorrhage in 2 cases, sepsis in one case, and splenic rupture in one case. Conclusion: Spontaneous bleeding or hematoma as an initial presentation of CML is rare. Thrombocytopenia and coagulopathy do not explain most of the cases. We hypothesize that male sex, Asian ethnicity, and hyperleukocytosis could be a risk factors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of Olverembatinib Based Regimen in Patients with Philadelphia Chromosome-Positive Advanced Leukemias: A Real-World, Single-Center Experience

Background Philadelphia chromosome-positive (Ph+) advanced leukemias including chronic myeloid leukemia blast phase and acute lymphoblastic leukemia have poor outcomes. Olverembatinib, a novel BCR-ABL tyrosine kinase inhibitor, has anti-tumor activity in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia cells(CML) and tumor models, is currently approved for treating resistant CML patients with T315I mutation by the National Medical Products Administration in China, and in phase Ib clinical trials in the US for ponatinib resistant and/or intolerant CML patients. Olverembatinib also inhibited p-KIT, p-AKT, p-ERK1/2, and p-STAT3 to a higher extent than ponatinib, and suppresses pre-B ALL cells through inhibition of the SRC kinase and PI3K/AKT pathways and may be a potential therapeutic agent for the management of pre-B ALL. However, the efficacy of Olverembatinib based regimen in Philadelphia chromosome- positive advanced leukemias is still unknown. Methods We conducted a retrospective study on patients with Philadelphia Chromosome- Positive Advanced Leukemias including Ph+ CML (n=11) and Ph+ ALL (n=5) who received a Olverembatinib-based regimens in our center. Results The trial included 11 patients with Ph+ CML and 5 patients with Ph+ ALL who had relapsed after transplantation. Among the 11 CML patients, there were 2 CML-AP, 6 chronic myeloid leukemia-myeloid blast phase (MBP), 2 chronic myeloid leukemia-lymphoblastic bast phase(LBP), 1 chronic myeloid leukemia- myeloid and lymphoblastic mixed blast phase. Median age was 34 years and the median follow-up time was 4 months. Also, two (18.2%) CML-AP patients were treated witholverembatinib alone. Six (54.5%) CML-BP patients were treated with olverembatinib in combination with demethylating agents. And two patients with LBP received VDP and stem cell transplantation (SCT)-based regimens combined with olverembatinib. Treatment for patients with chronic myeloid leukemia- myeloid and lymphoblastic mixed blast phase is consistent with patients with MBP. The overall response rate of 8 evaluable patients was 100%. CR/CRi rate was 100%, and CCyR/PCyR rates 62.5% vs 37.5%, respectively. In addition, 6 patients achieved major molecular responses (MMR). the remaining three patients were not yet due for evaluation. Of 5 patients with ph+ ALL that relapsed after transplantation, 1patient was treated with blinatumomab and olverembatinib, 2 patients were treated with intensive chemotherapy and olverembatinib followed by donor lymphocyte infusion(DLI), The treatment for the remaining 2 patients was Anti-CD19 chimeric antigen receptor T cell (CAR-T) technology followed by olverembatinib, and this 5 Ph+ ALL patients achieved complete molecular remission(CMR). In addition, treatment-related adverse reactions included cytopenias, skin pigmentation, proteinuria and high triglycerides, all grades less than 2. No deaths have occurred. Conclusion Olverembatinib-based regimens show encouraging activity and safety in very heavily pre-treated, advanced Ph+ leukemias.

Olverembatinib (HQP1351) Overcomes Ponatinib Resistance in Patients with Heavily Pretreated/Refractory Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Background Olverembatinib is a novel third-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) with antitumor activity against CML and Ph+ ALL regardless of genotype and a preliminarily favorable human safety profile. This study is the first to report on the safety, efficacy, and pharmacokinetic (PK) profiles of olverembatinib in patients with CML (all phases) and Ph+ ALL outside China, whose disease failed ponatinib treatment and at least 2 prior TKI treatments. Methods In this multicenter, open-label, randomized trial, olverembatinib is administered orally on alternate days (QOD) in adults with chronic-phase (CP-CML), accelerated-phase (AP-CML), or blast-phase CML (BP-CML) or Ph+ ALL. Enrolled patients have had no fewer than 2 prior TKI failures, except for those whose disease harbors T315I mutation, for whom the number of previous TKIs is not limited. Study participants are randomized 3:3:2 to olverembatinib 30, 40, or 50 mg QOD in 28-day cycles. Results A total of 30 patients have been enrolled, including 23 with CP-CML, 4 with AP-CML, 2 with BP-CML, and 1 with Ph+ ALL. The median (range) treatment duration is 4.8 (0.03-21.29) months and the median (range) interval from CML/Ph+ ALL diagnosis to olverembatinib treatment onset, 7.0 (1.5-24.0) years. Half (15/30) of patients are men, and the median (range) age is 47.0 (21.0-74.0) years. In all, 1 (3.3%), 7 (23.3%), 8 (26.7%), and 9 (30.0%) patients received 2, 3, 4, and ≥ 5 prior TKIs, respectively. A total of 21 (70.0%) patients were pretreated with third-generation TKI ponatinib, including 17 (81.0%) with resistance and 4 (19.0%) with intolerance; a total of 5 (16.7%) were pretreated with asciminib; 12 (40.0%) had T315I mutations; and 13 (43.3%), hypertension. At baseline, all patient BCR-ABL1IS levels were > 1%. Olverembatinib was well tolerated. Twenty-two (73.3%) patients experienced any-grade treatment-related AEs (TRAEs; Table 1), incidences of which tended to be dose-dependent. Most nonhematologic TRAEs were grade 1/2. Common grade 3/4 hematologic TRAEs included thrombocytopenia (7/30; 23.3%), neutropenia (5/30; 16.7%), and decreased leukocyte counts (4/30; 13.3%). In all, 11 (36.7%) of 30 patients experienced serious AEs, of which 6 (20.0%) were considered olverembatinib-related and 1 (3.3%) led to treatment discontinuation. One patient with AP-CML from the 50-mg dose cohort died of progressive disease. Olverembatinib conferred potent antileukemic activity in patients with CML and Ph+ ALL (Table 2). Of 21 efficacy-evaluable patients, 17 were evaluable for cytogenetic response, of whom 10 (58.8%) had complete cytogenetic response (CCyR); 9/21 (42.9%) patients had major molecular responses (MMR). Olverembatinib was effective in patients with either T315I-mutant (62.5%, CCyR; 50%, MMR) or T315IWT (55.6%, CCyR; 38.5%, MMR), and its effectiveness was not compromised by prior use of ponatinib or asciminib. Among patients pretreated with ponatinib with available responses, 5 (55.6%) of 9 patients with ponatinib-resistant disease experienced CCyR and 6 (54.5%) of 11, MMR. Four of 5 patients pretreated with asciminib showed response. PK analyses indicated an approximately dose-proportional increase in olverembatinib plasma exposure from 30 to 50 mg QOD and comparable plasma exposure between Chinese and US CML populations. Conclusions Olverembatinib monotherapy is efficacious and well tolerated in patients with TKI-refractory CML and Ph+ ALL. Even in patients with CML who were ponatinib or asciminib resistant, or who had T315I mutations, olverembatinib showed strong efficacy. This analysis confirms that olverembatinib is a potentially viable treatment option for patients with CML and Ph+ ALL, including those with ponatinib failure or T315I mutation. Internal study identifier: HQP1351-CU101. Clinicaltrials.gov identifier: NCT04260022. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Molecular Response of ≤10% BCR::ABL1IS Is Predictive of Positive Outcomes in Treatment-Resistant Patients with Chronic Phase Chronic Myeloid Leukemia (CP-CML) Treated with Ponatinib from the Phase 2 Optic Trial

Background:BCR::ABL1 mutations are key contributing factors to tyrosine kinase inhibitor (TKI) resistance in patients with chronic myeloid leukemia (CP-CML). Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) designed to potently inhibit BCR::ABL1 with or without any single resistance mutation, including T315I. The Phase 2 OPTIC trial evaluated benefit/risk outcomes of ponatinib using a novel response-based dosing strategy in patients with heavily pretreated resistant CP-CML. In the OPTIC trial, all 3 dosing regimens demonstrated benefit in resistant patients, with optimal benefit/risk outcomes observed in patients who received the response-based dosing of 45 → 15 mg/day. Here we present a post hoc analysis of long-term outcomes (progression-free survival [PFS] and overall survival [OS]) of patients in the OPTIC trial who reached landmark clinical responses (≤1%, >1%-≤10%, and >10% BCR::ABL1IS by Months 3, 6, and 12). Methods: The OPTIC trial design has been previously described (Cortes J, et al. Blood. 2021;138:2042-50). Overall, 99% of patients had treatment-resistant disease; 61% of patients had a best response to their last prior therapy of complete hematologic response or worse; and 84% had a best response of >10% BCR::ABL1IS to prior therapy. This landmark analysis describes PFS and OS in patients with ≤1%, >1%-≤10%, and >10% BCR::ABLIS by Months 3, 6, and 12. Disease progression was defined as the loss of complete hematologic response or major cytogenetic response, development of acute- or blast-phase CML, death, or 2 instances of white blood cell count increases (>20,000 cells/μL, ≥4 weeks apart) after the first 4 weeks of treatment. Patients with ≤1% BCR::ABL1IS at baseline were excluded from this analysis. The probabilities of PFS and OS at 24 months were calculated using the Kaplan-Meier method. The proportion of patients attaining ≤1% BCR::ABLIS by 36 months was also assessed. Results: A total of 276 patients with resistant CP-CML were included in the intention-to-treat (ITT) population: 45-mg (n=93), 30-mg (n=93), and 15-mg (n=90) starting dose cohorts. At the cutoff date of May 9, 2022, 56 (20%), 78 (28%), and 95 patients (34%) had reached ≤1% BCR::ABL1IS by Months 3, 6, and 12, respectively. Among patients remaining within each dosing cohort at 36 months, most had attained ≤1% BCR::ABLIS (57%-65%). Among all ITT patients within each dosing cohort (45 mg, n=93; 30 mg, n=93; 15 mg, n=90), the highest response rate by 36 months was observed in the 45-mg cohort (35%). Four patients with ≤1% BCR::ABL1IS at baseline were excluded from the landmark analysis. Based on this landmark analysis, regardless of starting dose, patients who attained landmark response levels of ≤1% and >1-≤10% BCR::ABL1IS in 3-12 months had substantially improved PFS outcomes at 24 months compared with patients with >10% BCR::ABL1IS (Table). In the landmark analysis population, patients who did not reach ≤10% BCR::ABL1IS within 12 months had unfavorable PFS outcomes (Table). Long-term OS outcomes in the landmark analysis population were similar across all BCR::ABL1IS levels, regardless of whether response was reached by 3, 6, or 12 months (Table). Conclusion: Ponatinib provided robust responses in the OPTIC trial population comprising patients with heavily pretreated, TKI-resistant CP-CML. In this landmark analysis, attainment of ≤10% BCR::ABL1IS with ponatinib within 12 months was associated with improved long-term PFS outcomes compared with PFS outcomes associated with remaining at >10% BCR::ABL1IS. These findings underpin the clinical benefit of achieving molecular responses with ponatinib, especially achieving ≤10% BCR::ABL IS within 12 months. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clonal Evolution of t(8;21) Coexisting with t(9;22) in a Blastic Transformation of Chronic Myeloid Leukemia

Abstract Introduction/Objective Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by chromosomal translocation t(9;22) and the production of the fusion protein BCR-ABL1. The clinical course of the disease is characterized by a chronic phase, accelerated phase, and blast phase. One of the criteria for the progress of chronic phase to accelerated phase is the presence of cytogenetic anomaly additional to t(9;22). The blast phase of CML usually presents as acute myelogenous leukemia (AML); however, its characteristics are different from de novo AML. One of the most common subtypes of de novo AML with balanced translocation is AML with t(8;21). Here, we present a case of the blast phase of CML that presents t(8;21). Methods/Case Report The peripheral blood from a 51-years-old-man presenting with fatigue and splenomegaly showed leukocytosis, mild anemia, marked neutrophilia with left shift, monocytosis, basophilia, and &amp;lt;1% blasts. Flow cytometry identified an increase in granulocyte events with the left shift. Chromosome studies detected t(9;22) by karyotyping and FISH. BCR-ABL1 transcript was detected at 41.98% on the International Scale by RT-PCR, consistent with chronic myeloid leukemia (CML). The following bone marrow biopsy confirmed a diagnosis of the chronic phase of CML with &amp;lt;5% myeloblasts. After a year of treatment with imatinib, the patient developed marked leukocytosis, anemia, and thrombocytopenia. Flow cytometry detected an immature cell population comprising ~50% of total cells positive for CD117, CD34 (partial), CD13 (dim), and CD33. A few blasts were also positive for cMPO and negative for CD14, CD64, TdT, Glycophorin A, cytoplasmic CD3, CD19, and other markers. BCR-ABL1 transcript was detected at 56.45% on the International Scale by RT-PCR. Chromosome analysis revealed all cells (20/20) exhibiting t(8;21) leading to a fusion between RUNX1 and RUNX1T1 genes with a maintained t(9;22). FISH analysis confirmed t(8;21) and t(9;22). These findings were consistent with a blast phase of CML. Results (if a Case Study enter NA) NA Conclusion Progression of CML is frequently accompanied by cytogenetic evolution. However, the development of t(8;21) in Ph+ clones is extremely rare. Only six cases have been previously reported. Misidentifying this blast phase of CML (in the absence of a clinical history of the chronic phase of CML) as AML with recurrent genetic abnormalities is a potential pitfall we should be aware of.

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.

Development of JAK2 positive myelofibrosis on a background of chronic myeloid leukaemia.

A 50-year-old male patient was admitted with a history of constitutional symptoms and weight loss with a marked leucocytosis (WBC 270 × 109/L) and blood film appearances suggestive of chronic myeloid leukaemia (CML). Platelet count was normal at presentation (298 × 109/L). BCR-ABL1 was detected (b2a2) confirming CML. Bone marrow trephine sections revealed a markedly expanded myeloid series but no excess of blasts (Figure 1). Megakaryocytes were noted to be reduced in size with some bare nuclei seen. Cytogenetics confirmed 46,XY, t(9;22)(q34;q11) with no additional anomalies. He was commenced on imatinib but developed progressive full blood count abnormalities (WBC 9.6 × 109/L, Neutrophils 6.7 × 109/L, Hb 99 g/L, Platelets 650 × 109/L) with an increase in his BCR-ABL1 ratio 3 months following this. He was switched to nilotinib and had a further bone marrow evaluation, which revealed a marked increase in reticulin fibres (MF-2) but no evidence progression to accelerated or blast phase CML. Despite an excellent initial response to nilotinib (achieving molecular response (MR-2) after 7 weeks), he developed a persistent neutrophilia and thrombocytosis. Due to his blood count abnormalities and bone marrow fibrosis, JAK2 testing was performed and revealed the V617F mutation. A repeat bone marrow examination (to assess cytogenetic response) revealed increased megakaryopoiesis with dysplastic, spindle-shaped, and hyperlobulated nuclei, with clustering, with increased reticulin fibres (MF-2 with some focal areas of MF-3) noted again (Figures 2 and 3). No ABL kinase domain mutations were detected at time of JAK testing. He was diagnosed with JAK2 positive myelofibrosis (independent of his known CML) (DIPSS score 0, associated with medial survival of over 14 years). The patient began to experience headaches and was commenced on hydroxycarbamide 500 mg once daily in case these were vaso-occlusive in origin. He remains well and in a good molecular BCR-ABL1 response on both therapies over 2 years following the diagnosis. He achieved major molecular remission (MR4) at 26 months. Fibrosis within the bone marrow in CML patients is common. The presence of both BCR-ABL1 and JAK2 V617F mutations is highly unusual. It is unclear whether these mutations arose within the same clone or within differing clones. Previous cases have reported unmasking of Philadelphia negative myeloproliferative neoplasms during treatment for CML [1]. Of note, retrospective testing on the initial bone marrow samples from the CML was first diagnosed for JAK2 V617F was negative. None. The authors report no conflict of interest. Christopher Gerard Mullen wrote the clinical summary. Tamasin Doig provided images of bone marrow trephine sections. Victoria Louise Campbell and Alice Klauser made revisions and edits to the clinical summary. None. This article involved no human or animal research participants. No patient identifiable information was submitted. Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Treatment of blast phase chronic myeloid leukaemia: A rare and challenging entity.

Despite the success of BCR-ABL-specific tyrosine kinase inhibitors (TKIs) such as imatinib in chronic phase (CP) chronic myeloid leukaemia (CML), patients with blast phase (BP)-CML continue to have a dismal outcome with median survival of less than one year from diagnosis. Thus BP-CML remains a critical unmet clinical need in the management of CML. Our understanding of the biology of BP-CML continues to grow; genomic instability leads to acquisition of mutations which drive leukaemic progenitor cells to develop self-renewal properties, resulting in differentiation block and a poor-prognosis acute leukaemia which may be myeloid, lymphoid or bi-phenotypic. Similar advances in therapy are urgently needed to improve patient outcomes; however, this is challenging given the rarity and heterogeneity of BP-CML, leading to difficulty in designing and recruiting to prospective clinical trials. This review will explore the treatment of BP-CML, evaluating the data for TKI therapy alone, combinations with intensive chemotherapy, the role of allogeneic haemopoietic stem cell transplantation, the use of novel agents and clinical trials, as well as discussing the most appropriate methods for diagnosing BP and assessing response to therapy, and factors predicting outcome.

BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph+ chronic myeloid leukemia.

In most patients with chronic myeloid leukemia (CML) clonal cells can be kept under control by BCR::ABL1 tyrosine kinase inhibitors (TKI). However, overt resistance or intolerance against these TKI may occur. We identified the epigenetic reader BRD4 and its downstream‐effector MYC as growth regulators and therapeutic targets in CML cells. BRD4 and MYC were found to be expressed in primary CML cells, CD34+/CD38− leukemic stem cells (LSC), and in the CML cell lines KU812, K562, KCL22, and KCL22T315I. The BRD4‐targeting drug JQ1 was found to suppress proliferation in KU812 cells and primary leukemic cells in the majority of patients with chronic phase CML. In the blast phase of CML, JQ1 was less effective. However, the BRD4 degrader dBET6 was found to block proliferation and/or survival of primary CML cells in all patients tested, including blast phase CML and CML cells exhibiting the T315I variant of BCR::ABL1. Moreover, dBET6 was found to block MYC expression and to synergize with BCR::ABL1 TKI in inhibiting the proliferation in the JQ1‐resistant cell line K562. Furthermore, BRD4 degradation was found to overcome osteoblast‐induced TKI resistance of CML LSC in a co‐culture system and to block interferon‐gamma‐induced upregulation of the checkpoint antigen PD‐L1 in LSC. Finally, dBET6 was found to suppress the in vitro survival of CML LSC and their engraftment in NSG mice. Together, targeting of BRD4 and MYC through BET degradation sensitizes CML cells against BCR::ABL1 TKI and is a potent approach to overcome multiple forms of drug resistance in CML LSC.