Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia Research Articles

Toxicities associated with tyrosine kinase inhibitor maintenance following allogeneic hematopoietic cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Allogeneic hematopoietic cell transplantation (HCT) offers a potential cure in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL); nonetheless, relapses are common and the major cause of mortality. One strategy to prevent relapse is tyrosine kinase inhibitor (TKI) maintenance post-HCT, but published clinical experience is primarily with the first-generation TKI imatinib while data with newer generation TKIs are limited. We conducted a retrospective analysis of 185 Ph+ ALL patients who underwent HCT followed by TKI maintenance from 2003 to 2021 at City of Hope. Initially, 50 (27.0%) received imatinib, 118 (63.8%) received a second-generation TKI (2G-TKI), and 17 (9.2%) received ponatinib. A total of 77 patients (41.6%) required a dose reduction of their initial TKI due to toxicity. Sixty-six patients (35.7%) did not complete maintenance due to toxicity; 69 patients (37.3%) discontinued 1 TKI, and 11 (5.9%) discontinued 2 TKIs due to toxicity. Initial imatinib versus 2G-TKI versus ponatinib maintenance was discontinued in 19 (38.0%) versus 68 (57.6%) versus 3 (17.6%) patients due to toxicity (p = .003), respectively. Patients on ponatinib as their initial TKI had a longer duration of TKI maintenance versus 2G-TKI: 576.0 days (range, 72-921) versus 254.5 days (range, 3-2740; p = .02). The most common reasons for initial TKI discontinuation include gastrointestinal (GI) intolerance (15.1%), cytopenia (8.6%), and fluid retention (3.8%). The 5-year overall survival and progression-free survival for the total population were 78% and 71%, respectively. Our findings demonstrate the challenges of delivering post-HCT TKI maintenance in a large real-world cohort as toxicities leading to TKI interruptions, discontinuation, and dose reduction were common.

Bilateral optic nerve infiltration and leukemic retinopathy as initial signs of leukemia relapse with central nervous system involvement in an adult: a case report

BackgroundWe describe a case in which bilateral optic nerve infiltration and leukemic retinopathy were the initial signs of disease relapse in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+-ALL) with central nervous system (CNS) involvement.Case presentationA 65-year-old Asian female with Ph+-ALL in complete remission presented at our institution with symptoms of visual disturbance, central scotoma and pain with eye movement in both eyes for a 1-month duration. Ophthalmic examination revealed remarkable optic disc swelling with multiple flame-shaped peripapillary hemorrhages, retinal venous dilation and retinal hemorrhages in both eyes. She was subsequently referred to the treating oncologist and diagnosed with Ph+-ALL relapse with multiple relapsed diseases involving the bone marrow and CNS. After intrathecal (IT) therapy, her visual acuity dramatically improved, and her leukemic infiltrates decreased.ConclusionsTo the best of our knowledge, this is the first case report of ALL relapse with CNS involvement presenting as bilateral optic nerve infiltration and leukemic retinopathy in an adult. Hence, we highlight the priority and sensitivity of ophthalmic examinations, as they are noninvasive methods for detecting leukemia relapse.

A Multicentre, Randomized Trial in Adults with de novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukaemia to Assess the Efficacy of Ponatinib versus Imatinib in Combination with Low-Intensity Chemotherapy, to Compare End of Therapy with Indication for Stem Cell Transplantation versus Tyrosine Kinase Inhibitor, Blinatumomab, and Chemotherapy in Optimal Responders, and to Evaluate Blinatumomab in Suboptimal Responders (GMALL-EVOLVE)

Introduction: Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ALL) is treated as standard of care (SoC) by imatinib-based treatment combined with induction and consolidation chemotherapy followed by allogeneic stem cell transplantation (SCT) in first remission. The German Multicenter ALL Study Group for Adult ALL (GMALL) reports about a trial to evaluate the impact of ponatinib-based therapy, blinatumomab treatment for suboptimal responders, and the possibility of omission of SoC Allo SCT in optimal responders entitled GMALL-EVOLVE. Methods: Herein, imatinib is randomized versus ponatinib as frontline treatment combined with chemotherapy, optimal responders also get randomized between SCT and chemo-immunotherapy, and suboptimal responders receive immunotherapy before SCT. The trial is registered under the EudraCT number 2022-000760-21. Conclusion: This trial will answer several major questions in the treatment of Ph+ALL.

Real-world outcomes of ponatinib treatment in 724 patients with CML and Ph+ ALL: a post-marketing surveillance study with a special interest in arterial occlusive events in Japan.

In September 2016, ponatinib was approved in Japan for the treatment of patients with chronic myeloid leukemia with resistance/intolerance to prior tyrosine kinase inhibitors and patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia. We conducted a post-marketing all-case surveillance to study the safety and efficacy of ponatinib in clinical practice, focusing on arterial occlusive events. Data from 724 patients were collected for 2years from the initiation of ponatinib. The arterial occlusive events were reported in 6.49% (47/724) with an exposure-adjusted incidence rate of 6.8/100 person-years. The risks associated with arterial occlusive events were age and comorbidities including hypertension and diabetes. At 104weeks, the cumulative major molecular response rate in patients with chronic-phase chronic myeloid leukemia was 67.2% and the complete cytogenetic response in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia was 80.0%. Furthermore, the estimated 1-year overall survival rate was 98.5% for chronic-phase chronic myeloid leukemia and 68.6% for Philadelphia chromosome-positive acute lymphoblastic leukemia. This surveillance demonstrated that ponatinib has a favorable safety and efficacy profile in Japanese patients and also showed the necessity of closely monitoring arterial occlusive events in older adults and patients with predisposing factors for atherosclerosis.

Ponatinib vs Imatinib in Frontline Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

In newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is common. Ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I. To compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL. Global registrational, phase 3, open-label trial in adults aged 18 years or older with newly diagnosed Ph+ ALL. From January 2019 to May 2022, eligible patients at 77 sites were randomized 2:1 to ponatinib (30 mg/d) or imatinib (600 mg/d) with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after the cycle 20 phase of the trial. The last date of follow-up for this analysis was August 12, 2022. Patients received ponatinib, 30 mg/d, or imatinib, 600 mg/d, with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. The ponatinib dose was reduced to 15 mg on achievement of minimal residual disease-(MRD) negative complete remission. The primary end point of this interim analysis was MRD-negative complete remission (≤0.01% BCR::ABL1 [MR4] centrally assessed by reverse transcriptase-quantitative polymerase chain reaction), with complete remission maintained for at least 4 weeks at the end of cycle 3. The key secondary end point was event-free survival. Of 245 patients randomized (median age, 54 years; 133 [54.3%] female), 232 (ponatinib, n = 154; imatinib, n = 78) who had p190 or p210 dominant isoforms verified by the central laboratory were analyzed for the primary end point. The MRD-negative complete remission rate (primary end point) was significantly higher with ponatinib (34.4% [53/154]) vs imatinib (16.7% [13/78]) (risk difference, 0.18 [95% CI, 0.06-0.29]; P = .002). At the data cutoff, event-free survival had not met the prespecified number of events. Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group. The most common adverse events were similar between treatment groups. Arterial occlusive events were infrequent and comparable between groups (ponatinib, 2.5%; imatinib, 1.2%). Ponatinib demonstrated a superior rate of MRD-negative complete remission at the end of induction vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. The safety profile of ponatinib was comparable with imatinib. ClinicalTrials.gov Identifier: NCT03589326.

Minimal residual disease monitoring in childhood Philadelphia chromosome-positive acute lymphoblastic leukemia: prognostic significance and correlation between multiparameter flow cytometry and real-time quantitative polymerase chain reaction

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CAR-T Therapy Followed by Hematopoietic Stem Cell Transplantation Can Improve Survival in Children Relapsed/Refractory Philadelphia Chromosome-positive B-cell Acute Lymphoblastic Leukemia.

Philadelphia chromosome (Ph)-positive B-cell acute lymphoblastic leukemia (ALL) has a high complete remission (CR) rate, but relapse and prolonged measurable residual disease remain serious problems. We sought to describe the CR rate measurable residual disease negative rate and address the results and safety of pediatric patients who underwent after receiving chimeric antigen receptor (CAR) specific for CD19 (CAR-19) followed by hematopoietic stem cell transplantation (HSCT) for the treatment of Ph-positive ALL. A descriptive study was conducted at Peking University People's Hospital from September 2013 to January 2021. 13 patients with relapsed/refractory Ph-positive B-ALL who received CAR-T therapy followed by allo-HSCT were included. We concentrated on the overall patient survival and CR rate. The median time between CAR-T therapy and allo-HSCT was 58 days. Among all the patients, the CR rate was 100%, the flow cytometry negativity rate was 84.62%, and the BCR-ABL negativity rate was 53.85% at 1 month after CAR-T infusion. All the patients achieved a major molecular response in 6 months after HSCT. After a median follow-up of 45 months, the 3-year OS rate was 66.7%, and the 3-year DFS rate was 61.5%. The 3-year OS rate of patients with BCR-ABL-positive pre-HSCT was significantly lower than that in the BCR-ABL-negative group (40.0% vs. 85.7%, P =0.042). Also, the same trend was observed for the 3-year DFS rate but did not differ significantly (40.0% vs. 75.0%, P =0.233). CAR-T therapy followed by allo-HSCT can be a safe and effective treatment for Ph-positive B-ALL pediatric patients.

Frontline combination of dasatinib and low-intensity chemotherapy in adults with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia

ABSTRACT Background Studies on dasatinib-based low-intensity induction regimens and post-remission strategies are limited in China. Therefore, we conducted a single-center phase 2 trial in newly diagnosed adult patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) to establish the efficacy and safety of this treatment approach. Research design and methods Patients received one month of dasatinib plus low-intensity chemotherapy and two months of dasatinib monotherapy for induction, followed by a single course of high-dose methotrexate for consolidation. Subsequently, they underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) or tyrosine kinase inhibitor (TKI)-based treatment for maintenance therapy between October 2015 and August 2022. Results Twenty-two patients were enrolled. Median age was 45 years (range, 20–71). The rates of major and complete molecular responses in the third month were 18.2% and 40.9% respectively. With a median follow-up of 15 months (range, 5–89), the estimated 3-year disease-free survival (DFS) and overall survival (OS) were 52.4% and 73.2%, respectively. The TKI-based cohort had a significantly poorer DFS (p = 0.014) and OS (p = 0.008) than the allo-HSCT cohort. Conclusions Our results suggest that dasatinib-based low-intensity chemotherapy is safe and effective as an induction strategy in the Chinese population. Allo-HSCT plays a crucial role in the long-term outcomes of patients with Ph+ ALL. Clinical trial registration The trial was registered at ClinicalTrials.gov as NCT02690922.

Clinical efficacy and safety of blinatumomab bridging CAR-T cell therapy in the treatment of patients with adult acute B-cell lymphoblastic leukemia

Objective: Exploring the efficacy and safety of bridging blinatumomab (BiTE) in combination with chimeric antigen receptor T (CAR-T) cell therapy for the treatment of adult patients with acute B-cell lymphoblastic leukemia (B-ALL) . Methods: Clinical data from 36 adult B-ALL patients treated at the First Affiliated Hospital of Suzhou University from August 2018 to May 2023 were retrospectively analyzed. A total of 36 cases were included: 18 men and 18 women. The median age was 43.5 years (21-72 years). Moreover, 21 cases of Philadelphia chromosome-positive acute lymphoblastic leukemia were reported, and 16 of these cases were relapsed or refractory. Eighteen patients underwent blinatumomab bridging followed by CAR-T cell therapy, and 18 patients received CAR-T cell therapy. This study analyzed the efficacy and safety of treatment in two groups of patients. Results: In the BiTE bridge-to-CAR-T group, 16 patients achieved complete remission (CR) after BiTE immunotherapy, with a CR rate of 88.9%. One month after bridging CAR-T therapy, bone marrow examination showed a CR rate of 100.0%, and the minimal residual disease (MRD) negativity rate was higher than the nonbridging therapy group (94.4% vs. 61.1%, Fisher, P=0.041). The incidence of cytokine release syndrome and other adverse reactions in the BiTE bridge-to-CAR-T group was lower than that in the nonbridging therapy group (11.1% vs. 50.0%, Fisher, P=0.027). The follow-up reveals that 13 patients continued to maintain MRD negativity, and five patients experienced relapse 8.40 months (2.57-10.20 months) after treatment. Two of five patients with relapse achieved CR after receiving the second CAR-T cell therapy. In the nonbridging therapy group, 10 patients maintained continuous MRD negativity, 7 experienced relapse, and 6 died. The 1 year overall survival rate in the BiTE bridge-to-CAR-T group was higher than that in the nonbridging therapy group, with a statistically significant difference at the 0.1 level (88.9%±10.5% vs. 66.7%±10.9%, P=0.091) . Conclusion: BiTE bridging CAR-T cell therapy demonstrates excellent efficacy in adult B-ALL treatment, with a low recent recurrence rate and ongoing assessment of long-term efficacy during follow-up.

Involvement of BCR::ABL1 in laminin adhesion of Philadelphia chromosome-positive acute lymphoblastic leukemia through upregulation of integrin α6.

Adhesion of cancer cells to extracellular matrix laminin through the integrin superfamily reportedly induces drug resistance. Heterodimers of integrin α6 (CD49f) with integrin β1 (CD29) or β4 (CD104) are major functional receptors for laminin. Higher CD49f expression is reportedly associated with a poorer response to induction therapy in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Moreover, a xenograft mouse model transplanted with primary BCP-ALL cells revealed that neutralized antibody against CD49f improved survival after chemotherapy. Considering the poor outcomes in Philadelphia chromosome (Ph)-positive ALL treated with conventional chemotherapy without tyrosine kinase inhibitors, we sought to investigate an involvement of the laminin adhesion. Ph-positive ALL cell lines expressed the highest levels of CD49f among the BCP-ALL cell lines with representative translocations, while CD29 and CD104 were ubiquitously expressed in BCP-ALL cell lines. The association of Ph-positive ALL with high levels of CD49f gene expression was also confirmed in two databases of childhood ALL cohorts. Ph-positive ALL cell lines attached to laminin and their laminin-binding properties were disrupted by blocking antibodies against CD49f and CD29 but not CD104. The cell surface expression of CD49f, but not CD29 and CD104, was downregulated by imatinib treatment in Ph-positive ALL cell lines, but not in their T315I-acquired sublines. Consistently, the laminin-binding properties were disrupted by the imatinib pre-treatment in the Ph-positive ALL cell line, but not in its T315I-acquired subline. BCR::ABL1 plays an essential role in the laminin adhesion of Ph-positive ALL cells through upregulation of CD49f.

Ponalfil trial for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia: Long-term results.

Ponalfil trial for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia: Long-term results.

Ponatinib-Related Vasospastic Angina.

Tyrosine kinase inhibitors (TKIs) are essential drugs for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Cardiovascular or arteriothrombotic adverse events have been reported in patients treated with TKIs. We report 3 cases of Ponatinib-related vasospastic angina, in which prophylactic administration of nitrates or calcium channel blockers was effective.

Dasatinib-Induced Chylothorax- A Rare Case

Dasatinib is an efficacious and highly potent second-generation oral tyrosine kinase inhibitor used in the therapy of Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL) or BCR-ABL-positive chronic myeloid leukaemia (CML). Pulmonary complications are commonly seen with Dasatinib therapy out of which pleural effusion is the most frequent finding. Pleural effusion in these cases is caused secondary to fluid retention, however, chylothorax causing pleural effusion is exceptionally rare. A 58-year-old man treated with second-line Dasatinib for CML presented to us with Empyema thoracis for a chest tube insertion. Thoracentesis showed thick dirty haemorrhagic aspirate, which was then inferred as chylothorax by cholesterol and triglyceride concentrations. After the exclusion of other common causes, drug-induced chylothorax was confirmed. Dasatinib was stopped, a short course of prednisolone was given and the chylothorax resolved. A substitute drug as suggested by the haematologist was started. There was no reoccurrence of pleural effusion.

Allogeneic stem cell transplantation is still a highly curative therapy in adults with philadelphia chromosome-positive acute lymphoblastic leukaemia.

The application of tyrosine kinase inhibitors (TKIs) and novel immunotherapies has improved outcomes in patients with Ph + acute lymphoblastic leukaemia (ALL), and the issue of whether there is still a need for stem cell transplantation has become controversial. We performed a retrospective study to explore whether stem cell transplantation still held a place in patients with Ph + ALL if only imatinib and 2nd generation TKIs are available and affordable. A total of 292 patients were included. The median age was 38 years [range 14-64, IQR 28-48]. Patients receiving transplants (n = 216) had better rates of 4-year disease-free survival (DFS, 68% vs. 24%, P < .0001) and overall survival (OS, 72% vs. 47%, P < .0001) than those receiving continuous TKIs plus chemotherapy (TKI-chemo) (n = 76). In the multivariate analysis, male sex, WBC count ≥ 95 × 109/L and PLT count ≤ 154 × 109/L at diagnosis were significantly associated with poorer outcomes, and transplantation was significantly associated with favourable DFS and OS. In addition, the transplant outcomes were superior in any subgroup according to the number of risk variables. Furthermore, propensity score matching (PSM) analyses showed similar findings in the whole cohort and in age- and BCR-ABL1 level-based subgroups after the first or second consolidation. In conclusion, transplantation as a one-time procedure for adults with Ph + ALL patients remains important in countries lacking accessibility to third-generation TKIs or immunotherapies, regardless of the depth of the molecular response.

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Children: A Retrospective Cohort Study at a Pediatric Oncology Center.

Background and objective Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL Ph+) is quite rare among pediatric patients. Its management has undergone significant changes in the past few years, leading to some variability in how it is approached. At the Portuguese Oncology Institute of Porto (IPOP),a tertiary oncological center, the standard of carehas been aligned with the guidelines proposed by the European intergroup study of post-induction treatment of ALL Ph+ (EsPhALL). In this study, we aimed to examine the experience and outcomes related tothe treatment of pediatric patients with ALL Ph+ at IPOP. Methods This retrospective cohort study involvedpediatric patients diagnosed with ALL Ph+ at IPOP between January 2008 and December 2022 and analyzed their outcomes. Results A total of 14 patients were included. IKFZ1 was altered in five patients (out of nine in whom it was searched). Five patients were treated according to EsPhALL 2004, which involved starting imatinib later in a discontinuous manner [resulting in both five-year overall survival (OS) and progression-free survival (PFS) of 60%]. The EsPhALL 2010 (preconizing a continuous imatinib regimen instead) was employed in three patients, with a five-year OS and PFS of 66.7%. Allchildren mentioned above received cranial irradiationtherapy (CRT). Finally, six were treated according to the EsPhALL 2015, which stopped including CRT in its backbone. The five-year OS was 100%, whereas every patient progressed with an increase in BCR::ABL1 levels greater than 1-log. Moreover, until 2015, all patients had been recommended to undergo allogeneic hematopoietic stem cell transplantation (alloHSCT). However, since 2015, alloHSCT has been exclusively reserved for relapsed/refractory (R/R) disease or poor responders with positive measurable residual disease (MRD). In total, alloHSCT was performed in nine patients. Conclusions Although initially associated with a poor prognosis, the ALL Ph+ paradigm is drastically shifting. Further studies will hopefully clarify the outcomes in this population and help understand the role of central nervous system (CNS) prophylaxis, alloHSCT, and MRD quantification.

Utility of allogeneic stem cell transplantation for adult Ph+ALL with complete molecular remission.

This study aimed to investigate the usefulness of allogeneic stem cell transplantation (allo-SCT) for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) in the first complete remission (CR1) with complete molecular remission (CMR). We compared the outcomes between Ph+ALL patients who did or did not undergo allo-SCT in CR1. We included patients enrolled in the prospective clinical studies in the tyrosine kinase inhibitor era conducted by the Japan Adult Leukemia Study Group, who achieved CMR within 3 months. A total of 147 patients (allo-SCT: 101; non-SCT: 46) were eligible for this analysis. In the multivariate analyses, allo-SCT was significantly associated with both superior overall survival (OS) (adjusted hazard ratio (aHR): 0.54; 95% CI: 0.30-0.97; p = .04) and relapse-free survival (RFS) (aHR: 0.21; 95% CI: 0.12-0.38; p < .001). The 5-year adjusted OS and RFS were 73% and 70% in the allo-SCT cohort, whereas they were 50% and 20% in the non-SCT cohort. Despite the higher non-relapse mortality (aHR: 3.49; 95% CI: 1.17-10.4; p = .03), allo-SCT was significantly associated with a lower relapse rate (aHR: 0.10; 95% CI: 0.05-0.20; p < .001). In addition, allo-SCT was also associated with superior graft-versus-host disease-free, relapse-free survival (aHR: 0.43; 95% CI: 0.25-0.74; p = .002). Propensity score-matched analyses confirmed the results of the multivariate analyses. In patients who achieved CMR within 3 months, allo-SCT in CR1 had superior survival and lower relapse compared with the non-SCT cohort.

Targeting IL-17A enhances imatinib efficacy in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia

Dysregulated hematopoietic niches remodeled by leukemia cells lead to imbalances in immunological mediators that support leukemogenesis and drug resistance. Targeting immune niches may ameliorate disease progression and tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive B-ALL (Ph+ B-ALL). Here, we show that T helper type 17 (Th17) cells and IL-17A expression are distinctively elevated in Ph+ B-ALL patients. IL-17A promotes the progression of Ph+ B-ALL. Mechanistically, IL-17A activates BCR-ABL, IL6/JAK/STAT3, and NF-kB signalling pathways in Ph+ B-ALL cells, resulting in robust cell proliferation and survival. In addition, IL-17A-activated Ph+ B-ALL cells secrete the chemokine CXCL16, which in turn promotes Th17 differentiation, attracts Th17 cells and forms a positive feedback loop supporting leukemia progression. These data demonstrate an involvement of Th17 cells in Ph+ B-ALL progression and suggest potential therapeutic options for Ph+ B-ALL with Th17-enriched niches.

Philadelphia chromosome-positive acute lymphoblastic leukemia presenting with bilateral serous retinal detachment: A case report and review of the literature

We report a case who presented with bilateral serous retinal detachment (SRD) as the initial sign of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). A 49-year-old female presented with blurred vision. A colored fundus image of the patient revealed SRD around the posterior pole’s optic disc. Bone marrow aspiration showed infiltration with lymphoblasts. The patient was diagnosed with Ph+ ALL. SRD regressed in the color fundus image of the patient after induction chemotherapy and intrathecal methotrexate. The patient’s visual symptoms completely regressed. In conclusion, acute leukemia should be considered in the differential diagnosis of cases presenting with SRD.

Ponatinib Improved the Prognosis of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Japanese Single-Center Cohort Study.

Introduction The overall survival (OS) of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) has improved with the combination of tyrosine kinase inhibitor (TKI) with intensive chemotherapy. In recent years, there has been increased interest in the possibility of long-term survival without allogeneic hematopoietic stem cell transplantation (HSCT) or maintenance therapy. The aim of this study was to determine the effectiveness of treatment and the resultant outcomes in Ph+ALL patients using real-world data. Methods We performed a single-center retrospective analysis utilizing Akita University Hospital data (Akita, Japan) from November 2000 to June 2023 to evaluatethe outcomes of TKI with intensive chemotherapy for Ph+ALL. Results Twenty-three patients with Ph+ALL were treated with intensive chemotherapy combined with TKI, including six imatinib, four dasatinib, and 13 ponatinib. The median patient age was 53 years (range; 28-67). Eighteen patients (78%) achieved complete molecular remission (CMR) within three months. HSCT was performed in 16 patients (70%), all of whom did not receive post-transplant TKI maintenance therapy. Six of the seven patients who did not undergo HSCT received maintenance therapy with ponatinib after intensive chemotherapy. The three-year OSwas 81%. Ponatinib treatment resulted in a much higher OS rate than imatinib/dasatinib (100% vs. 60%;P=0.011). CMR within three months was identified as a prognostic factor for molecular relapse-free survival (hazard ratio (HR)=0.22;P=0.027). CD20 positivity was identified as a risk factor for hematological relapse (HR=5.2, P=0.032). Conclusion Even in a single-center cohort study, ponatinib, as a combination TKI with intensive chemotherapy or maintenance therapy, may improve the prognosis of Ph+ALL. Patients with CMR within three months might not necessarily needto receive HSCT, but a subsequent treatment-free status could have been achieved only by HSCT. Furthermore, CD20 positivity may be a useful biomarker for future treatment decisions in patients with Ph+ALL.

Olverembatinib Combined with Venetoclax and Reduced-Intensity Chemotherapy for Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Early Results from a Phase II Study

Background The combination of olverembatinib (HQP1351), a novel third-generation tyrosine kinase inhibitors (TKIs), with venetoclax generated high response rates in patients with relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). However, the efficacy and safety of these two agents-based regimens as frontline treatment remains unknown. Methods This is a single-arm phase II study (NCT05594784) that enrolled patients (pts) ≥ 14 years (yrs) of age with newly diagnosed Ph + ALL. Pts were required to have an ECOG performance score ≤ 2 and adequate organ function. Pts with accelerated phase or blastic phase of chronic myeloid leukemia were excluded. Pts were treated with a combination of venetoclax (100 mg d1, 200 mg d2, 400 mg d3-28), olverembatinib 40 mg once every continuously other day, vincristine 1.4 mg/m 2 (maximum dose 2 mg) on day 1, 8, 15, 22, and prednisone 60 mg/m 2 on day 1-14; 40 mg/m 2 on day 15-28 in cycle 1. In cycle 2-3, oral treatment with venetoclax 400 mg × 7 days, olverembatinib once every other day continuously and prednisone 60 mg/m 2 × 7 days was administrated in the form of outpatient treatment (Figure 1A). Cycles were repeated every 28 days. Olverembatinib 40 mg once every other day was given during cycle 1 and was reduced to 30 mg once every other day for pts achieving a complete molecular response (CMR). Routine triple intrathecal injection (methotrexate 10 mg, cytarabine 50 mg, and dexamethasone 10 mg) was performed to prevent central nervous system involvement. The selection of subsequent treatment was determined based on the patient's molecular response at 3 months and the availability of donor. The primary end point of this study was the CMR rate at 3 months. CMR was defined as undetectable BCR:ABL1 transcripts by using RT-PCR method with sensitivity of 0.001%. Major molecular response (MMR) was defined as more than 3-log reduction of BCR:ABL1 transcripts. Results From August 2022 to April 2023, a total of 31 pts were enrolled. All pts completed 3 cycles of treatment and could be assessed for the primary end point. Th data cutoff date was 25 th July 2023 with a median follow-up time of 5.8 months. The median age was 40 years (range, 20-66 years) and males accounted for 58.1%. Twenty-three pts (74.2%) expressed the p190 transcript and 8 pts (25.8%) expressed the p210 transcript. The median expression level of BCR:ABL1 was 96.33% (range, 70.79%-175.39%). All patients achieved CR at the end of cycle 1 and no tumor lysis syndrome or treatment-related deaths occurred. Molecular response at the end of cycle 1 was CMR in 17 patients (54.8%), MMR in 8 (25.8%), and less than MMR in 6 (19.4%). Molecular response at 3 months was CMR in 19 patients (61.3%), MMR in 10 (32.3%), and less than MMR in 2 (6.5%) (Figure 1B). Of the 10 pts with MMR at 3 months, 8 pts had BCR:ABL1 transcript levels fluctuating between 0.001% and 0.01%. No patients developed relapses or deaths at the last follow-up. The regimen was well-tolerated and safe. Most side effects were grade 1-2. The demand for transfusion and the incidence of infections significantly decreased compared to our historic data treating with intensive chemotherapy plus TKIs. No patient discontinued olverembatinib or venetoclax due to toxicity. Conclusion The combination of olverembatinib and venetoclax with reduced-intensity chemotherapy is a safe and effective regimen in patients with newly diagnosed Ph + ALL. The regimen results in high rates of CMR in the absence of intensive chemotherapy or immunotherapy.