Philadelphia Chromosome-positive Leukemia Research Articles

Impact of additional cytogenetic aberrations at diagnosis on prognosis of adults patients with Philadelphia chromosome positive acute lymphoblastic leukemia undergoing allogeneic hematopoietic cell transplantation: a retrospective analysis.

Additional chromosomal abnormalities(ACAs) at diagnosis are associated with inferior prognosis in chronic myeloid leukemia. However, the prognostic significance of ACAs in adult patients with Philadelphia Chromosome Positive acute lymphoblastic leukemia (Ph + ALL) receiving TKI-targeted drugs and allogeneic hematopoietic stem cell transplantation(HSCT) is unknown. One hundred thirty-six adult patients with Ph + ALL were included in the study and retrospectively analysed, evaluating the effect of ACAs on outcomes of transplantation. ACAs are observed in 60 cases (44%). ACAs detected in more than 5% of cases were defined as major-route and encompass: +der(22), +der(9), + 8, -7 and complex karyotype. The median follow-up was 26.4 months. In the subgroup analyses of major route ACAs, three-year cumulative incidence of relapse (CIR) and progression-free survival(PFS) are statistically significant in + 8[66.7% vs.23.7%, P = 0.024; 77.8% vs. 23.7%, P = 0.0087], -7[53.8% vs. 23.7%, P = 0.035%; 61.5% vs. 32.9%, P = 0.033], and complex karyotypes[42.9% vs. 23.7%, P = 0.027; 47.6% vs. 23.7%] compared with t(9;22) sole. Additionally, the 3-year CIR for Ph + ALL with + der(22) is 44% vs. 23.7% for t(9;22) sole(P = 0.045). The 3-year overall survival (OS) in the - 7 group is 46.5%, which is statistically significant compared with the other groups(P = 0.001). In multivariate analyses, three years CIR and PFS are statistically significant in + der(22), + 8, -7 and complex karyotype compared with t(9;22) sole(P < 0.05). More importantly, Ph + ALL with - 7 was negatively associated with the rate of 3-year OS(P = 0.012). Thus, ACAs at diagnosis appear to have a significant prognostic impact on transplantation outcomes in patients with Ph + ALL.

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

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

RAPSYN-mediated neddylation of BCR-ABL alternatively determines the fate of Philadelphia chromosome-positive leukemia

Philadelphia chromosome-positive (Ph+) leukemia is a fatal hematological malignancy. Although standard treatments with tyrosine kinase inhibitors (TKIs) have achieved remarkable success in prolonging patient survival, intolerance, relapse, and TKI resistance remain serious issues for patients with Ph+ leukemia. Here, we report a new leukemogenic process in which RAPSYN and BCR-ABL co-occur in Ph+ leukemia, and RAPSYN mediates the neddylation of BCR-ABL. Consequently, neddylated BCR-ABL enhances the stability by competing its c-CBL-mediated degradation. Furthermore, SRC phosphorylates RAPSYN to activate its NEDD8 E3 ligase activity, promoting BCR-ABL stabilization and disease progression. Moreover, in contrast to in vivo ineffectiveness of PROTAC-based degraders, depletion of RAPSYN expression, or its ligase activity decreased BCR-ABL stability and, in turn, inhibited tumor formation and growth. Collectively, these findings represent an alternative to tyrosine kinase activity for the oncoprotein and leukemogenic cells and generate a rationale of targeting RAPSYN-mediated BCR-ABL neddylation for the treatment of Ph+ leukemia.

RAPSYN-mediated neddylation of BCR-ABL alternatively determines the fate of Philadelphia chromosome-positive leukemia.

Philadelphia chromosome-positive (Ph+) leukemia is a fatal hematological malignancy. Although standard treatments with tyrosine kinase inhibitors (TKIs) have achieved remarkable success in prolonging patient survival, intolerance, relapse, and TKI resistance remain serious issues for patients with Ph+ leukemia. Here, we report a new leukemogenic process in which RAPSYN and BCR-ABL co-occur in Ph+ leukemia, and RAPSYN mediates the neddylation of BCR-ABL. Consequently, neddylated BCR-ABL enhances the stability by competing its c-CBL-mediated degradation. Furthermore, SRC phosphorylates RAPSYN to activate its NEDD8 E3 ligase activity, promoting BCR-ABL stabilization and disease progression. Moreover, in contrast to in vivo ineffectiveness of PROTAC-based degraders, depletion of RAPSYN expression, or its ligase activity decreased BCR-ABL stability and, in turn, inhibited tumor formation and growth. Collectively, these findings represent an alternative to tyrosine kinase activity for the oncoprotein and leukemogenic cells and generate a rationale of targeting RAPSYN-mediated BCR-ABL neddylation for the treatment of Ph+ leukemia.

Results of ponatinib as frontline therapy for chronic myeloid leukemia in chronic phase.

Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with robust activity in Philadelphia chromosome-positive leukemias. Herein, we report the long-term follow-up of the phase 2 trial of ponatinib in chronic myeloid leukemia in chronic phase. Patients received ponatinib 30 to 45 mg/day. The primary end point was the rate of 6-month complete cytogenetic response (CCyR). The study was held in June 2014 because of the risk of cardiovascular toxicity, requiring patients to change TKI. Fifty-one patients were treated with ponatinib (median dose, 45 mg/day). Median age was 48 years (range, 21-75); 30 (59%) had baseline cardiovascular comorbidities. Median treatment duration was 13 months (range, 2-25). Fourteen patients (28%) discontinued ponatinib because of toxicities, 36 (71%) after the Food and Drug Administration warning/study closure, and one for noncompliance. Dasatinib was the most frequently chosen second-line TKI (n=34; 66%). Among 46 patients evaluable at 6 months, 44 (96%) achieved CCyR, 37 (80%) major molecular response, 28 (61%) MR4, and 21 (46%) MR4.5. The cumulative 6-month rates of CCyR, major molecular response, MR4, and MR4.5 were 96%, 78%, 50%, and 36%, respectively. Durable MR4 ≥24 or ≥60 months was observed in 67% and 51% of patients, respectively. The 24-month event-free survival rate was 97%. After a median follow-up of 128 months, the 10-year overall survival rate was 90%. Eight patients (16%) had serious grade 2 to 3 cardiovascular adverse events, leading to permanent discontinuation in five (10%). Ponatinib yielded high cytogenetic and molecular responses in newly diagnosed chronic myeloid leukemia in chronic phase. Its use in the frontline setting is hindered by arterio-/vaso-occlusive and other severe toxicities.

Targeted degradation of oncogenic BCR-ABL by silencing the gene of NEDD8 E3 ligase RAPSYN

Tyrosine kinase inhibitors have been the standard treatment for patients with Philadelphia chromosome-positive (Ph+) leukemia. However, a series of issues, including drug resistance, relapse and intolerance, are still an unmet medical need. Here, we report the targeted siRNA-based lipid nanoparticles in Ph+ leukemic cell lines for gene therapy of Ph+ leukemia, which specifically targets a recently identified NEDD8 E3 ligase RAPSYN in Ph+ leukemic cells to disrupt the neddylation of oncogenic BCR-ABL. To achieve the specificity for Ph+ leukemia therapy, a single-chain fragment variable region (scFv) of anti-CD79B monoclonal antibody was covalently conjugated on the surface of OA2-siRAPSYN lipid nanoparticles to generate the targeted lipid nanoparticles (scFv-OA2-siRAPSYN). Through effectively silencing RAPSYN gene in leukemic cell lines by the nanoparticles, BCR-ABL was remarkably degraded accompanied by the inhibition of proliferation and the promotion of apoptosis. The specific targeting, therapeutic effects and systemic safety were further evaluated and demonstrated in cell line-derived mouse models. The present study has not only addressed the clinical need of Ph+ leukemia, but also enabled gene therapy against a less druggable target.Graphical

Biological Markers of High-Risk Childhood Acute Lymphoblastic Leukemia.

Childhood acute lymphoblastic leukemia (ALL) has witnessed substantial improvements in prognosis; however, a subset of patients classified as high-risk continues to face higher rates of relapse and increased mortality. While the National Cancer Institute (NCI) criteria have traditionally guided risk stratification based on initial clinical information, recent advances highlight the pivotal role of biological markers in shaping the prognosis of childhood ALL. This review delves into the emerging understanding of high-risk childhood ALL, focusing on molecular, cytogenetic, and immunophenotypic markers. These markers not only contribute to unraveling the underlying mechanisms of the disease, but also shed light on specific clinical patterns that dictate prognosis. The paradigm shift in treatment strategies, exemplified by the success of tyrosine kinase inhibitors in Philadelphia chromosome-positive leukemia, underscores the importance of recognizing and targeting precise risk factors. Through a comprehensive exploration of high-risk childhood ALL characteristics, this review aims to enhance our comprehension of the disease, offering insights into its molecular landscape and clinical intricacies in the hope of contributing to future targeted and tailored therapies.

Avatrombopag Safe and Effective in Treatment of Severe Refractory Thrombocytopenia in a Pediatric Patient with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Following Allogeneic Hematopoietic Stem Cell Transplantation

Avatrombopag Safe and Effective in Treatment of Severe Refractory Thrombocytopenia in a Pediatric Patient with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Following Allogeneic Hematopoietic Stem Cell Transplantation

Dasatinib induced nephrotic range proteinuria in pediatric patient with acute lymphoblastic leukemia with hyper-eosinophilia

Tyrosine kinase inhibitors (TKIs) have improved outcomes for Philadelphia chromosome positive acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML). There has been reports of dasatinib induced proteinuria or nephrotic syndrome. We present a case of a 14-year-old male with high-risk B- ALL who developed nephrotic syndrome due to dasatinib. Proteinuria and nephrotic syndrome should be considered as related adverse effects from dasatinib. This is the first reported case of dasatinib induced nephrotic range proteinuria in a patient with high-risk B-ALL with hyper-eosinophilia.

Long-Term Follow up for SWOG 1318: Combination of Dasatinib, Prednisone, and Blinatumomab for Older Patients with Philadelphia-Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL)

Tyrosine kinase inhibitors (TKIs) have improved the outcomes of patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Many older patients (pts) are not good candidates for intensive chemotherapy and are treated with TKIs plus corticosteroids or low-intensity chemotherapy. Although the remission rates with this approach have been high, the median disease-free survival (DFS) has been short. Therefore, novel treatment strategies are needed. This trial evaluated the feasibility of combining the TKI dasatinib with prednisone and blinatumomab in older pts with Ph+ ALL. Here we present updated results (median follow-up, 4.3 years). Methods: This trial was activated through the NCTN in January 2015 and closed to accrual in April 2021. Pt eligibility included: age ≥ 65 years; Ph+ or Ph-like ALL (with dasatinib-sensitive fusions or mutations); newly diagnosed or relapsed/ refractory; no evidence of central nervous system (CNS) disease; and adequate organ function. Treatment: For induction, pts received dasatinib 140 mg/d orally (PO) Days 1-56 along with prednisone 60 mg/m 2/d PO Days 1-24. Pts achieving complete remission (CR) or CR with incomplete count recovery (CRi) (Day 28 or Day 56) continued dasatinib until Day 84, followed by 3 cycles of post-remission therapy (PRT) with blinatumomab/ dasatinib. Pts not achieving CR or CRi by Day 56 received re-induction with blinatumomab. The response rate was assessed on Day 35 of blinatumomab. Pts not achieving CR/ CRi could receive a second cycle of blinatumomab. This was followed by 3 cycles of PRT with blinatumomab/ dasatinib. Maintenance therapy consisted of prednisone 60 mg/m 2/d x 5 days every 28 days for a total of 18 cycles, along with dasatinib 140 mg po qd indefinitely. CNS prophylaxis included intrathecal (IT) methotrexate every 4-6 weeks x 8 doses. IT methotrexate was given at least 2 days apart from blinatumomab. Response was assessed at Days 28, 56, and 84, and additional time points were dependent on response. Minimal residual disease (MRD) was assessed centrally by multi-color flow cytometry on Day 28. Statistics: A total of 24 eligible patients were accrued. The primary objective was the feasibility of the combination therapy. The combination was to be deemed feasible if the dose-limiting toxicity (DLT) was &amp;lt; 33%. DLT included: &amp;gt; Grade 3 non-hematologic toxicities (excluding nausea, vomiting, diarrhea) and Grade 4 neutropenia lasting &amp;gt; 42 days. The primary results were reported in 2022 with a median of 2.7 years of follow-up. Herein, we report long-term outcomes for these patients. Results: The median age was 73 years (range 65-87). All pts had newly diagnosed Ph+ ALL; 79% of Ph+ pts had additional cytogenetic abnormalities. During induction, 2 pts experienced treatment-related non-hematologic Grade 4 toxicities. No Grade 4 or higher treatment-related non-hematologic toxicities occurred during post-remission therapy or maintenance. The toxicity of the combination was deemed acceptable. Twenty-two of 24 pts (92%) achieved a CR during dasatinib and prednisone induction therapy. Four did not receive PRT (2 due to adverse events, 1 to receive a transplant, and 1 because of insurance issues). Sixteen pts who achieved CR had MRD data. Six of 16 pts (38%) were MRD undetectable by multi-color flow cytometry on Day 28. Most sites also monitored patients' blood or bone marrow with real-time quantitative PCR to quantify the BCR-ABL1 transcript for molecular response. Of 19 patients analyzed, 17 (89%) were in a major or complete molecular remission at some time point after treatment, with at least 12 of these patients achieving complete molecular remission. Four patients remain on maintenance. The median follow- up for pts who are alive is 4.3 years (range 2.6-6.5 years). The median overall survival (OS) is 6.5 years (95% CI 3-NA) and the median DFS has not been reached as of June 29, 2023. Kaplan-Meier 3-year estimates of OS and DFS are 75% (95% CI 52%-88%) and 72% (95% CI 49%-87%), respectively (Figure). Of the 8 relapses, 4 patients were CD19+ and 3 had T315I mutations. Conclusions: Median DFS and OS with dasatinib and blinatumomab in this older group of Ph+ ALL patients remain excellent despite only 1 patient proceeding to an allogeneic transplant. Further correlative studies (single cell transcriptomics and DNA methylation sequencing) are being planned to evaluate predictors of relapse and will be presented at the meeting.

Avatrombopag Safe and Effective in Treatment of Severe Refractory Thrombocytopenia in a Pediatric Patient with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Following Allogeneic Hematopoietic Stem Cell Transplantation

Background: Persistent thrombocytopenia following allogeneic stem cell transplantation (alloHSCT) leads to an increase in morbidity and mortality. Causes of severe thrombocytopenia following HSCT include poor graft function, graft-versus-host disease (GVHD), infections, drug toxicities, underlying autoimmune diseases and relapse of underlying disease. Treatments can include thrombopoietin receptor agonists (TPO-RA), immunomodulators, and stem cell boost. Avatrombopag is a second generation TPO-RA approved for the treatment of primary chronic immune thrombocytopenia (ITP) in adult patients with poor response to standard treatments or in patients with chronic liver disease (CLD) associated thrombocytopenia requiring surgical interventions. Phase III clinical trials have shown greater platelet responses in chronic ITP and reduced transfusion needs in patients with CLD. Avatrombopag differs from other TPO-RA medications due to majority of elimination occurring in the gut, thus avoiding hepatic toxicity. Additionally, it does not require dietary restrictions. As there is limited literature in pediatric patients following alloHSCT, we describe the use of avatrombopag in a pediatric patient with chronic severe thrombocytopenia (&amp;lt;10 x10 3/uL) post HSCT. Objective: To describe the use of avatrombopag for severe refractory thrombocytopenia in a pediatric alloHSCT recipient. Case Presentation: We present a 14-year-old Hispanic male with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) who received a maternal haploidentical HSCT with myeloablative conditioning and post-transplant cyclophosphamide. His post HSCT course was complicated by adenoviremia, hepatic variant GVHD, Enterobacter cloacae bacteremia and poor graft function. Seven months following HSCT, patient was found to be severely pancytopenic. Bone marrow morphology demonstrated 20-30% cellularity without evidence of leukemia relapse or GVHD. Lab evaluation was not consistent with transplant associated thrombotic microangiopathy. He received a stem cell boost for presumed poor graft function. Patient demonstrated partial response by resolution of neutropenia and anemia; however, severe thrombocytopenia persisted. Multiple bone marrow evaluations remained negative for disease with full donor chimerism and negative TCR clonality. CXCL9 was noted to be elevated at 4270 and Immature Platelet fraction was elevated at 8.8. Platelet antibodies remained negative and all findings consistent with persistent severe ITP. Multiple treatments including romiplostim; eltrombopag; high dose immune globulin (IVIG); rituximab; methylprednisolone; and decitabine were not successful in improving platelet count (Figure 1). Evaluation for severe thrombocytopenia remained negative. During the course of severe thrombocytopenia, patient required several hospitalizations for symptomatic thrombocytopenia, requiring multiple platelet transfusions. Due to the severity of disease, he was granted a compassionate use investigational new drug (IND 165837) for avatrombopag and began on day +332. Dosing was initiated at 20 mg daily with a dosage adjustment to achieve platelet recovery to &amp;gt;50 x10 3/uL free from transfusion. The dose was titrated per manufacturer to maximum dose of 40 mg daily with response to platelet count &amp;gt;100 x10 3/uL in approximately 6 weeks time. By three months of treatment, dose was titrated down 40 mg three times a week and 20 mg on alternating days. Patient continues to maintain platelets above 100 x10 3/uL with no medication toxicities or adverse events noted. Patient has been able to return to his pre-alloHSCT lifestyle including contact sports and re-immunizations.

Outcomes of Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia: An Indian Multi-Institution, Prospective Study from the Haematology Cancer Consortium (HCC)

Introduction One of the commonest genetic abnormalities seen in adult Acute Lymphoblastic Leukemia (ALL) is the reciprocal translocation between chromosomes (Chr.) 9 and 22, leading to the formation of the BCR-ABL fusion gene. This manifests as a shortened Chr 22 (Philadelphia chromosome, Ph+ALL). Despite the widespread use of tyrosine kinase inhibitors (TKI) which target the BCR-ABL fusion protein, Ph+ALL is considered high risk with more relapses and lesser long-term cures. The Haematology Cancer Consortium (HCC) maintains a multi-center database of several hematological malignancies. The ALL database was established in 2018, and the data of the Ph+ALL patients entered into the registry are presented here. The baseline presenting features and induction outcomes were available for all patients, while the survival data is yet to mature. Methods Prospective data of patients (≥ 18 years) with Ph+ ALL (Diagnosed between January 2018 to December 2022) from 10 centers were entered into an independent centralized online data capture system and analyzed for presenting characteristics, treatment, and survival outcomes. Ph+ ALL was defined by the demonstration of t(9,22) [conventional karyotype/ Fluorescent in situ hybridization (FISH)] or the demonstration of BCR-ABL (by polymerase chain reaction) at diagnosis. Treatment (protocol for ALL, TKI used) was per individual-center preference. Intensive protocols (MCP-841, BFM-95, COG), predominantly meant for children, were labeled as “pediatric-type,” and less intense protocols (GMALL, Hyper CVAD, UKALL) were considered “adult-type”. Results In the four years, 1684 patients with ALL registered and 1409 had been tested for Phor BCR-ABL gene, and 292 were labeled as Ph+ALL [Males: 183(63%), Median age: 35 years (18-77); Subtype: B -ALL: 271(93%), T-ALL: 6 (2%), Mixed phenotype: 13 (4%) ; CNS 2 or 3: 60 (18%)]. Of these, 289 underwent treatment. “Pediatric-type” protocols (BFM, MCP841, ICICLE) were used in 241 (84%) patients, followed by the GMALL protocol in 44 patients (15%) and others in 5 patients. TKIs were used in 234 patients (81%) [Imatinib (29%) and Dasatinib (49%)]. Figure 1 shows the baseline characteristics. Induction complications (all grades) were as follows: tumor lysis (18%), pneumonia (11%), neuropathy (15%), pancreatitis (4%), venous thrombosis (5%), and hyperglycemia (44%). After induction, 72% achieved complete remission (CR), 8% were refractory, and 8% died during induction. The rest (12%) were lost from follow-up during induction and were not evaluable. Post-induction minimal residual disease (MRD) status was assessed in 177 patients and was positive in 75 (42%). To date, 21 patients have undergone allogenic transplants. Survival analysis: After a median follow-up of 12 months (0.06-59), 61 patients have relapsed and 57 have died, and 52 (18%) have been lost from follow-up. The estimated 1-year event-free (EFS), relapse-free (RFS), and overall survival (OS) were 85% (S.E:+/-0.027), 87% (+/- 0.033), and 89%(+/- 0.024) respectively ( Figure 2). No factors affecting prognosis were identified in the current analysis. Conclusions In a large prospective database of 12 centers, we found that most adult Ph+ALLs in India are treated with a pediatric-type intensive protocol. Dasatinib is the preferred TKI, followed by imatinib. There was a high degree of treatment abandonment, with an 18% loss from follow-up within six months (including 12% during the induction phase).

The Clinical Outcome of Patients with Refractory/Relapsed Lymphoid Blastic Phase of Chronic Myeloid Leukemia Treated with CAR T-Cells Therapy

Introduction : Chimeric antigen receptor T (CAR T) is an effective therapy for refractory/relapsed (R/R) philadelphia chromosome positive acute lymphoblastic leukemia (ph+ ALL) patients in TKIs era. Patients with lymphoid blastic phase of chronic myeloid leukemia (CML-LBC) also have BCR-ABL fusion oncogenes, and usually shows an aggressive clinical course with a poor prognosis. However, outcomes of CAR T therapy for patients with R/R CML-LBC is still uncertain. This study was designed to compare the efficacy and safety of CAR T-cells therapy in patients with R/R CML-LBC and ph+ ALL. Patients and Methods : Clinical data from 13 patients with R/R CML-LBC and 121 R/R ph+ ALL patients who received CAR T treatments at our center from February 2017 to March 2023 were retrospectively collected and analyzed. Before CAR T-cells treatment, fifty patients (11.2%) had primary refractory disease, 106 patients (79.1%) were experiencing the first relapse, and 13 patients (9.7%) were experiencing the second or more relapse. All patients received lymphodepletion with fludarabine (30 mg/m2 /d) and cyclophosphamide (300 mg/m2 /d) -based conditioning regimens on day −5 to −3. CAR T-cells were then infused at day 0. Among them, 8 patients with CML-LBC and 92 ph+ ALL patients received single CD19 CAR T therapy, others received tandem CD19/CD22 CAR T. Results:The baseline characteristics of all patients were shown in Table 1. Patients with CML-LBC carried a higher proportion of mutations in the ABL kinase region ( P=0.036).The clinical timeline of CML-LBC patients as shown in Figure 1A,and ABL kinase region mutations and gene mutations of patients are shown in Figure 1B. Patients with CML-LBC (58.3%) had significantly lower CR rates than ph+ ALL (97.2%) patients at +2 month after CAR-T therapy (P&amp;lt;0.001) ( Fig. 1B). ABL kinase region mutation (odds ratio, 0.091; 95% CI, 0.015-0.571) and CML-LBC (odds ratio, 0.063; 95% CI, 0.010-0.376) remained risk factors in multivariate logistic regression analysis of CR rate in all patients. Furthermore, minimal residual disease (MRD)-negative CR rates were 58.3% and 95.3% at +2 month after CAR T-cells therapy, respectively (P&amp;lt;0.001) ( Fig. 1B). There was no significant difference in the incidence of adverse events among the two groups. Severe cytokine release syndrome (CRS, Grade ≥ 3) occurred in 7.7% of patients with CML-LBC and 8.3% in ph+ ALL patients (P=1.000). Moreover, patients with CML-LBC showed poorer 2-year prognoses than the ph+ ALL patients (overall survival: P=0.0068; leukemia-free survival: P&amp;lt;0.0001; cumulative incidence of relapse: P&amp;lt;0.001) ( Fig. 1C-1E). Univariate and multivariate Cox regression analyses showed that a poorer LFS was related to ABL kinase region mutation (hazard ratio, 3.257; 95% CI, 1.404-7.553) and CML-LB (hazard ratio, 3.803; 95% CI, 1.507-9.596). Conclusions: Worser sustained antitumor efficacy and long-term survival with CAR T-cells therapy in patients with CML-LBC compared to ph+ ALL patients, and ABL kinase region mutation is an independent risk factor for CR and LFS.

Achievement of Undetectable BCR::ABL1 (uBCR::ABL1) Is Predictive of Improved Survival in Philadelphia Chromosome Positive (Ph+ve) Acute Lymphoblastic Leukemia (ALL) Patients Not Receiving Allogeneic Stem Cell Transplantation

Background With the advent of tyrosine kinase inhibitor (TKI)-based therapy the outcome of Philadelphia chromosome-positive (Ph +) acute lymphoblastic leukemia (ALL) has significantly improved. Moreover, patients (pts) who achieved undetectable (u) BCR::ABL1 at 3 months (mo) from the time of initiating therapy, tend to have improved outcomes (Short et al. Blood 2016; 128 [4];504-507). We conducted a retrospective multicenter study to analyze the predictors of achieving uBCR::ABL1 in adult (&amp;gt; 18 years) Ph + ALL pts. Methods A total of 458 adult Ph + ALL pts from 10 US academic institutions, who were diagnosed between May 2003 and April 2023, were evaluated to assess the rates of uBCR::ABL1 at 3 mo after initiating therapy and factors that predict the achievement of molecular response. Continuous variables were summarized as median (range), while categorical variables were reported as frequency (percentage). Unadjusted comparisons of patient/ treatment related characteristics and molecular response were made using a non-parametric test (continuous variables) or Fisher's exact test (categorical variables). Survival curves were estimated using the Kaplan-Meier method and compared between molecular responses via the log-rank test. Results Baseline characteristics The median age of the pts was 53 years (range [R] 19-85), median white blood cell count (WBC) was 17.6 (10 9/L) (R, 1.2-571), 249 (55%) pts had additional cytogenetic (CG) abnormalities, 98 (22%) pts had p210 fusion protein, and 35 (8%) pts had CNS disease at diagnosis. A higher proportion of pts received TKI in combination with intensive chemotherapy (IC) (69%), than TKI + steroids (15%), TKI + low intensity chemotherapy (LC; combination of vincristine, steroids +/- rituximab) (9%), TKI + blinatumomab (3%) and IC without TKI (4%) during induction. During induction, the highest proportion of pts received 2 nd generation TKI combinations (67%; majority dasatinib 98%), compared to imatinib (19%) or ponatinib (10%): 4% of pts did not receive TKI with induction. The complete remission (CR) rate was 94%; measurable residual disease (MRD) negative by flow cytometry 51% (181/352 evaluable pts) and 58.5% (209/354 evaluable pts) of pts had uBCR::ABL1 by PCR at 3 mo from induction. A total of 212 (46%) pts received allogeneic stem cell transplantation (allo-HCT) in CR1, among them 61% of pts received TKI maintenance post allo-HCT. Predictors of uBCR::ABL1 at 3 months Predictors for uBCR::ABL1 at 3 mo are summarized in Table 1. The proportion of pts with WBC &amp;gt; 100 (45% vs 60%, p= 0.04), p210 fusion protein (35% vs 85%, p= &amp;lt;0.001), additional CG abnormality with monosomy 7 (40% vs 61%, p= 0.03), additional somatic myeloid co-mutation (39% vs 61%, p= 0.09; 94 pts evaluable), received induction with steroid plus TKI (41% vs 63%, p= 0.002) or received imatinib based induction (47% vs 61%,p= 0.07) had inferior uBCR::ABL1 rates at 3 mo. Conversely pts who received ponatinib based induction had significantly better uBCR::ABL1 rates (79% vs 57%, p= 0.009). Survival The median relapse free survival (RFS) was 72.3 mo (95% CI; 50.1-94.4), RFS was numerically higher among pts who achieved uBCR::ABL1 at 3 mo but not statistically significant (84.2 mo vs 62.9 mo, p= 0.20). The median overall survival (OS) was 129.2 mo (95% CI; 81.2-177.2), OS was not significantly different among pts who achieved uBCR::ABL1 at 3 mo (129.2) versus no uBCR::ABL1 (not reached; 50% alive at 94 mo), p= 0.47. In sub-set analysis, among non-transplanted pts, RFS was not statistically significant between those who achieved uBCR::ABL1 vs those who did not (38.9 vs 22.0 mo, respectively p= 0.24). However, the median OS was significantly higher in pts who achieved uBCR::ABL1 at 3 mo compared to pts who did not achieve uBCR::ABL1 at 3 mo: 149.3 vs 77.5 mo, p= 0.04 ( Figure 1). Conclusion In this large multicenter study, we observed significantly inferior uBCR::ABL1 rates among pts with WBC &amp;gt; 100, p210 fusion protein, monosomy 7 CG abnormality, pts receiving induction with steroid plus TKI or imatinib based induction. Conversely, uBCR::ABL1 rates were significantly better in pts receiving ponatinib based induction therapy. Overall, we did not see significant impact of uBCR::ABL1 at 3 mo, on RFS or OS. It is likely subsequent therapies and allo-HCT abrogates the negative impact of not achieving uBCR::ABL1 at 3 mo. However, among non-transplanted pts achievement of uBCR::ABL1 at 3 mo showed a significantly improved OS.

Physiologically Based Pharmacokinetic Modeling of Nilotinib for Drug-Drug Interactions, Pediatric Patients, and Pregnancy and Lactation.

Nilotinib is a second-generation BCR-ABL tyrosine kinase inhibitor for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia in both adult and pediatric patients. The pharmacokinetics (PK) of nilotinib in specific populations such as pregnant and lactating people remain poorly understood. Therefore, the objectives of the current study were to develop a physiologically based pharmacokinetic (PBPK) model to predict nilotinib PK in virtual drug-drug interaction (DDI) studies, as well as in pediatric, pregnant, and lactating populations. The nilotinib PBPK model was built in PK-Sim, which is part of the free and open-source software Open Systems Pharmacology. The observed clinical data for the validation of the nilotinib models were obtained from the literature. The model reasonably predicted nilotinib concentrations in the adult population; the DDIs between nilotinib and rifampin or ketoconazole in the adult population; and the PK in the pediatric, pregnant, and lactating populations, although in the latter 2 populations plasma concentrations were slightly underestimated. The ratio of predicted versus observed PK parameters for the adult model ranged from 0.71 to 1.11 for area under the concentration-time curve and 0.55 to 0.95 for maximum concentration. For the DDI, the predicted area under the concentration-time curve ratio and maximum concentration ratio fell within the Guest criterion. The current study demonstrated the utility of using PBPK modeling to understand the mechanistic basis of PK differences between adults and specific populations, such as pediatrics, and pregnant and lactating individuals, indicating that this technology can potentially inform or optimize dosing conditions in specific populations.

Differential vascular endothelial cell toxicity of established and novel BCR-ABL tyrosine kinase inhibitors.

BCR-ABL tyrosine kinase inhibitors (TKIs) have dramatically improved survival in Philadelphia chromosome-positive leukemias. Newer BCR-ABL TKIs provide superior cancer outcomes but with increased risk of acute arterial thrombosis, which further increases in patients with cardiovascular comorbidities and mitigates survival benefits compared to imatinib. Recent studies implicate endothelial cell (EC) damage in this toxicity by unknown mechanisms with few side-by-side comparisons of multiple TKIs and with no available data on endothelial impact of recently approved TKIs or novels TKIs being tested in clinical trials. To characterize BCR-ABL TKI induced EC dysfunction we exposed primary human umbilical vein ECs in 2D and 3D culture to clinically relevant concentrations of seven BCR-ABL TKIs and quantified their impact on EC scratch-wound healing, viability, inflammation, and permeability mechanisms. Dasatinib, ponatinib, and nilotinib, the TKIs associated with thrombosis in patients, all significantly impaired EC wound healing, survival, and proliferation compared to imatinib, but only dasatinib and ponatinib impaired cell migration and only nilotinib enhanced EC necrosis. Dasatinib and ponatinib increased leukocyte adhesion to ECs with upregulation of adhesion molecule expression in ECs (ICAM1, VCAM1, and P-selectin) and leukocytes (PSGL1). Dasatinib increased permeability and impaired cell junctional integrity in human engineered microvessels, consistent with its unique association with pleural effusions. Of the new agents, bafetinib decreased EC viability and increased microvessel permeability while asciminib and radotinib did not impact any EC function tested. In summary, the vasculotoxic TKIs (dasatinib, ponatinib, nilotinib) cause EC toxicity but with mechanistic differences, supporting the potential need for drug-specific vasculoprotective strategies. Asciminib and radotinib do not induce EC toxicity at clinically relevant concentrations suggesting a better safety profile.

A Phase I/II Study to Investigate the Addition of Venetoclax to Dasatinib and Steroids in Patients with Newly Diagnosed or Relapsed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL): The Venda Trial, in Progress

Background: Acute Lymphoblastic Leukemia (ALL) is a hematologic malignancy of immature lymphocytes of either B cell or T cell origin. One particularly high -risk subset is Ph+ ALL, characterized by a translocation of chromosome 9 and 22, which generates the constitutively active BCR-ABL1 fusion tyrosine kinase capable of driving proliferation and survival of leukemic cells. Currently treatment options include multi-agent chemotherapy along with an ABL-specific tyrosine kinase inhibitor (TKI), though these regimens can lead to significant toxicity, particularly in older adults. Venetoclax is a potent and selective small molecule inhibitor of the B-cell lymphoma 2 (BCL-2) anti-apoptotic protein. Strong mechanistic and preclinical data have demonstrated strong synergistic activity between dasatinib and venetoclax I xenograft models and ex vivo patient samples, and provide an impetus to further explore the combination of BCR-ABL and BCL-2 inhibition in vivo. Based on these data, we designed a clinical trial to investigate the safety and preliminary efficacy of venetoclax in combination with the second generation TKI dasatinib in Ph+ ALL. Study Design and Methods This is an open label, Phase I/II investigator initiated trial evaluating the addition of venetoclax to dasatinib and steroids (with Rituximab in CD20+ patients). Phase I is the safety and dose-finding portion of the trial combining the BCL2 inhibitor venetoclax with dasatinib and steroids during the first 28 days of induction followed by dasatinib and venetoclax for the final 48 days of induction in newly diagnosed and relapsed Ph+ ALL and mixed phenotype acute leukemia (MPAL) patients, including patients with molecular only relapse. Primary inclusion criteria include a histologically confirmed diagnosis of Ph+ ALL or MPAL. Newly diagnosed Ph+ ALL or MPAL patients may not have received leukemia-directed therapy other than for steroids or hydrea, and relapsed patients must have not had prior dasatinib exposure. Key exclusion criteria include subjects with CML in myeloid blast crisis or Ph+ AML, ECOG &amp;lt; 2 and patients with a history of pleural effusions. n order to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), a Bayesian toxicity probability interval design applied to a pre-specified targeted dose limiting toxicity rate of 30%. Three dose cohorts investigating increasing doses of venetoclax will be enrolled. Once the RP2D dose has been identified, a Phase II expansion will examine preliminary efficacy of the combination. The primary endpoint is the rate of measureable residual disease (MRD) negative remission rate as assessed by both BCR-ABL RT-PCR and next generation sequencing (NGS) after induction. Secondary endpoints include relapse-free survival (RFS) and overall survival (OS). Correlative studies include BH3 profiling (measure of apoptosis) and ex vivo screening to dasatinib and venetoclax alone and in combination. Consolidation phase with blinatumomab plus dasatinib and venetoclax is planned for the cohort expansion group. Enrollment began in September 2022 and is expected to be complete by September 2025. This trial is registered at clinicaltrials.gov (NCT04872790).

Toxicities Associated with Tyrosine Kinase Inhibitor Maintenance Following Allogeneic Hematopoietic Cell Transplantation in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Background Use of tyrosine kinase inhibitor (TKI) maintenance following allogeneic hematopoietic cell transplantation (HCT) in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia may help to prevent post HCT relapse but is difficult to administer due to toxicity. However, these toxicities and their impact on maintenance is not fully characterized. Herein, we report our experience at a single, large transplant center to describe toxicities encountered with post HCT TKI maintenance in Ph+ ALL. Methods Ph+ ALL patients (pts) who underwent 1st allogeneic HCT at City of Hope between 2003-2021 and received at least one dose of TKI maintenance were included in this retrospective analysis. Baseline characteristics and toxicities were summarized via descriptive analysis, and groups were compared via Fischer test. Survival analyses were calculated from the time of TKI initiation. Results Baseline characteristics are described in Table 1. Of the 186 pts studied, 50 (26.8%) received imatinib and 136 (73.2%) received a newer generation TKI (NG-TKI: 112 dasatinib, 6 nilotinib, 1 bosutinib, 17 ponatinib) at a median time of 78 days (IQR, 41-134) and 91 days (IQR, 58-129), respectively. A total of 96 patients (51.6%) began TKI maintenance within 90 days of HCT. Post HCT TKI was started prophylactically in 149 patients (80.1%) while 37 patients (19.9%) received TKI preemptively for positive MRD. The MRD status at time of HCT differed between the imatinib group and NG-TKI group. In the imatinib group MRD was negative in 33 of 50 patients (66.0%) compared with 78 of 136 patients (57.4%) in the NG-TKI group (P&amp;lt;0.01). There were 12 (24.0%) vs 18 (13.2%) with an unknown MRD-status at HCT in the imatinib vs NG-TKI groups, respectively ( P&amp;lt;0.01). The median follow-up duration for surviving patients in the entire cohort was 5.5 years (range, 1.0-17.5). The median cumulative TKI exposure was 413.5 days (range, 4-2740). The median cumulative imatinib exposure in patients initially receiving imatinib was 328 days (range, 3-2216), while the median cumulative NG-TKI exposure in patients initially receiving NG-TKI was 268.5 days (range, 3-2740), respectively. The median cumulative exposure of dasatinib, nilotinib, bosutinib and ponatinib were 249 days (range, 3-2740), 222 days (range, 114-839), 371 days, and 576 days (range, 72-921), respectively. Twenty-seven (54.0%) vs 75 (55.2%) patients completed &amp;gt;12 months of initial imatinib and NG-TKI maintenance (P=1.0), respectively. Of the treated patients, 78 pts (41.9%) required at least one dose reduction of their initial TKI due to toxicity; 19 of them (10.2%) required ≥2 dose reductions. When imatinib maintenance was used as the initial TKI, a dose reduction due to toxicity was required in 18 patients (36.0%), of whom 7 patients (14.0%) required ≥2 dose reductions. Initial NG-TKI maintenance required a dose reduction due to toxicity in 60 (44.1%), of whom 12 (8.8%) required ≥2 dose reductions. One hundred and thirty-nine patients (74.7%) had their maintenance TKI therapy interrupted, 122 (65.6%) due to toxicity. Sixty-seven patients (36.0%) did not complete their pre-determined maintenance period owing to toxicity; 70 pts (37.6%) discontinued one TKI, and 11 (5.9%) discontinued two TKIs, due to toxicity. The most common reasons for discontinuing the initial TKI are listed in Table 2, including 45.2% of patients due to toxicity, and 12.9% due to progressive disease. Toxicity-related discontinuations occurred within 6 months on that TKI in 63.0% of patients, and 75.3% within the first 12 months. Five-year overall survival and progression-free survival from the start of TKI were similar between the imatinib and NG-TKI group; 83.1% vs 76.9% (P=0.74) and 72.8% vs 70.5% (P=0.63), respectively (Figure 1). Conclusion Toxicities resulting in dose reductions, interruptions, and discontinuation are common in TKI maintenance post HCT. The toxicity profile (mainly GI and blood count related), frequency, and severity of TKIs in the post HCT setting appears to be different than what has been previously reported in the pre-HCT setting, making it a formidable challenge to meet the recommended cumulative TKI maintenance exposure (2 years) per the NCCN guidelines. While the choice of TKI did not appear to impact on long-term outcomes and relapse rates were not excessive in our analysis, further studies are needed to develop tolerable and personalized TKI maintenance strategies.

Olverembatinib(HQP1351)-Based Therapy in Adults with Relapsed or Refractory Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or Advanced Chronic Myeloid Leukemia: Results of the Real-Life Study

Background Relapsed or refractory (R/R) Philadelphia chromosome positive acute lymphoid leukemia (ALL) and advanced chronic myeloid leukemia (CML) including accelerated phase (AP) and blast phase (BP) usually result in treatment failure due to therapeutic resistance, intolerance, T315I mutations, or compound mutations, with a poor prognosis. Olverembatinib (HQP1351) is a novel third generation BCR-ABL tyrosine kinase inhibitor (3G-TKI), exhibiting a high potency of inhibition on wild and almost all mutated BCR-ABL1 kinases, including the T315I mutation and exhibiting preliminary favorable efficacy and safety profile in clinical trials. Methods In this open label, single-arm, single-center study, patients with advanced Ph+ leukemia (including CML-BP, CML-AP and R/R Ph+ ALL) were enrolled. Patients with severe cardiovascular diseases, arterial occlusion, hypertension, and pulmonary arterial hypertension were excluded . Eligible patient received olverembatinib monotherapy, combined chemotherapy, or combined immunotherapy. The primary endpoints was overall response rate (ORR) at 28 days, including complete remission (CR) and complete remission with incomplete hematological recovery (CRi), in patients with advanced Ph+ leukemia. Results Between Dec 8, 2021, to Jun 1, 2023, a total of 56 patients (Ph+ALL (n=40), CML-BP (n=13) and CML-AP(n=3)) assessed were included and received olverembatinib-based therapy. 34(60.7%) patients were men and 22 (39.3%) were women. The median age was 38 years old (IQR 29-48) and the median duration of follow-up was 8.3 months (IQR 4.6-11.9). BCR::ABL1 transcript was of p210 type in 29 (51.8%), p190 in 27 (48.2%). 13 (23.2%) and 11 (19.6%) patients had received 2 and ≥ 3 prior TKIs, respectively. 17 (30.4%) patients were pretreated with third-generation TKI (ponatinib). Genetic testing revealed mutations in 48 (85.7%) patients including compound mutation in 11 (19.6%%) patients, of whom 8 (72.3%) patients had the T315I mutation. 11 (19.6%) patients had central nervous system leukemia (CNSL) and 1 (1.8%) had extramedullary disease. Of 56 evaluable patients, 48 (85.7%) patients reached CR/CRi. After achieving CR/CRi, 13/48 (27.1%) patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT), 3/48 (6.3%) patients received donor lymphocyte infusion (DLI), and 3/48 (6.3%) patients received chimeric antigen receptor T-cell immunotherapy (CAR-T therapy). During further follow-up, 24 (42.9%) patients achieved BCR::ABL1&amp;lt; 0.1% and 29 (49.2%) achieved BCR::ABL1 &amp;lt; 1%. In additional, probabilities of DFS, EFS and OS at 12 months were 80.3% (95%CI 61.0%-90.7%), 80.2% (95%CI 61.0%-90.7%), 93.3% (95%CI 75.8%-98.3%) in R/R Ph+ALL and 55.4% (95%CI 18.4%-81.4%), 38.6% (95%CI 9.8%-67.6%), 80.0% (95%CI 37.4%-95.1%) in advanced CML, respectively (Fig. 1). Common treatment-related adverse events (TRAEs) included skin hyperpigmentation, proteinuria, Elevated liver enzyme and hypertriglyceridemia (Table 1). Most nonhematologic TRAEs were grade 1/2. Only one patient died from pulmonary embolism. As of the data cutoff date, 37 (66.1%) patients continued on treatment and 19(33.9%) discontinued because of disease progression, intolerance, loss to follow-up or death. Conclusion Olverembatinib-based therapy showed strong efficacy and tolerable toxicity in advanced Ph+ leukemia.

Higher incidence of delayed methotrexate clearance in pediatric acute lymphoblastic leukemia patients treated with imatinib

BackgroundPediatric patients with Philadelphia chromosome positive (Ph+) or ABL-class fusion positive acute lymphoblastic leukemia (ALL) are currently treated with the tyrosine kinase inhibitor (TKI) imatinib added to a chemotherapy backbone that also contains several courses of high-dose methotrexate (HDMTX). A limited number of case studies suggested delayed MTX clearance in patients concomitantly using HDMTX and imatinib. MethodsMTX clearance and serum creatinine in 24 newly diagnosed Ph+/ABL-class fusion positive pediatric ALL patients treated with imatinib (imatinib group) were compared with 281 randomly selected age-matched Ph-negative pediatric ALL patients treated without TKI (control group), receiving in total 61 and 897 HDMTX courses, respectively. ResultsMild to severe delayed MTX clearance (MTX level at T48 hours>0.4 µM) was more frequently found in the imatinib group than in the control group in all courses (55.7% vs 41.1% p = 0.036). After the first HDMTX course, 12.5% (n = 3) of the imatinib group presented with a severe delayed MTX clearance (T48 > 5 µM) versus 2.3% in the control group (p = 0.039). In two (8.3%) of these patients in the imatinib group, this was accompanied by increased creatinine, therefore meeting the criteria for Delayed MTX Elimination (DME). In the control group 12/281 (4.3%) patients presented with DME. Glucarpidase was administered in 2 (8.3%) vs 4 (1.4%) patients in the imatinib group and control group, respectively. ConclusionImatinib increased the risk of delayed MTX clearance in newly diagnosed pediatric Ph+ chromosome or ABL-class fusion positive ALL patients. We therefore recommend stringent supportive care measures and for patients with severe delayed MTX clearance resulting in severe toxicities temporary discontinuation of imatinib or a lower dose of MTX during the next HDMTX courses.