Chromosome-positive Acute Lymphoblastic Leukemia Research Articles

Olverembatinib After Failure of Tyrosine Kinase Inhibitors, Including Ponatinib or Asciminib: A Phase 1b Randomized Clinical Trial.

Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) resistant or intolerant to BCR-ABL1 tyrosine kinase inhibitors (TKIs) have limited treatment options. Olverembatinib, which is approved in China, has only been tested in Chinese patients. To assess the pharmacokinetics, safety, efficacy, and recommended dose of olverembatinib in patients with CML or Philadelphia chromosome-positive ALL resistant or intolerant to at least 2 TKIs. This multicenter phase 1b randomized clinical trial was conducted from January 28, 2020, to January 2, 2024, with a median (range) follow-up of 48 (0-166) weeks. Patients with CML or Philadelphia chromosome-positive ALL were enrolled. This bridging study was performed in part to confirm that there are no racial differences in the pharmacokinetic profile of olverembatinib. Patients were randomly assigned to 30, 40, or 50 mg of olverembatinib orally every other day in 28-day cycles. Pharmacokinetic profile of olverembatinib. Of 80 included patients, 46 (58%) were male, and the median (range) age was 54.0 (21-80) years. The pharmacokinetic profile of olverembatinib was compatible with alternate-day dosing and similar to that in Chinese patients. Based on investigators' assessments, 60 patients (75%) experienced at least 1 treatment-related adverse event; 32 (40%) experienced grade 3 or higher treatment-related adverse events; and 12 (15%) experienced treatment-related serious adverse events, none of which were fatal. Frequently reported (10% or more) treatment-emergent adverse events included elevated blood creatine phosphokinase (all grades, 31 [39%]; grade 3 or higher, 10 [13%]) and thrombocytopenia (all grades, 23 [29%]; grade 3 or higher, 14 [18%]). Among evaluable patients with chronic-phase CML, complete cytogenetic response (CCyR) occurred in 31 of 51 patients (61%; 95% CI, 46.1-74.2), and major molecular response (MMR) occurred in 25 of 59 patients (42%; 95% CI, 29.6-55.9). Cytogenetic and molecular responses were similar in patients with or without T315I variants. A total of 15 of 26 patients with prior ponatinib treatment (58%; 95% CI, 36.9-76.6) achieved CCyR, and 11 of 30 (37%; 95% CI, 19.9-56.1) achieved MMR. A total of 4 of 8 patients with asciminib resistance (50%; 95% CI, 15.7-84.3) had CCyR, and 4 of 12 (33%; 95% CI, 9.9-65.1) had MMR. The recommended phase 3 dose of olverembatinib is 30 mg every other day in patients without T315I variants. In this trial, olverembatinib had a favorable pharmacokinetic profile, was generally well tolerated, and showed strong antileukemic activity in patients with heavily pretreated chronic-phase CML with or without T315I variants, including prior ponatinib and/or asciminib failure. Olverembatinib may provide a viable new treatment option for patients after failure of 2 or more TKIs. ClinicalTrials.gov Identifier: NCT04260022.

Isolated Unilateral Optic Nerve Involvement as the Presenting Feature of Early Relapse in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Central Mervous System involvement (CNS) in Acute Lymphoblastic Leukemia (ALL) can be present at initial diagnosis or at disease relapse and early detection is crucial for prompt intervention. Optic nerve infiltration by leukemic cells is an oncologic emergency that requires urgent therapy to spare vision along with systemic therapy, with limited data about the optimal therapeutic strategy. Isolated optic nerve Involvement at relapse is rare; described in Philadelphia chromosome negative (Ph-) ALL in 2.2% of relapses in children and exceeding rare in Philadelphia chromosome positive (Ph+) cases, particularly in the absence of systemic disease. Here we report isolated unilateral optic nerve involvement as the sole feature of early disease relapse in Ph+ ALL in the absence of systemic disease, leading to early detection of molecular relapse.

Isolated Unilateral Optic Nerve Involvement as the Presenting Feature of Early Relapse in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Central Mervous System involvement (CNS) in Acute Lymphoblastic Leukemia (ALL) can be present at initial diagnosis or at disease relapse and early detection is crucial for prompt intervention. Optic nerve infiltration by leukemic cells is an oncologic emergency that requires urgent therapy to spare vision along with systemic therapy, with limited data about the optimal therapeutic strategy. Isolated optic nerve Involvement at relapse is rare; described in Philadelphia chromosome negative (Ph-) ALL in 2.2% of relapses in children and exceeding rare in Philadelphia chromosome positive (Ph+) cases, particularly in the absence of systemic disease. Here we report isolated unilateral optic nerve involvement as the sole feature of early disease relapse in Ph+ ALL in the absence of systemic disease, leading to early detection of molecular relapse.

ALL-438 Minimal Residual Disease–Negative Complete Remission at the End of Induction Is a Prognostic Indicator of Long-Term Survival in Adult Patients With Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia Receiving First-Line Therapy

ALL-438 Minimal Residual Disease–Negative Complete Remission at the End of Induction Is a Prognostic Indicator of Long-Term Survival in Adult Patients With Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia Receiving First-Line Therapy

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

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

Minimal Residual Disease–Negative Complete Remission at the End of Induction Is a Prognostic Indicator of Long-Term Survival in Adult Patients With Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia Receiving First-Line Therapy

Minimal Residual Disease–Negative Complete Remission at the End of Induction Is a Prognostic Indicator of Long-Term Survival in Adult Patients With Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia Receiving First-Line Therapy

CML-400 Olverembatinib (HQP1351) Overcomes Ponatinib and/or Asciminib Resistance in Patients With Heavily Pretreated/Refractory Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

CML-400 Olverembatinib (HQP1351) Overcomes Ponatinib and/or Asciminib Resistance in Patients With Heavily Pretreated/Refractory Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

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.

CRISPR-based rapid molecular diagnostic tests for fusion-driven leukemias

AbstractFusion oncogenes can be cancer-defining molecular alterations that are essential for diagnosis and therapy selection.1,2 Rapid and accessible molecular diagnostics for fusion-driven leukemias such as acute promyelocytic leukemia (APL), Philadelphia chromosome–positive acute lymphoblastic leukemia, and chronic myeloid leukemia (CML) are unavailable, creating a barrier to timely diagnosis and effective targeted therapy in many health care settings, including community hospitals and low-resource environments. We developed CRISPR-based RNA-fusion transcript detection assays using SHERLOCK (specific high-sensitivity enzymatic reporter unlocking) for the diagnosis of fusion-driven leukemias. We validated these assays using diagnostic samples from patients with APL and CML from academic centers and dried blood spots from low-resource environments, demonstrating 100% sensitivity and specificity. We identified assay optimizations to enable the use of these tests outside of tertiary cancer centers and clinical laboratories, enhancing the potential impact of this technology. Rapid point-of-care diagnostics can improve outcomes for patients with cancer by expanding access to therapies for highly treatable diseases that would otherwise lead to serious adverse outcomes due to delayed or missed diagnoses.

A case of Ph+ acute lymphoblastic leukemia and EGFR mutant lung adenocarcinoma synchronous overlap: may one TKI drug solve two diseases?

BackgroundPhiladelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) refers to ALL patients with t(9;22) cytogenetic abnormalities, accounting for about 25% of ALL. Lung adenocarcinoma (LUAD) is the most common pathological type of non-small-cell lung cancer, which has a frequency of approximately 45% cases with mutations in EGFR. Both Ph+ ALL and EGFR mutant LUAD are involved in the pathogenesis of the abnormal activation of the tyrosine kinase pathway. Although the second primary hematological malignancy after the treatment of solid tumors is common in clinics, the synchronous multiple primary malignant tumors of hematological malignancy overlap solid tumors are uncommon, even both tumors involved in the pathogenesis of the abnormal activation of the tyrosine kinase pathway are extremely rare.Case presentationAn 84-year-old man with fatigue and dizziness was diagnosed with Ph+ ALL. Meanwhile, a chest CT indicated a space-occupying lesions, characterized by the presence of void, in the right lower lope with the enlargement of mediastinal lymph node and right pleural effusion. After a few weeks, the patient was diagnosed with LUAD with EGFR exon 19 mutation. Both tyrosine kinase inhibitors (TKI) (Flumatinib) and EGFR-TKI (Oxertinib) was used for the patients, and finally have controlled both diseases.ConclusionAs far as we know, we for the first time reported a case of Ph+ ALL and EGFR mutant LUAD synchronous overlap, of which pathogenesis is related to abnormal tyrosine kinase activation. This patient was successfully treated with two different TKIs without serious adverse events.

MRD in Philadelphia Chromosome-Positive ALL: Methodologies and Clinical Implications.

Measurable residual disease (MRD) is integral in the management of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). This review discusses the current methods used to evaluate MRD as well as the interpretation, significance, and incorporation of MRD in current practice. New molecular technologies have allowed the detection of MRD to levels as low as 10- 6. The most used techniques to evaluate MRD are multiparametric flow cytometry (MFC), quantitative reverse transcription polymerase chain reaction (RT-qPCR), and high-throughput next-generation sequencing (NGS). Each method varies in terms of advantages, disadvantages, and MRD sensitivity. MRD negativity after induction treatment and after allogeneic hematopoietic cell transplantation (HCT) is an important prognostic marker that has consistently been shown to be associated with improved outcomes. Blinatumomab, a new targeted therapy for Ph + ALL, demonstrates high efficacy in eradicating MRD and improving patient outcomes. In the relapsed/refractory setting, the use of inotuzumab ozogamicin and tisagenlecleucel has shown promise in eradicating MRD. The presence of MRD has become an important predictive measure in Ph + ALL. Current studies evaluate the use of MRD in treatment decisions, especially in expanding therapeutic options for Ph + ALL, including tyrosine kinase inhibitors, targeted antibody therapies, chimeric antigen receptor cell therapy, and HCT.

Integrated systems biology analysis of acute lymphoblastic leukemia: unveiling molecular signatures and drug repurposing opportunities.

Acute lymphoblastic leukemia (ALL) is a hematological malignancy characterized by aberrant proliferation and accumulation of lymphoid precursor cells within the bone marrow. The tyrosine kinase inhibitor (TKI), imatinib mesylate, has played a significant role in the treatment of Philadelphia chromosome-positive ALL (Ph + ALL). However, the achievement of durable and sustained therapeutic success remains a challenge due to the development of TKI resistance during the clinical course.The primary objective of this investigation is to propose a novel and efficacious treatment approach through drug repositioning, targeting ALL and its Ph + subtype by identifying and addressing differentially expressed genes (DEGs). This study involves a comprehensive analysis of transcriptome datasets pertaining to ALL and Ph + ALL in order to identify DEGs associated with the progression of these diseases to identify possible repurposable drugs that target identified hub proteins.The outcomes of this research have unveiled 698 disease-related DEGs for ALL and 100 for Ph + ALL. Furthermore, a subset of drugs, specifically glipizide for Ph + ALL, and maytansine and isoprenaline for ALL, have been identified as potential candidates for therapeutic intervention. Subsequently, cytotoxicity assessments were performed to confirm the in vitro cytotoxic effects of these selected drugs on both ALL and Ph + ALL cell lines.In conclusion, this study offers a promising avenue for the management of ALL and Ph + ALL through drug repurposed drugs. Further investigations are necessary to elucidate the mechanisms underlying cell death, and clinical trials are recommended to validate the promising results obtained through drug repositioning strategies.

Naked antibodies and antibody-drug conjugates: targeted therapy for childhood acute lymphoblastic leukemia.

The treatment of childhood acute lymphoblastic leukemia (ALL) has reached overall survival rates exceeding 90%. The present and future challenges are to cure the remainder of patients still dying from disease, and to reduce morbidity and mortality in those who can be cured with standard-of-care chemotherapy by replacing toxic chemotherapy elements while retaining cure rates. With the novel therapeutic options introduced in the last years, including immunotherapies and targeted antibodies, the treatment of ALL is undergoing major changes. For B-cell precursor ALL, blinatumomab, an anti-CD19 bispecific antibody, has established its role in the consolidation treatment for both high- and standard-risk first relapse of ALL, in the presence of bone marrow involvement, and may also have an impact on the outcome of high-risk subsets such as infant ALL and Philadelphia chromosome-positive ALL. Inotuzumab ozogamicin, an anti-CD22 drug conjugated antibody, has demonstrated high efficacy in inducing complete remission in relapsed ALL, even in the presence of high tumor burden, but randomized phase III trials are still ongoing. For T-ALL the role of CD38-directed treatment, such as daratumumab, is gaining interest, but randomized data are needed to assess its specific benefit. These antibodies are currently being tested in patients with newly diagnosed ALL and may lead to major changes in the present paradigm of treatment of pediatric ALL. Unlike the past, lessons may be learned from innovations in adult ALL, in which more drastic changes are piloted that may need to be translated to pediatrics.

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.

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.

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.

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.

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).

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.