Iclusig (ponatinib) / Takeda, Otsuka, Incyte, Endo, Specialised Therap, Pint Pharma, Biologix Pharma - LARVOL DELTA

Molecular characterization and predictors of relapse in patients with Ph + ALL after frontline ponatinib and blinatumomab. (PubMed, J Hematol Oncol) - P2 | "WBC ≥ 70 × 109/L is a high-risk feature in patients with Ph + ALL receiving frontline blinatumomab and ponatinib and may supersede the prognostic importance of baseline molecular features. Alternative frontline treatment strategies may be needed for these patients to reduce the risk of relapse and improve long-term outcomes."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • CD19 • IKZF1 • VPREB1

Venetoclax plus inotuzumab ozogamicin for relapsed and refractory ALL: Results of a phase I trial (ASH 2025) - P1 | "Due to distinct mechanisms of action and non-overlapping toxicities, we hypothesized that adding VEN to INO would be safe and effective. This investigator-sponsored phase I study (NCT05016947) enrolled pts ≥18 years with CD22+ (≥20% ofblasts) R/R ALL (≥5% bone marrow [BM] blasts) or lymphoblastic lymphoma (LBL, BM <5% blasts).Philadelphia chromosome-negative (Ph-) pts had received ≥1 line of therapy; Ph+ pts were ponatinib(PON)-refractory or ineligible...Dexamethasone (10 mg/m2) was given during Lead-In and D1-4 of C1 Induction...BH3 profiling showed that ptsMRD- by C2 had lower pre-treatment mitochondrial apoptotic priming.Of the 21 CR patients, 1 pt (KMT2Ar) progressed during C2, and the remaining 20 pts (95.2%) wereconsolidated with blinatumomab (n=9, 42.9%), SCT (n=14, 66.7%, 6 after blinatumomab), DLI (n=1), XRT(n=1), or POMP (n=1)... VEN can be safely added to INO in pts with R/R CD22+ ALL/LBL including Ph+ ALL, with a very high anddurable rate of MRD- CR...."

P1 data • CNS Disorders • Febrile Neutropenia • Gastrointestinal Disorder • Hepatology • Lymphoblastic Lymphoma • Lymphoma • Neutropenia • Thrombocytopenia • KMT2A

First results of the Phase III GIMEMA ALL2820 trial comparing ponatinib plus blinatumomab to imatinib and chemotherapy for newly diagnosed adult ph+ acute lymphoblastic leukemia patients (ASH 2025) - "Compared to the GIMEMA LAL2116 trial, anincrease in MRD negativity and less relapses were observed. A chemo-free approach should be the newstandard for adult Ph+ ALL."

Clinical • IO biomarker • P3 data • Acute Lymphocytic Leukemia • Cardiovascular • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myocardial Infarction • Pneumonia • Renal Disease • Respiratory Diseases • Septic Shock • ABL1 • IKZF1

Primary efficacy analysis of phase II study investigating tyrosine kinase inhibitor (TKI) and inotuzumab ozogamicin-based therapy for newly diagnosed Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) (ASH 2025) - "Tyrosine kinase inhibitor (TKI) + blinatumomab regimenshave demonstrated high MR4 rates and favorable overall survival (OS); however, these regimens includeup to 5 courses of blinatumomab which is a continuous 28-day infusion (Kantarjian et al, JCO 2024; Foa etal, JCO 2024)...Eligibilitycriteria includes newly diagnosed Ph+ ALL, age ≥ 18, ECOG ≤2, CD22+ on ≥20% blasts, and no centralnervous system (CNS) disease.Schema 1 was as follows; Course (C) 1 was (28 days) dasatinib (DAS) 140mg daily, dexamethasone (dex)10mg/m2 D1-7 & D15-21, and InO 0.8mg/m2 D8, 0.5mg/m2 D15 and D22...If MR4 was not achieved by end of C2 (EOC2), DAS was switched to ponatinib(PON)...TKI + InO-based therapy for newly diagnosed pts with Ph+ ALL has an MR3+ rate of 81% within 2 coursesand 100% of pts achieved MR4 and/or NGS MRD- disease by EOC3. No cases of VOD were seen withSchema 2. Given the excellent rates of MR3+ with limited cycles of InO, further development of thisinduction approach is..."

Clinical • P2 data • Acute Lymphocytic Leukemia • CNS Disorders • Hematological Malignancies • Hepatology • Infectious Disease • Leukemia • Pulmonary Disease • Respiratory Diseases • Septic Shock • IKZF1

Ponatinib and Blinatumomab for Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Subgroup Analysis from a Phase II Study (ASH 2022) - "Twelve doses of prophylactic IT chemotherapy with alternating cytarabine and methotrexate were administered. Simultaneous ponatinib and blinatumomab is safe and effective in pts with newly diagnosed Ph+ ALL. This chemotherapy-free regimen results in high rates of CMR and NGS MRD negativity. Encouraging survival has been observed without the need for SCT."

Clinical • P2 data • Acute Lymphocytic Leukemia • Bone Marrow Transplantation • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Oncology • Transplantation • ABL1 • CD19

Blinatumomab and Ponatinib for Adults with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Updated Results and Predictors of Relapse (ASH 2024) - "The study has now been amended to increase the number of doses of IT chemotherapy from 12 to 15 and also institutes 2 cycles of high-dose methotrexate and cytarabine for patients with high WBC. The association of genomic alterations (including IKZF1plus genotype) with MRD responses and relapse risk is being analyzed and will be presented at the meeting."

Clinical • Acute Lymphocytic Leukemia • Central Nervous System Leukemia • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • ABL1 • IKZF1

LONG-TERM OUTCOMES OF ADULT PH+ ALL TREATED WITH DASATINIB OR IMATINIB BEFORE THE BLINATUMOMAB ERA: A RETROSPECTIVE ANALYSIS OF 250 PATIENTS FROM THE PALG REGISTRY (EBMT 2026) - "Background: The prognosis of Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) has improved substantially with the introduction of tyrosine kinase inhibitors (TKIs). In this pre-blinatumomab era subgroup analysis, adults with Ph+ ALL undergoing allo-HSCT achieved favorable long-term outcomes. Despite being part of a clinically high-risk subgroup (imatinib resistance or central nervous system involvement), patients receiving dasatinib demonstrated promising 10-year OS probability, exceeding that of imatinib and yielding statistical significance compared to that the Ph-negative ALL group. Rates, grades and involved sites of aGvHD, cGvHD, and causes of death did not differ significantly between groups, suggesting that survival differences may be driven mainly by disease control rather than transplant-related toxicity."

Retrospective data • Acute Graft versus Host Disease • Acute Lymphocytic Leukemia • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia

HEALTH-RELATED QUALITY OF LIFE BENEFITS OF FRONTLINE PONATINIB PLUS BLINATUMOMAB IN ADULT PATIENTS WITH PH+ ACUTE LYMPHOBLASTIC LEUKEMIA. PRELIMINARY ANALYSIS OF THE GIMEMA ALL2820 TRIAL (EHA 2025) - "We report the first evidence-based data on HRQoL of adult patients with newly diagnosed Ph+ ALL treated in induction/consolidation with ponatinib plus blinatumomab. Our findings indicate notable HRQoL improvements across all age groups, although younger patients seem to benefit the most from this novel treatment approach, devoid of systemic chemotherapy. Further analyses will elucidate on the value of this approach compared with standard of care."

Clinical • HEOR • Acute Lymphocytic Leukemia • Fatigue • Hematological Malignancies • Leukemia • Oncology • Pain • Pulmonary Disease

Updated Results from the Phase II Study of Blinatumomab in Combination with Ponatinib in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (SOHO 2022) - "The chemotherapy-free combination of blinatumomab and ponatinib demonstrated robust clinical activity in Ph-positive ALL, with high rates of CMR and durable remissions. This strategy will potentially obviate the need for chemotherapy and allo-SCT in many patients, particularly in the frontline setting."

Combination therapy • P2 data • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1

A phase II trial of a chemotherapy-free combination of ponatinib and blinatumomab in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). (ASCO 2022) - P2 | "The chemotherapy-free combination of ponatinib and blinatumomab was safe and effective in Ph+ ALL and CML-LBP. Longer follow-up continues to demonstrate durable remissions, particularly in ND Ph+ ALL, even without SCT in first remission."

Clinical • P2 data • Acute Lymphocytic Leukemia • Bone Marrow Transplantation • Cardiovascular • Hematological Malignancies • Leukemia • Oncology • Transplantation

Advances and Controversies in the Management of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Navigating First-Line Therapies. (PubMed, Curr Hematol Malig Rep) - "Successive generations of TKIs have transformed Ph + ALL from a uniformly fatal leukemia into a highly treatable disease, with dasatinib or ponatinib-based and TKI-blinatumomab regimens achieving high rates of complete molecular remission...Novel agents, including asciminib and olverembatinib, are expanding options for resistant or relapsed disease, while CAR-T cell therapy and next-generation bispecific T-cell engagers are emerging as promising tools for refractory and post-TKI settings...Integrating potent TKIs with immunotherapy enables deep and durable remissions, potentially eliminating the need for upfront transplantation in selected patients. Future research should define molecular predictors of treatment-free remission, optimize CNS prophylaxis in targeted regimens, and establish standardized monitoring for safe TKI discontinuation."

IO biomarker • Journal • Review • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • Transplantation • IKZF1

Efficacy and Toxicity of Frontline Ponatinib Plus Blinatumomab for Adult Ph+ ALL Patients of All Ages. Intermediate Analysis of the Gimema ALL2820 (ASH 2024) - "In the previous GIMEMA LAL2116 trial, we showed the effectiveness of a chemo-free approach based on dasatinib followed by blinatumomab (Foà et al, NEJM 2020), with long-term (median follow-up 53 months) overall survival (OS) and disease-free survival (DFS) of 80.7% and 75.8%, respectively (Foà et al, JCO 2023). The combination was overall well tolerated, with very few treatment discontinuations, also in the elderly, suggesting that a ponatinib dose adjustment according to age may prevent severe toxicities. Lastly, with the biology-driven transplant allocation only 12% of patients have been transplanted so far."

Clinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Infectious Disease • Leukemia • Novel Coronavirus Disease • Oncology • Pneumonia • Respiratory Diseases • Septic Shock • ABL1 • IKZF1

PONATINIB AND BLINATUMOMAB FOR PATIENTS WITH PHILADELPHIA CHROMOSOME-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA: UPDATED RESULTS FROM A PHASE II STUDY (EHA 2022) - "Twelve doses of prophylactic IT chemotherapy with alternating cytarabine and methotrexate were administered. Conclusion The chemotherapy-free regimen of simultaneous ponatinib and blinatumomab is safe and effective in pts with Ph+ ALL. For pts with ND Ph+ ALL, SCT does not appear to be needed in first remission."

Clinical • P2 data • Acute Lymphocytic Leukemia • Bone Marrow Transplantation • Cardiovascular • Cerebral Hemorrhage • Chronic Myeloid Leukemia • CNS Disorders • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Movement Disorders • Oncology • Transplantation • ABL1

Comparison between Dasatinib-Blinatumomab Vs Ponatinib-Blinatumomab Chemo-Free Strategy for Newly Diagnosed Ph+ Acute Lymphoblastic Leukemia Patients. Preliminary Results of the Gimema ALLL2820 Trial (ASH 2023) - "So far, the benefit of the current protocol appears to rely on a lower relapse rate, with only 1 relapse being observed to date, while in the same time period 3 relapses were documented with the dasatinib-blinatumomab combination. Further details will be provided."

Clinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Infectious Disease • Leukemia • Oncology • Pneumonia • Respiratory Diseases • CD19 • IKZF1

PONATINIB AND BLINATUMOMAB IN RELAPSED/REFRACTORY PHILADELPHIA-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA OR CHRONIC MYELOID LEUKEMIA IN LYMPHOID BLAST PHASE: SUBGROUP ANALYSIS FROM A PHASE II TRIAL (EHA 2023) - "Our results show that the combination of blinatumomab and ponatinib represent an effective chemotherapy-free regimen for pts with R/R Ph+ ALL and CML-LBP, with a favorable safety profile. The rate of deep molecular response was relatively low in CML-LBP suggesting that some chemotherapy might still be needed in these pts. Chronic myeloid leukemia, Ph+ ALL, Phase II"

P2 data • Acute Lymphocytic Leukemia • Bone Marrow Transplantation • Cardiovascular • Chronic Lymphocytic Leukemia • Chronic Myeloid Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Movement Disorders • Neutropenia • Oncology • Thrombosis • Transplantation • Venous Thromboembolism • ABL1 • CD19

Randomized comparison of ponatinib versus imatinib in combination with chemotherapy in patients 55 years of age and older with newly diagnosed ph+ ALL: Molecular response and initial outcome analysis of the EWALL PH03 Study (ASH 2025) - P2 | "Moreover, the bispecific T-cell engager blinatumomab (BLIN) hasemerged as a potent front-line modality in Ph+ALL. In older pts with Ph+ALL receiving upfront reduced-intensity chemotherapy (EWALL), PONinduces a higher, albeit not significant, deep molecular response rate compared to IM, The safety profileof PON was consistent with known AEs and did not lead to a higher rate of withdrawals from studytreatment than IM. The impact on survival will require longer follow-up."

Clinical • Combination therapy • Acute Lymphocytic Leukemia • Hypertension • Pancreatitis • Thrombosis • ABL1 • BCR

Immunomodulatory effect of dasatinib plus blinatumomab versus ponatinib plus blinatumomab in newly diagnosed Ph+ acute lymphoblastic leukemia (Nature) - "The phase III GIMEMA ALL2820 trial has explored ponatinib with blinatumomab (pona+blina)...Complete molecular responders (CMR) after dasatinib induction had significantly higher lymphocytes, T and NK cells compared to non-CMR patients. Bone marrow analyses showed higher activation (CD25, CD69) and lower exhaustion (PD1, TIM3) markers on NK and NK-T cells in dasa+blina treated patients. Dasa+blina patients exhibited a significantly enhanced NK cell capacity compared to ponatinib treated patients. Patients remaining on dasatinib maintained elevated NK cells with a more mature phenotype, suggesting a durable effect."

Retrospective data • Philadelphia Chromosome Positive B-ALL

Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) yields durable remissions and survival in adults with newly diagnosed acute lymphoblastic leukemia/lymphoma (ALL): Long-term follow-up of a prospective trial (ASH 2025) - P2 | "In a single-arm Phase II trial weconducted, DA-EPOCH ± rituximab (R) ± TKI yielded comparable morphologic (morph) and measurableresidual disease (MRD)- remissions with less toxicity than seen in a comparable cohort of patientsreceiving hyperCVAD. This study completed accrual in 2021, before routine upfront incorporation ofimmunotherapy and ponatinib (if Ph+)...Imatinib or dasatinib was added if Ph+, and R if CD20+...8 pts (15%) switched to blinatumomab whenMRD+ after DA-EPOCH, with none receiving it when MRD-. DA-EPOCH±R±TKI yields durable remissions, with survival comparable toimmunotherapy-based strategies for ALL... DA-EPOCH±R±TKI yields durable remissions, with survival comparable toimmunotherapy-based strategies for ALL. Unlike many other approaches, outcomes for older pts weresimilar to the general study population. These results support DA-EPOCH±R±TKI as a curative-intentoption, particularly in resource-limited settings."

Clinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • ABL1 • CD20

Interleukin signaling mitigates the inhibitory effects of combined Src/BCR-ABL1 blockade on T-cell activity in Philadelphia chromosome-positive acute lymphoblastic leukemia. (PubMed, Haematologica) - "Consistent with prior preclinical studies, we demonstrate that dasatinib and ponatinib, unlike SRC sparing TKIs (imatinib, nilotinib), antagonize blinatumomab's T-cell engaging efficacy by potently inhibiting LCK Y394 phosphorylation, a critical step in proximal TCR signaling. We show that TKI-induced T-cell suppression and antagonism can be significantly improved by supplementing co-cultures with common gamma-chain cytokines, particularly IL-7. IL-7 robustly enhances human T-cell proliferation, reduces exhaustion, and significantly improves blinatumomab's cytotoxic efficacy in the presence of Src/BCRABL1 TKIs."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCR • IL7

A Phase I Study of Asciminib (ABL001) in Combination with Dasatinib and Prednisone for BCR-ABL1-Positive ALL and Blast Phase CML in Adults (ASH 2023) - P1 | "Both patients with imatinib-refractory CML-LBC progressed (C9, C3). Of those with ALL, 8 bridged to SCT after 2-8 cycles; 2 elected local care (C5, C7); 1 transitioned to ponatinib for inadequate response plus recurrent DAS pulmonary toxicity (C4); 6 remained on study treatment until disease progression (C4 – MRD+, C45, C11, C11); 3 remain on study... Dual ABL1 kinase inhibition with ASC and DAS plus pred in BCR::ABL1+ ALL and CML-LBC is feasible and tolerable in adults with BCR::ABL1+ ALL and CML-LBC. DLTs at ASC 160 mg/d were asymptomatic amylase and lipase elevation, without clinical sequelae. ASC 80 mg/day was declared the RP2D, and an expansion cohort of 10 pts was completed."

Clinical • Combination therapy • P1 data • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Chronic Myeloid Leukemia • CNS Disorders • Hematological Malignancies • Leukemia • Oncology • Pancreatitis • ABL1 • BCR

Immunomodulatory effect of dasatinib plus blinatumomab versus ponatinib plus blinatumomab in newly diagnosed Ph+ acute lymphoblastic leukemia. (PubMed, Leukemia) - "Patients remaining on dasatinib maintained elevated NK cells with a more mature phenotype, suggesting a durable effect. These results highlight the greater dasa+blina immune activation, supporting a potential synergistic effect of the drug combination."

IO biomarker • Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Immune Modulation • Immunology • Leukemia • Oncology • CD69 • HAVCR2 • IL2RA • ISG20 • PD-1

A CHEMOTHERAPY-FREE COMBINATION OF PONATINIB AND BLINATUMOMAB FOR PATIENTS WITH NEWLY DIAGNOSED PHILADELPHIA CHROMOSOME-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA: SUBGROUP ANALYSIS FROM A PHASE II STUDY (EHA 2023) - "Twelve doses of prophylactic IT chemotherapy with alternating cytarabine and methotrexate were administered. The chemotherapy-free combination of ponatinib and blinatumomab results in high rates of CMR and NGS MRD negativity. Encouraging duration of remission and survival has been observed without the need for SCT. Acute lymphoblastic leukemia, Clinical trial, Ph+ ALL"

Clinical • P2 data • Acute Lymphocytic Leukemia • Bone Marrow Transplantation • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Transplantation • Vascular Neurology • ABL1

RESOURCE-ADAPTED IMMUNOTHERAPY BRIDGING TO ACHIEVE MRD-NEGATIVITY PRIOR TO ALLOGENEIC HSCT IN HIGH-RISK ALL: A SINGLE-CENTRE REAL-WORLD EXPERIENCE (EBMT 2026) - "We implemented a structured resource-adapted bridging program using blinatumomab and/or inotuzumab ozogamicin (InO) with feasibility-focused operational modifications...Bridging included blinatumomab in 6/9 (1 cycle in 5; 2 cycles in 1) and InO in 4/9 (3 doses each; dose-capped); one Ph+ multiply-relapsed post–CAR-T patient received ponatinib + asciminib + InO before transplant... A structured, feasibility-focused bridging program—combining label-supported 7-day blinatumomab infusion bags, age/BSA -adapted graded escalation, and dose-capped, washout-protected InO with vial sharing—enabled MRD-negative status and allo-HSCT in all patients with 0% NRM and encouraging early survival outcomes in a high-risk real-world cohort. Larger cohorts and prospective validation are warranted."

Clinical • Minimal residual disease • Real-world • Real-world evidence • Acute Lymphocytic Leukemia • Bone Marrow Transplantation • CNS Disorders • Epilepsy • Hematological Malignancies • Leukemia

Ponatinib and blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukaemia: a US, single-centre, single-arm, phase 2 trial. (PubMed, Lancet Haematol) - P2 | "The chemotherapy-free combination of ponatinib and blinatumomab resulted in high rates of complete molecular response in patients with newly diagnosed and relapsed or refractory Ph-positive acute lymphoblastic leukaemia. Patients with newly diagnosed Ph-positive acute lymphoblastic leukaemia could be spared the toxicities associated with chemotherapy and the need for allogeneic haematopoietic stem-cell transplantation in first response."

Journal • P2 data • Acute Lymphocytic Leukemia • Bone Marrow Transplantation • Cardiovascular • Chronic Lymphocytic Leukemia • Chronic Myeloid Leukemia • Hematological Disorders • Hematological Malignancies • Hypertension • Infectious Disease • Leukemia • Movement Disorders • Oncology • Pain • Thrombosis • Transplantation • Venous Thromboembolism • ABL1 • BCR

Results of the Simultaneous Combination of Ponatinib and Blinatumomab in Philadelphia Chromosome-Positive ALL. (PubMed, J Clin Oncol) - "In conclusion, the simultaneous combination of ponatinib and blinatumomab is a highly effective and relatively safe nonchemotherapy regimen. This regimen also reduces the need for intensive chemotherapy and HSCT in first remission in the majority of patients."

Journal • Bone Marrow Transplantation • Cardiovascular • Thrombosis • Transplantation • CRLF2