A Resistant Case of Ph+ Acute Lymphoblastic Leukemia in a Young Adult Male

Presentation 

A 33-year-old male with Philadelphia chromosome–positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL) initially achieved complete remission (CR) with persistent minimal/measurable residual disease (MRD) as detected by flow cytometry and ClonoSEQ® following two cycles of hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) combined with dasatinib. 

He subsequently transferred care and was treated with blinatumomab plus dasatinib in preparation for potential allogeneic hematopoietic stem cell transplantation (HSCT). However, due to persistent disease, his regimen was modified to blinatumomab and olverembatinib as part of a clinical trial protocol, which he received for two cycles with only minimal response. 

Given the suboptimal response, his treatment was further adjusted to an off-protocol combination of mini-CVD (cyclophosphamide, vincristine, dexamethasone), inotuzumab ozogamicin, ponatinib, and venetoclax. He also underwent 15 lumbar punctures with intrathecal chemotherapy, with no evidence of central nervous system (CNS) involvement throughout. 

Following this treatment, he achieved a second CR with MRD negativity by flow cytometry and detection of 10 residual clones via ClonoSEQ®. He now returns to his hematologist/oncologist to discuss next steps aimed at preventing relapse. 

Lab Values at Diagnosis Initial Workup 

Bone marrow aspiration/biopsy:  

Hypercellular (>90%) marrow with sheets of blasts occupying nearly the entire marrow. FISH positive for BCR::ABL1/AAS1 translocations (9;22) positive. Analysis of Ph-like ALL (PDGFRB [5q33], JAK2 [9p24], EPOR [19p3.2]) and ALL adult FISH panel (chromosome 4, chromosome 6, chromosome 10, IgH rearrangement, KMT2A [MLL] [11q23], MYC [8q24] rearrangement, PBX1/TCF3 t[1;19]) negative.  

Progression (5 months after diagnosis):  

80-90% blasts by immunohistochemistry; CG (cytosine and guanine): 46,XY,t(9;22)[12]/46,XY[8], >100% BCR-ABL1 by PCR with ABL1 kinase domain testing: T315i mutation (VAF [variant allele frequency] 100%), development of mutations in BCORL1 (VAF 14%) and RUNX1 (VAF 30%). 

Treatment History 

• Hyper-CVAD + dasatinib 50 mg daily x 2 cycles à CR, MRD+ by FC and ClonoSEQ® 

• Blinatumomab + dasatinib à relapse 

• Blinatumomab + olverembatinib x 2 cycles à persistent disease 

• MiniCVD + inotuzumab + ponatinib + venetoclax x 2 cycles à CR, MRD+ 

• CAR T-cell based therapy (brexucabtagene autoleucel) followed by a matched related donor hematopoietic stem cell transplant (HSCT) for consolidation 

• Day +30 from HSCT: Reverse transcriptase polymerase chain reaction (RT-PCR) negative for BCR::ABL; restarted ponatinib at 15 mg daily 30 days post-HSCT 

• Day +100 from HSCT: RT-PCR 0.029% IS, ClonoSEQ® 45 residual cells; increased ponatinib to 30 mg daily 

• Day +130 from HSCT: RT-PCR 0.82% IS, T315i present, ClonoSEQ® 482 residual cell; increased ponatinib to 45 mg daily 

• Day +160 from HSCT: RT-PCR 18.69% IS 

• Day +176 from HSCT: RT-PCR >100% 

• Received blinatumomab + venetoclax + asciminib without response 

Management 

Given the patient’s lack of response to prior combination therapy with blinatumomab, venetoclax, and asciminib, he was enrolled in a phase I clinical trial investigating AZD0486, a novel, fully human IgG CD19 × CD3 bispecific T-cell engager (BiTE). According to Gaballa et al., AZD0486 is designed to mitigate cytokine release during T-cell activation while maintaining cytotoxic activity against malignant B cells.¹ He is currently being monitored in clinic every 2 weeks with close surveillance using RT-PCR and ClonoSEQ® next-generation sequencing (NGS) for disease assessment. 

Discussion 

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is characterized by the presence of a chromosomal translocation between the Abelson murine leukemia viral oncogene (ABL) on chromosome 9 and the breakpoint cluster region (BCR) on chromosome 22, resulting in the formation of the BCR::ABL fusion gene.¹ This translocation leads to constitutive activation of the ABL tyrosine kinase, driving leukemogenesis. Detection is commonly performed using RT-PCR. 

The advent of tyrosine kinase inhibitors (TKIs) has significantly improved outcomes in BCR::ABL-positive leukemias. However, resistance remains a major clinical challenge due to factors such as advanced disease stage, intrinsic or acquired drug tolerance, and the emergence of resistant leukemic clones. While several mechanisms of resistance have been identified—including alterations in downstream-signaling pathways—this discussion focuses on the T315I mutation, often referred to as the “gatekeeper” mutation.² 

Zafar et al. demonstrated that the T315I mutation not only confers resistance but also activates additional signaling pathways, altering the biology of BCR::ABL-positive chronic myeloid leukemia (CML) and ALL compared to T315I-negative cases. As of 2019, this mutation rendered disease resistant to all approved TKIs except ponatinib. 

As of 2025, patients with the T315I mutation have access to two additional TKIs, asciminib and olverembatinib, expanding treatment options. The integration of TKIs with chemotherapy has significantly improved outcomes, with response rates in CML lymphoid blast phase reaching 70-80%.³ 

Wang et al. analyzed 19 patients with relapsed or refractory Ph+ ALL harboring the T315I mutation who were treated with venetoclax, ponatinib, and dexamethasone. The study reported an 89.5% complete remission/complete remission with incomplete count recovery (CR/CRi) rate, with 6 patients proceeding to allogeneic hematopoietic stem cell transplant (HSCT).4 Importantly, venetoclax demonstrated synergistic activity with ponatinib and dexamethasone in inducing apoptosis of primary blast cells, an effect that was significantly reduced when ponatinib was replaced by dasatinib. Additionally, ponatinib-based regimens were associated with improved survival in patients who did not undergo HSCT compared to those treated with earlier-generation TKIs. 

Allogeneic HSCT remains a key therapeutic strategy for patients with advanced disease or TKI resistance. 

The use of ClonoSEQ® next-generation sequencing has enhanced the precision of residual disease monitoring. Compared to RT-PCR, NGS may offer superior sensitivity and utility—especially in patients with persistently low-level BCR::ABL transcripts—potentially becoming the preferred modality for long-term disease surveillance.⁵ 

Further Directions 

CAR T-cell therapy for relapsed Ph+ ALL 

• According to the ELIANA trial, CAR T-cell therapy with tisagenlecleucel achieved a 100% complete remission (CR) rate in 18 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), with a 2-year relapse-free survival (RFS) rate of 88%⁶ 

• In the ZUMA-3 trial, 15 adult patients with Ph+ ALL were treated with brexucabtagene autoleucel. Among them, 80% achieved complete remission or complete remission with incomplete hematologic recovery (CR/CRi). At 6 months, relapse-free survival (RFS) was comparable between Ph+ and Ph− patients (60% vs. 58%, respectively), while the overall survival (OS) at 12 months was notably higher in the Ph+ group (93% vs. 63%, respectively)⁶ 

• CAR T-cell therapy is also being investigated as a consolidation strategy in Ph+ ALL, with the goal of deepening remission and potentially reducing the need for allogeneic stem cell transplantation. 

Use of ClonoSEQ® NGS testing in Ph+ ALL 

• According to Jabbour et al., in patients treated with obecabtagene autoleucel (obe-cel), an autologous CD19-directed CAR T-cell therapy, there is a significant correlation between the depth of MRD and clinical outcomes.⁷ Patients who achieved MRD negativity demonstrated improved response durability and long-term outcomes compared to those with detectable residual disease. 

Optimal management of patients with relapsed/refractory Ph+ ALL 

• The integration of next-generation TKIs, bispecific antibodies (e.g., BiTEs), CAR T-cell therapy, and antibody-drug conjugates has contributed to significant improvements in survival for patients with Ph+ ALL. According to an analysis of the European Society for Blood and Marrow Transplantation registry, advancements in conditioning regimens and post-transplant maintenance strategies have increased 2-year overall survival rates from 27.8% to 54.8%.⁶ 

Clinical Trials 

• Clinical trials remain a critical treatment option for patients with Ph+ ALL, particularly those with relapsed or refractory disease, offering access to novel therapies and emerging treatment strategies that may not yet be widely available. 

References 

1. Gaballa S, Hou JZ, Sumana Devata, et al. Evaluation of AZD0486, a novel CD19xCD3 T-cell engager, in relapsed/refractory diffuse large B-cell lymphoma in an ongoing first-in-human phase 1 study: High complete responses seen in CAR-T-naive and CAR-T-exposed patients. Blood. 2024;144(suppl 1):868-868. doi:10.1182/blood-2024-193681 
2. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2025 update on diagnosis, therapy, and monitoring. Am J Hematol. 2024;99(11):2191-2212. doi:10.1002/ajh.27443 
3. Zafar U, Yusuf M, Chakraborty R, et al. The “gatekeeper” mutation T315I in BCR/ABL confers additional oncogenic activities to Philadelphia chromosome positive leukemia. Blood. 2019;134(suppl_1):5196. doi:10.1182/blood-2019-131694 
4. Wang H, Yang C, Shi T, et al. Venetoclax-ponatinib for T315I/compound-mutated Ph+ acute lymphoblastic leukemia. Blood Cancer J. 2022;12(1):20. doi:10.1038/s41408-022-00621-9  
5. Short NJ, Jabbour E, Macaron W, et al. Ultrasensitive NGS MRD assessment in Ph+ ALL: Prognostic impact and correlation with RT-PCR for BCR::ABL1. Am J Hematol. 2023;98(8):1196-1203. doi:10.1002/ajh.26949 
6. Abou Dalle I, Moukalled N, El Cheikh J, et al. Philadelphia-chromosome positive acute lymphoblastic leukemia: Ten frequently asked questions. Leukemia. 2024;38(9):1876-1884. doi:10.1038/s41375-024-02319-2  
7. Jabbour E, Park JH, Shaughnessy P, et al. Obecabtagene autoleucel (obe-cel) for adult relapsed/refractory b-cell acute lymphoblastic leukemia (R/R B-ALL): Deep molecular remission may predict better outcomes. Blood. 2024;144(suppl 1):963. doi:10.1182/blood-2024-194508