Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: From Discovery to the Edge of Cure

It all began in 1960 in Philadelphia, when David Hungerford, MD, and Peter Nowell, MD, observed that cells from patients with chronic myeloid leukemia (CML) harbored an abnormally small chromosome.¹ Later, in 1973, Janet Rowley, MD, at the University of Chicago, improved cytogenetic techniques and demonstrated that the Philadelphia chromosome results from a reciprocal translocation between chromosomes 9 and 22 (ie, t(9;22)(q34;q11)).²

This translocation results in a chimeric BCR-ABL1 fusion protein, with a constitutively active tyrosine kinase that drives unchecked proliferation of hematopoietic cells. These discoveries were pivotal; they not only illuminated the pathogenesis of CML and Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) but also laid the foundation for the development of imatinib, the first targeted cancer therapy, which was approved by the FDA in 2001 based on results of a phase 1 trial conducted by Brian J. Druker, MD, and colleagues.^3,4

The Philadelphia chromosome is present in nearly all patients with CML. In contrast, acute lymphoblastic leukemia (ALL) follows a bimodal age distribution, peaking between ages 4 and 5 years and again around age 50. Approximately 25% of adult patients with ALL have Ph+ ALL, whereas among children with ALL, it is less prevalent and present in less than 5% of patients. Depending on the breakpoint within the BCR gene, different BCR-ABL fusion proteins are formed. The two most common isoforms are p190 and p210, with p190 expressed in about 75% of Ph+ ALL cases.

Historically, Ph+ ALL was associated with a dismal prognosis. The 5-year overall survival (OS) rarely exceeded 20% with standard multi-agent chemotherapy. Allogeneic hematopoietic stem cell transplantation (alloHSCT) was considered the only potential curative option once remission was achieved. However, alloHSCT was often not feasible, given the older age and comorbidities common at the time of diagnosis in many patients with ALL.

Between 2001 and 2002, imatinib was introduced in the refractory setting of Ph+ ALL, with encouraging results.⁴ In 2004, Thomas and colleagues⁵ reported that imatinib could be safely combined with the hyper-CVAD (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride [Adriamycin], and dexamethasone) chemotherapy backbone, showing further promise. Since then, the management of Ph+ ALL has evolved dramatically.

Currently, treatment is determined based on age and comorbidities. According to the 2025 National Comprehensive Cancer Network (NCCN) guidelines for management of ALL, patients younger than 65 years and without significant comorbidities may be treated with a second- or third-generation tyrosine kinase inhibitor (TKI) in combination with either hyper-CVAD or blinatumomab.⁶ For patients older than 65, therapy often includes a TKI with blinatumomab with or without steroids and with or without low-intensity chemotherapy, depending on performance status and comorbidities.

Evidence supporting TKI plus chemotherapy combinations comes from multiple studies, including the single-arm trial by Jabbour et al,⁷ in which ponatinib plus hyper-CVAD resulted in a 2-year event-free survival (EFS) of 81% (95% CI, 64%-90%). Despite the proven efficacy of newer TKIs, head-to-head comparisons remain limited. Second- and third-generation TKIs often induce faster molecular responses than imatinib, although survival benefits remain unclear, particularly among adult patients with Ph+ ALL. In a recent phase 3 randomized trial comparing ponatinib (30 mg/d) with imatinib (600 mg/d)—both with reduced-intensity chemotherapy—measurable residual disease (MRD)–negative complete remission was significantly greater with ponatinib (34.4% vs 16.7%).⁸ However, no difference in EFS or OS was observed, likely due to higher toxicity-related mortality in the ponatinib arm.⁹

The introduction of blinatumomab, a bispecific T-cell engager that redirects T cells to kill CD19+ leukemia cells, has been transformative in the treatment of Ph+ and Ph– ALL. Its tolerability and potent antileukemic activity have encouraged investigators to explore chemotherapy-free regimens, placing traditional chemo in the background. One key study is the D-ALBA trial (GIMEMA LAL2116), a phase 2 study combining dasatinib and steroids for induction, followed by blinatumomab consolidation. This approach achieved a remarkable 98% complete remission rate, with molecular responses up to 60% after two blinatumomab cycles, and a 3-year OS of 80%.¹⁰ Impressively, nearly half of the patients did not need salvage chemotherapy and alloHSCT, even though the median age was 54 years.

Such findings have led clinicians to question whether alloHSCT is still necessary for patients with Ph+ ALL who achieve deep molecular remission, particularly those who become MRD negative according to next-generation sequencing–based BCR::ABL1 testing. In the most recent NCCN guidelines publication, the use of alloHSCT is considered a suggestion for patients who achieve MRD-negative disease.¹¹ An even more provocative question is whether we need chemotherapy at all. Currently, no randomized trials directly compare TKI + blinatumomab versus TKI + chemotherapy, but this critical question is being addressed in ongoing trials such as GIMEMA LAL2820 and ECOG-ACRIN EA9181.

Meanwhile, asciminib, a first-in-class allosteric BCR::ABL1 inhibitor, has emerged as a promising agent. Although currently approved for CML, its role in Ph+ ALL is being actively studied. At the American Society of Clinical Oncology 2025 Annual Meeting, Marlise Rachael Luskin, MD, MSCE, of the Dana-Farber Cancer Institute, presented phase 1 data (NCT03595917) on combining dasatinib, asciminib, and blinatumomab, which showed encouraging results: 100% complete response, 100% MRD-negative by flow cytometry, 67% MRD-negative by clonoSEQ testing, and 45% MR3 molecular response.¹²  Although these results are impressive, the true benefit of adding asciminib to a blinatumomab + TKI backbone still requires confirmation in randomized trials, especially given concerns about added toxicity and the significant financial impact associated with these novel regimens. Such trials usually require a large sample size to have adequate power to detect minor differences between highly efficacious regimens.

In conclusion, the management of Ph+ ALL has evolved rapidly, from a disease once managed solely with chemotherapy and alloHSCT to regimens incorporating TKIs, then TKIs + blinatumomab, and now novel combinations that may obviate the need for chemotherapy or alloHSCT altogether. We are now entering an era when Ph+ ALL can be cured in a substantial proportion of patients, without ever resorting to an alloHSCT.