Clinical Pearls & Morning Reports
Published June 22, 2022
The Philadelphia chromosome (Ph) was the first cytogenetic abnormality associated with a human cancer, chronic myeloid leukemia (CML). The rearrangement between chromosome 9 and chromosome 22, a hallmark of the disease, contains the BCR-ABL1 fusion gene, which encodes for a constitutively activated tyrosine kinase signaling protein that sustains the leukemia. The Ph chromosome can also be found in patients with acute lymphoblastic leukemia (ALL). Read the NEJM Review Article here.
Q: What class of therapeutics has improved survival in Ph-positive ALL?
A: In the late 1990s, the first tyrosine kinase inhibitor (TKI), imatinib, was developed, which changed the natural history of CML. For decades, Ph-positive ALL was considered the leukemia with the worst outcome, in both children and adults, because of the poor response to conventional multiagent chemotherapy. Allogeneic stem-cell transplantation was the only chance for a cure, which was achievable in only a minority of patients because of older age and a poor response to conventional treatment. The scenario changed when the use of TKIs was extended from CML to Ph-positive ALL. Survival rates have improved from about 10 to 20% before the introduction of TKIs to current rates of 50 to 60%.
Q: What age group is most at risk for Ph-positive ALL?
A: Most patients with Ph-positive ALL are elderly. Although rare in children (incidence, 2 to 5%), the Ph chromosome represents the most common genetic subgroup in ALL in adults, with an overall incidence of 20 to 25%. The incidence increases with age and accounts for more than 50% of cases of ALL in patients who are older than 50 years of age.
A: Since 2004, in all multicenter frontline trials from a group in Italy, a TKI has been used in induction without the addition of systemic chemotherapy. These studies showed that induction therapy with a TKI alone, plus glucocorticoids and central nervous system prophylaxis, was associated with a complete hematologic remission in 94 to 100% of all adults with Ph-positive ALL, with virtually no deaths during induction. TKIs have greatly improved induction treatment, and more potent TKIs than imatinib — dasatinib and ponatinib — are currently being tested. In patients with CML, the host immune system can be boosted through interferon alfa and TKI treatment, an approach that may also extend to Ph-positive ALL. In this context, the bispecific monoclonal antibody blinatumomab has gained attention. Blinatumomab binds to B-lineage ALL cells, and the antileukemic effect is exerted through the immune system by activating host T cells, making blinatumomab a very attractive prospect for improving the response to TKIs in Ph-positive ALL, with or without chemotherapy.
A: Although allogeneic transplantation has been, and possibly still is, the standard approach to curative therapy for patients with Ph-positive ALL, its role is debated. Chalandon et al. and Sasaki et al. reported that transplantation did not improve survival for patients with no measurable residual disease (MRD). Since the depth of the treatment response is continually increasing, owing to the more potent TKIs and immunotherapy, it is likely that fewer patients will undergo transplantation as part of the frontline treatment program. However, patients in hematologic remission who have persistent MRD, with IKZF1plus mutations, deleterious ABL1 mutations, or both, should be considered for allogeneic hematopoietic stem-cell transplantation at the earliest convenience. The situation is different for patients with a relapse after a second hematologic (and possibly molecular) remission, who should undergo allogeneic transplantation as soon as possible.