Poor Ph+ ALL outcomes require reexamination of treatment standard
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Philadelphia chromosome-positive acute lymphoblastic leukemia is a rare and aggressive form of leukemia characterized by the presence of the BCR-ABL1 fusion.
This gene fusion is formed through reciprocal translocation of portions of chromosomes 9 and 22, as is also observed in chronic myeloid leukemia.
An estimated 1,000 cases of Ph+ ALL occur each year in the United States, accounting for 25% of adults with ALL. It disproportionately affects older adults.
When patients with Ph+ ALL receive chemotherapy alone, their long-term prognosis is extremely poor. Median OS is less than a year, and less than 25% of patients achieve durable remissions.
Although clinical trials and retrospective analyses have established that incorporation of BCR-ABL1 tyrosine kinase inhibitors into treatment improves outcomes, no TKIs are approved in the U.S. for adults with newly diagnosed Ph+ ALL.
There also is no consensus on the optimal TKI for this disease, either in the front-line or relapsed/refractory settings. Guidelines offer varied recommendations, and patient- and disease-related factors may inform therapy selection.
Broader-spectrum TKIs
BCR-ABL1 TKIs have the ability to target the driver genetic abnormality of Ph+ ALL in a way that standard cytotoxic chemotherapy cannot.
However, several well-established mutations in the kinase domain of the ABL1 gene can affect treatment response to TKIs and evolve over time, eventually leading to relapse.
For example, the T315I mutation of ABL1 — one of the most frequent causes of TKI resistance in Ph+ ALL — has been identified in approximately 70% of patients with Ph+ ALL who relapse after first-line TKI treatment.
Other mutations — including E255K, F317L and Y253H — also can cause TKI resistance. Additionally, the development of compound mutations may be associated with increased drug resistance.
Earlier incorporation of targeted TKIs that are directed toward these common resistance mutations may help prevent the development of these mutations and/or additional compound mutations among patients with Ph+ ALL.
Such an approach may lead to deeper and more durable responses, ultimately reducing the relapse rate and treatment dependence.
Challenges with consolidation therapy
Historically, the preferred option for consolidation therapy for patients with Ph+ ALL has been allogeneic stem cell transplantation (allo-HSCT).
Unfortunately, many patients for whom allo-HSCT may be recommended based on disease features are unable to undergo the procedure due to advanced age or comorbidities associated with unacceptably high risk for transplant-related mortality.
Further, even when allo-HSCT is performed for younger and fit patients, it still is associated with potentially serious risks. These include infections, graft failure, graft-versus-host disease and development of secondary malignancies.
For patients for whom allo-HSCT is not appropriate — for example, older patients — maintenance therapy typically involves a combination of low-intensity chemotherapy, steroids and a BCR-ABL1 TKI for at least 1 year. The TKI often is continued for at least 5 years.
Front-line TKI selection
The depth of response achieved with front-line therapy has been shown in several studies to correlate with long-term outcomes in Ph+ ALL.
One retrospective analysis included patients treated with intensive chemotherapy plus a BCR-ABL1 TKI who did not undergo subsequent allo-HSCT. Achievement of complete molecular response (CMR) — defined as absence of a quantifiable BCR-ABL transcript by polymerase chain reaction assay — after 3 months of therapy appeared associated with longer OS. Researchers reported 4-year OS of 66% in this group, even in the absence of allo-HSCT, suggesting that many patients who achieve CMR after front-line therapy could be spared the potential morbidity and mortality of allo-HSCT in first remission.
These data also support the notion that selection of treatment regimens and TKIs for patients with newly diagnosed Ph+ ALL should be informed by their established effectiveness at inducing deep responses. As such, in clinical trials, the achievement of negative measurable residual disease (eg, CMR) likely is a good indicator for OS in Ph+ ALL and should be considered a key endpoint for drug development.
Conclusions
The incorporation of targeted, effective agents in the front-line setting is critical to improve outcomes of patients with Ph+ ALL.
Early success in the front-line setting potentially can circumvent the need for allo-HSCT consolidation, and it also may help patients avoid relapse.
Although further studies and rigorous trials are needed to investigate the efficacy and dosing of new combination treatments, a wealth of evidence supports the use of TKIs as a critical component of front-line treatment for patients with Ph+ ALL.
Various BCR-ABL1 TKIs are available, so clinicians should consider both their ability to induce deep levels of remission and their toxicity profile when selecting therapy for their patients.
Additionally, enrollment in a clinical trial is encouraged when possible. Clinical trial advancements are imperative to improving the outcomes of patients with Ph+ ALL and ultimately may lead to the development of life-saving new therapies.
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For more information:
Nicholas J. Short, MD, can be reached at nshort@mdanderson.org.
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