Prior to the advent of tyrosine kinase inhibitors (TKIs) directed against the constitutively active ABL1 kinase, the prognosis of adults with Philadelphia-chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) was dismal. Allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1) conferred a survival benefit in the pre-TKI era, though cure rates remained low at approximately 40 percent.1 The addition of imatinib to multiagent chemotherapy improved survival in adult Ph+ ALL insofar as it allowed more patients to proceed with curative allo-HCT.2 As more potent second- and third-generation TKIs, including dasatinib, nilotinib, and ponatinib, have resulted in high remission rates with or without intensive chemotherapy, the optimal postremission therapy for these patients has come into question. In a single-institution case series of adults treated with intensive chemotherapy plus TKI (83% received either dasatinib or ponatinib), absence of detectable BCR-ABL1 transcripts (< 0.01%) within 90 days of treatment initiation indicated favorable long-term outcomes (4-year OS, 66%) without allo-HCT,3 thereby raising the question of whether allo-HCT can safely be omitted in patients who achieve a deep molecular response early in the course of therapy.
In a multi-institutional retrospective study by Dr. Armin Ghobadi and colleagues, the authors attempt to address this question by comparing outcomes of 230 adult patients who achieved deep molecular remission (BCR-ABL1 transcripts, < 0.01% by real-time polymerase chain reaction) within 90 days of initiating TKI-based therapy for de novo Ph+ ALL and either did (n=98) or did not (n=132) undergo allo-HCT in first complete remission (CR1). Many (92%) of the patients in both cohorts received intensive chemotherapy (most commonly hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone]) with either dasatinib or ponatinib, and most transplanted patients (82%) received myeloablative conditioning. In a multivariable analysis, lower cumulative incidence of relapse with allo-HCT (aHR, 0.32; 95% CI, 0.17-0.62; p<0.001) was offset by higher nonrelapse mortality (aHR, 2.59; 95% CI, 1.37-4.89; p=0.003) resulting in absence of overall (aHR, 1.05; 95% CI, 0.63-1.73; p=0.86) or relapse-free (aHR, 0.86; 95% CI, 0.54-1.37; p=0.53) survival benefit with allo-HCT. Graft-versus-host disease relapse-free survival, regarded as a surrogate for quality of life, was worse in the allo-HCT group (aHR, 2.27; 95% CI, 1.51-3.41; p<0.001) as expected.
In Brief
The analysis by Dr. Ghobadi and colleagues therefore concluded that allo-HCT did not improve overall or relapse-free survival in a cohort of adults achieving BCR-ABL1 transcript level of less than 0.01% within 90 days of intensive chemotherapy plus TKI induction. This large retrospective analysis adds important insight for clinicians choosing postremission therapy for adults with Ph+ ALL in CR1 and suggests that allo-HCT may not be beneficial for patients achieving deep molecular remission early in the course of therapy. Still, the authors concede that “early referral to a high-volume transplant center to evaluate transplant eligibility, identify potential allogeneic donors and discuss the risks and benefits of allogeneic transplant as a therapeutic option remains an essential component of management in Ph+ ALL.” It is important to contextualize the findings of this analysis within the rapidly expanding therapeutic landscape of Ph+ ALL. Prior trials have taught us that a significant proportion of adults treated with second-generation TKI-based therapies will relapse with the T315I ABL1 kinase domain mutation,4 suggesting that frontline use of ponatinib may be optimal, particularly if allo-HCT is not used.5, 6 The present article included only large leukemia/transplant programs and did not describe the proportion of patients receiving care in each of the five institutions included in the analysis; these data would help demonstrate lack of bias and support generalizability. Finally, the combination of blinatumomab plus TKI (“chemotherapy-free” approach) is being actively studied in the frontline setting, and so far, results appear promising.6 It remains to be determined if favorable long-term outcomes can be achieved with a chemotherapy-free and transplant-free approach in Ph+ ALL, though the prospects of such a paradigm shift reveal how far we have come in the management of this complex disease.
Competing Interests
Dr. Schwartz and Dr. Muffly indicated no relevant conflicts of interest.
