A challenging choice: consolidation in Ph⁺ ALL

In this issue of Blood, Ghobadi and colleagues examine the role of allogeneic hematopoietic cell transplantation (allo-HCT) in adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph⁺ ALL) who achieve a complete molecular response within 90 days of starting treatment and conclude that allo-HCT does not improve overall survival compared with treatment with a tyrosine kinase inhibitor (TKI) plus intensive chemotherapy.¹ Ph⁺ ALL is an aggressive, frequently fatal leukemia that occurs mainly in adults. Potent inhibitors of the constitutively active ABL kinase have drastically improved outcomes for patients with Ph⁺ ALL and are a compulsory component of therapy. Historically, allo-HCT has also been a standard recommendation for all eligible patients in first complete remission (CR1).

In the preimatinib era, allo-HCT improved the rate of cure from dismal (<20%) to low (40%).² The benefit of allo-HCT in CR1 was confirmed in the imatinib era.^3,4 Subsequently, the potent second-generation (dasatinib, nilotinib) and then third-generation (ponatinib) TKIs have further improved outcomes, and cure is now achieved in the majority of transplant-eligible patients diagnosed with Ph⁺ ALL. As powerful TKIs move the survival needle upward, the necessary role of allo-HCT has become less certain for patients who respond rapidly and deeply to treatment with a TKI and intensive cytotoxic chemotherapy.^5,6 A recent noncomparative, large case series of patients treated with a TKI plus the hyper-CVAD (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone) regimen reported excellent outcomes in patients who achieved a BCR-ABL1 transcript level <0.01% by 3 months, even without allo-HCT.⁷ 

In this context, investigators from 5 transplant centers collaborated to report outcomes of a combined cohort of 230 adult patients diagnosed with Ph⁺ ALL over 2 decades (2001-2018) who had achieved a complete molecular response, defined as a BCR-ABL1 transcript level < 0.01% by quantitative polymerase chain reaction assay, within 90 days of treatment with TKI plus chemotherapy. Outcomes between those who did (n = 98) and did not (n = 132) receive allo-HCT in CR1 were compared. Most patients in the study were treated with hyper-CVAD (81%) plus dasatinib or ponatinib. Recipients of allo-HCT were younger, fitter, and less likely to have received ponatinib. Most transplants were myeloablative (82%), and approximately half (54%) included total body irradiation (TBI) conditioning.

The primary study conclusion was that allo-HCT in CR1 did not improve overall and relapse-free survival in a cohort of intensively treated patients achieving BCR-ABL1 transcript level <0.01% within 90 days. In these patients, allo-HSCT was associated with less relapse but more nonrelapse mortality (and of course more graft-versus-host disease) so that overall survival was not statistically different between cohorts (see figure). In the absence of a randomized trial, this relatively large, retrospective study represents a noteworthy contribution to our knowledge. Importantly, the authors endeavored to address imbalances in patient and treatment characteristics between the allo and non-allo HCT cohorts with statistical adjustments, although the methods applied may not account for all factors biasing transplant referral.

Hematologists caring for adults with Ph⁺ ALL are hungry for data to guide practice. The findings of this study are significant, but the conclusions must be limited to comparable patients: those with newly diagnosed, de novo Ph⁺ ALL who achieve a deep remission (BCR-ABL1 transcript level <0.01%) within 90 days of treatment being managed with an intensive induction and consolidation chemotherapy regimen. This study does not address the role of allo-HCT in patients with chronic myeloid leukemia (CML) in lymphoid blast crisis, therapy-related ALL (an increasingly recognized entity), or Ph⁺ ALL that responds more slowly to therapy. It also does not apply to those treated with a chemotherapy-free or chemotherapy-light approach. Indeed, a recent report from the ongoing GRAAPH 2014 study revealed inferior outcomes in patients who did not receive either intensive (cytarabine-based) consolidation or allo-HCT.⁸ Finally, this study does not address the need for allo-HCT in patients treated with novel chemotherapy-free regimens such TKI plus blinatumomab.⁹ 

Perhaps the biggest challenge of applying the findings of this study to current practice is the rapid expansion of knowledge and improvements in clinical practice in both Ph⁺ ALL and allo-HCT. Thus, the risk-benefit ratio of allo-HCT overall, and particularly within specific patient subgroups, is likely to continually evolve. Will patients with additional high-risk genetic features such as IKZF1 plus other copy number abnormalities be found to benefit from allo-HCT?¹⁰ Will use of measurable residual disease (MRD) assays more specific for the lymphoblastic disease compartment better identify patients needing therapeutic intensification with allo-HCT? Will advances in prevention and management of graft-versus-host disease, and development of non-TBI allo-HCT conditioning decrease toxicity and treatment-related mortality after allo-HCT? Will availability of more effective salvage therapies (TKI and non-TKI based) ensure that allo-HCT in CR2 can be reliably realized so that we do not need to “get it right the first time”? Will advances in chimeric antigen receptor therapy (CAR-T) make it the preferred and definitive salvage option in relapsed or refractory disease?

The management of Ph⁺ ALL is evolving at lightning speed, and it is imperative that prospective, randomized trials of transplant and nontransplant approaches be conducted to obtain the necessary high-quality data to rationally advance the field. In the meantime, the study by Ghobadi et al suggests that allo-HCT may be reasonably deferred in transplant-eligible patients who respond rapidly and deeply to a TKI plus intensive chemotherapy. Still, given the complexity of the disease and treatment landscape, as recommended by the authors, “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.” Until all the cards have been dealt, transplant colleagues: we still need you!

Conflict-of-interest disclosure: The author declares no competing financial interests.