Has MRD graduated from its adolescence in ALL?

In this issue of Blood, Ribera et al¹  demonstrate that in adolescent and young adult (AYA) patients with Philadelphia chromosome–negative acute lymphoblastic leukemia (Ph⁻ ALL) who present with high-risk features, the depth of response to initial therapy, as measured by measurable residual disease (MRD), is a powerful and clinically relevant predictive tool. The authors show that even high-risk patients who achieve MRD negativity may be able to forego allogeneic hematopoietic transplantation without impairing their chances of long-term survival.

Despite the high probability of obtaining complete remission (CR) in Ph⁻ ALL, treatment failure as a result of either relapse or toxicity remains a major obstacle. These challenges are even more striking in AYA or older patients with ALL, where the disease is inherently more resistant than in pediatric ALL, and where patients may be less resilient than children to the effects of prolonged intensive treatment.

Traditional tools for risk stratification and assignment of postremission therapy have, for many years, consisted of the classical clinical and laboratory features at initial diagnosis (age, white blood cell count, and cytogenetics) and, more recently, the Ph-like gene expression signature.

Although the recognition that allogeneic hematopoietic cell transplant (alloHCT) may cure a proportion of AYA patients with Ph⁻ ALL, the precise identification of candidates who should undergo this procedure in first CR remains a conundrum. Clinical trials and meta-analyses derived from patients treated in the 1980s and 1990s suggested that alloHCT reduces relapse risk and improves overall survival (OS) compared with conventional postremission chemotherapy in adults with Ph⁻ ALL.²  However, these data have been overshadowed by newer studies that support 2 key interventions: first, the efficacy of more intensive “pediatric-inspired” regimens for AYA patients with Ph⁻ ALL³  that result in improved outcomes, even in the absence of consolidation with alloHCT⁴ ; and second, the independent prognostic potential of response assessments by MRD, whether by real-time quantitative polymerase chain reaction or flow cytometry (FCM), to assign patients to alloHCT after initial pediatric-inspired therapy.⁵  In standard-risk (SR) Ph⁻ ALL, it is now increasingly accepted practice that in those patients who achieve a satisfactory MRD response (after either remission induction or consolidation therapy) following a pediatric-inspired regimen, alloHCT may be avoided in favor of ongoing chemotherapy, the latter still offering a reasonable chance of cure.^6,7  However, for patients presenting with high-risk (HR) features, despite achieving MRD negativity, it is still uncertain whether alloHCT in CR1 can be safely avoided.

In this single-arm multicenter trial from the Spanish Programa para el Tratamiento de Hemopatias Malignas (PETHEMA) group,¹  HR-ALL patients aged 15 to 60 years in CR1 whose FCM-based MRD studies (measured centrally) were <0.1% after remission induction and <0.01% after 3 cycles of subsequent combination chemotherapy (early consolidation) were assigned to further consolidation and maintenance therapy. Patients who did not meet these FCM criteria were assigned to alloHCT if a suitable (matched related, unrelated, haplo-identical, or cord blood) donor was available. Of the 348 patients who underwent initial therapy, CR was achieved in 91%. There were 155 patients who achieved the 2 successive MRD milestones by completion of early consolidation. By intention-to-treat analysis, the 5-year OS rates were 59% and 38% in the chemotherapy and alloHCT arms, respectively, with corresponding cumulative incidence of relapse (CIR) of 45% and 40%. In view of the relatively frequent protocol deviations, the authors also analyzed outcomes by actual treatment administered. They found that 5-year OS for chemotherapy patients was 72%, with a CIR of 40% and nonrelapse mortality (NRM) of 3% compared with 5-year OS of 54%, with a CIR of 33% and NRM of 24% in the alloHCT recipients. Outcomes within the alloHCT arm did not differ by donor type. Importantly, their long-term outcomes appear to have temporally improved when the investigators compared their results with those of the preceding PETHEMA ALL-AR-3 trial.

Despite the absence of randomized trials that evaluate the predictive role of MRD in Ph⁻ ALL, the cumulative data from this and other clinical trials consistently point to its predictive utility in assigning patients to alloHCT, a procedure that is able to rescue some, if not all, patients from dangerously high risks of relapse. Unfortunately, the study by Ribera et al did not risk stratify patients upfront by the Ph-like gene signature, which is now considered a major disease-related risk factor in AYA-ALL.⁶  In addition, they did not incorporate blinatumomab for those patients with persistent or recurrent MRD; therefore, it plausible that this intervention might have further improved the outcomes of these patients beforeo allografting.⁸ 

It is sobering that despite the maturity of alloHCT as a procedure for ALL, NRM remains very high, even in this relatively young group of adults with ALL. Frontline clinical trials that incorporate highly active immunotherapy or chemo-immunotherapy conjugates will hopefully increase the likelihood of early MRD negativity, with the expectation that alloHCT could be restricted to an ever smaller, yet deserving, group of patients with Ph⁻ ALL.^9,10  The randomized controlled trial by the German Multicenter Study Group for Adult ALL (GMALL) group, where alloHCT vs chemotherapy is being examined in MRD-negative adults with HR-ALL (ClinicalTrials.gov identifier #NCT02881086) will hopefully clarify any residual uncertainty about the predictive power of postremission MRD assessments in Ph⁻ ALL.

Clinical guidelines on the overall management of AYAs with ALL are also needed. In 2019, the American Society of Hematology Committee on Quality added this topic to their pipeline of guidelines. The development process for ASH guidelines includes systematic reviews of available evidence and a structured approach to forming recommendations, yielding guidance that has defined uses and interpretations. ASH aims to complete the guidelines in 2021 or 2022. In the interim, it is reasonable to adopt MRD testing, as described by the PETHEMA group, as 1 major tool to allocate alloHCT in the therapy of AYA HR-ALL.