Measurable residual disease at myeloablative allogeneic transplantation in adults with acute lymphoblastic leukemia: a retrospective registry study on 2780 patients from the acute leukemia working party of the EBMT

Assessment of measurable residual disease (MRD) is rapidly transforming the therapeutic and prognostic landscape of a wide range of hematological malignancies. Its prognostic value in acute lymphoblastic leukemia (ALL) has been established and MRD measured post-induction or consolidation is increasingly used to guide further therapy [1].

The prognostic value of MRD measured prior to allogeneic hematopoietic cell transplantation (HCT) on its outcomes was first observed in small retrospective [2, 3] and prospective [4] studies of children and adolescents and later also in adults [5‐7], and confirmed in a recent meta-analysis [8]. However, it remains unclear if or to what extent the choice of conditioning regimen impacts on this. We have recently studied the interaction of myeloablative versus reduced-intensity conditioning and MRD in acute myeloid leukemia [9]. As ALL patients rarely receive reduced-intensity conditioning, we explored if MRD detectable before allogeneic HCT for ALL is associated with different outcomes in recipients of myeloablative total body irradiation (TBI)-based versus chemotherapy-based conditioning.

In this large study, we confirmed that adult patients with ALL who are MRD-negative prior to allogeneic HCT achieve superior outcomes, namely, lower RI, higher LFS, and OS. We were interested in exploring potential differing outcomes between recipients of TBI-based conditioning and conditioning based on chemotherapy only. While TBI-based conditioning is associated with significant short as well as long-term toxicity [16], it remains part of most conditioning protocols for ALL because it is believed to have a better anti-leukemic potential in lymphoid malignancies. In animal experiments, administration of high doses of busulfan had little impact on lymphoid organs [17] or on antibody responses [18]. In children, a small randomized trial [19] showed better event-free survival with TBI-based regiments, and a recent large international randomized trial closed, after an interim analysis showed a survival benefit in patients who received TBI-based conditioning over chemotherapy-based conditioning [20]. There are no such randomized prospective trials in adults, but data in many retrospective studies, including recently published large analysis by the EBMT suggested advantages of TBI-based over chemotherapy-based regimens, particularly in terms of reduced risk of relapse and improved LFS [21]. This effect was also seen in adults transplanted for primary refractory ALL [22] with a large tumor bulk as well as in patients with T-ALL, regardless of their remission status [23]. So far, however, the impact of conditioning has not been studied in the context of MRD. It has been unclear if TBI is necessary for patients who achieved MRD negativity as a graft-versus-leukemia effect may be sufficient to eliminate very low level of residual disease.

This study showed significantly superior outcomes with the use of TBI-based conditioning in both MRD-positive and MDR-negative patients, but the impact of MRD did not differ significantly between the TBI-based or chemotherapy-based conditioning. MRD positivity was associated with lower OS and LFS and higher RI in the larger (n = 1943) TBI subgroup, and with higher RI in the smaller (n = 571) chemotherapy subgroup. The reasons for this cannot be concluded from this study, but it is possible that ALL cells are able to escape the effect of chemotherapy in sanctuary sites such as CNS, and/or that the ALL is simply more susceptible to effects of radiotherapy. No patients received radiotherapy before starting transplantation conditioning, so irradiation represents a different anti-leukemic treatment modality to chemotherapy in patients transplanted after TBI-based conditioning. Also, patients in this cohort did not receive modern immunotherapy such as inotuzumab, ozogamicin, or blinatumomab that are able to induce MRD negativity on their own [24, 25] or in addition to chemotherapy [26, 27]. It is likely that with the use of these agents, more patients may become MRD-negative. Whether they will or will not benefit from TBI-based conditioning as the MRD-negative patients in this cohort remains unclear, but clinicians should not rush into rejecting TBI-based conditioning in patients with ALL.

Compared to related donors, unrelated donors both 10/10 and 9/10 had a lower incidence of relapse. This suggests better anti-leukemic activity and increased GVHD with lower degree of histocompatibility. Unlike in recent studies of T cell-replete haploidentical transplantation with post-transplantation cyclophosphamide [28, 29], this increase in anti-leukemic activity did not improve OS due to higher incidence of aGVHD, cGVHD, and NRM.

Interestingly, in vivo T cell depletion was associated with higher RI, lower NRM, and lower incidence of aGVHD and cGVHD only in patients who received TBI-based, but not chemotherapy-based conditioning. This phenomenon may suggest more profound immune allogeneic effect in conjunction with the use of TBI-based conditioning, perhaps due to more significant lymphodepletion seen in animal experiments after TBI but not after chemotherapy [17, 18]. Some previous publications suggested an increased incidence of GVHD after TBI-based conditioning [30, 31], but there is also data in contrary to this [32]. Surprisingly, in the chemotherapy-based, but not TBI-based conditioning subgroup, MRD-positive patients experienced higher RI, but comparable LFS and OS. Although it is possible to speculate that patients who relapsed after chemotherapy-based conditioning benefited more from salvage treatments with donor lymphocytes, the difference may be also due to the size of the groups and resulting statistical power.

Although the majority of EBMT centers use highly sensitive methods of MDR detection [33], and our an additional audit showed that all 56 centers but 1 regarded an MRD level of 10⁻⁴ or lower as negative (for one center this was less than 10⁻³), an obvious limitation of this registry study is the lack of access to details of MRD methodologies and targets used in individual patients. However, the proportion of reported MRD-positive cases seen was 35% of the total eligible for the study and this is similar to the 21 to 38% reported in studies where detailed review of MRD methodology and targets were feasible [34, 35]. Centers were required to declare the MRD status of patients prior to HCT, but we did not have access to the precise timing of the relevant MRD assay. Another important issue is potential heterogeneity of conditioning regimens within the TBI and chemotherapy groups [36].

The challenge of how best to manage MRD positivity pre-HCT in the clinic is a familiar dilemma since further therapy may incur toxicity that renders subsequent HCT undeliverable or may result in frank relapse should the leukemia show resistance to the new treatment modality. In the post-HCT setting, management of MRD-positive patients has involved strategies such as rapid withdrawal of immunosuppressive medication, pre-emptive use of donor lymphocyte infusions, and maintenance therapy with tyrosine kinase inhibitors in Philadelphia-positive patients. In the future, immunotherapy such as blinatumomab [37], chimeric antigen receptor T cells, natural killer cells, or check-point inhibitors may be useful mostly in patients with B cell ALL.

In this large study, we confirmed that adult patients with acute lymphoblastic leukemia who are MRD-negative prior to HCT achieve superior outcomes. This was particularly apparent with the use of TBI-based conditioning. With increasing availability of new therapies MRD negativity is likely to become achievable for more patients, hopefully leading to improved treatment outcomes. As all patients with ALL irrespective of MRD status benefit from TBI-based conditioning, avoidance of it on the basis of achievement of MRD negativity is not justified.