One of the most common cytogenetic abnormalities in adult ALL is the presence of Ph that is established as an adverse prognostic marker. The incorporation of TKIs in the frontline treatment of Ph-positive ALL followed by allo-HCT in first CR has shown improvement in long-term survival (1). Despite the progress in allo-HCT techniques in Ph-positive ALL and the substantial improvement in post-transplant relapse therapies with a steady increase in 2-year OS over the years from 28% to 55%, leukemia relapse remains the main cause of failure post allo-HCT (28). Thus, maintenance therapies with TKI were developed to mitigate the risk of relapse. Nowadays, the use of TKIs after allo-HCT is encouraged for all patients with Ph-positive ALL irrespective of the MRD status (prophylactic approach) once hematopoietic stability is achieved, or at least preemptively upon MRD recurrence. In a prospective randomized trial, prophylactic use of imatinib post allo-HCT showed a lower incidence of molecular relapse compared to MRD driven imatinib use (40% versus 69%, p=0.046), with a relatively high 5-year OS of 80% and 74.5% respectively, despite early discontinuation of imatinib due to adverse events (10). Imatinib was used prophylactically or preemptively post-transplant in seven prospective studies and five retrospective studies showing a 1.5 to 3 years OS ranging between 62% to 92% and 1.5 to 5 years disease free survival of 60.4% to 92%. On the other hand, second generation TKIs such as dasatinib and nilotinib were studied post allo-HCT with limited data suggesting better OS with second-generation TKIs especially in MRD positive patients. Dasatinib maintenance led to an OS of 87% to 100% at 1.4 to 3 years and disease-free survival was 89% to 100% which is higher than that with imatinib. In a study using nilotinib in Ph positive ALL, OS at 5 years was only 60% (29, 30). Furthermore, up to 50% of relapses post allo-HCT are caused by the BCR-ABL T315I mutation. Thus, prophylactic or pre-emptive use of ponatinib in this setting was tested in retrospective studies showing good tolerability of 15 mg daily dosing, and efficacy in molecular response as well as long-term OS and leukemia-free survival (31, 32). The use of TKIs (from all generations) after allo-HCT for patients in first CR improved OS when given as a prophylactic or preemptive regimen (33). In addition, imatinib failed to improve OS in patients who were beyond first CR at the time of allo-HCT and no data were available with newer generation TKIs for this population (33).

In a retrospective study conducted by the European Society for Blood and Marrow Transplantation (EBMT), the use of a prophylactic TKI in 60 patients post allo-HCT was associated with improved leukemia-free survival (hazard ratio [HR]=0.44, p=0.002) and OS (HR=0.42, p=0.004) (34). Based on this and many other published reports, the EBMT published a consensus statement encouraging the use of maintenance TKI post allo-HCT to reduce risk of relapse (35).

The duration of TKI maintenance post allo-HCT is another debate. There are no current prospective trials evaluating the optimal duration of TKI maintenance. Institutional guidelines recommend continuing TKI for at least 2 years and up to 5 years, if no major toxicities arise. In the GMALL study, imatinib maintenance was given for one year of continuous complete molecular remission (10). A recent retrospective study from MD Anderson cancer center evaluated 84 Ph-positive ALL patients who were alive and in complete molecular remission at 3 months post allo-HCT and still receiving TKI. The median duration of TKI maintenance was 13 months. Patients who received TKI beyond 24 months had significantly lower risk of relapse than those who stopped before 24 months (HR=0.12, p=0.045) (36). Nevertheless, prolonged administration of TKI post allo-HCT may increase drug-related toxicities over time affecting drug tolerability and compliance.

Donor lymphocyte infusions (DLIs) are often used to treat leukemia relapse post allo-HCT by re-instituting the T-cell immunity against the leukemia cells. It is now known that DLI effectiveness is dependent on many factors, including the type of underlying disease, the bulk of disease, and the pre-treatment immunologic state, mainly CD8+ T-cell infiltrates (37). While DLI response rates are relatively high in chronic myeloid leukemia, reaching 80%, the use of therapeutic DLIs in relapsed B-cell ALL after allo-HCT is still disappointing with remissions not exceeding 15% (38–40). One of the proposed reasons for the relative ineffectiveness of therapeutic DLI in ALL is the lack of proliferative capacity of ALL-reactive T-cells (41). Considering the limited efficacy of DLI in relapsed B-ALL, several groups have shown that prophylactic or pre-emptive DLI based on the MRD status or the loss of complete chimerism may have a role in preventing overt hematological relapse by infusing multiple escalated doses of DLI guided by the occurrence of GVHD (11, 12, 42). This approach was proven to reduce the relapse risk and increase survival post allo-HCT in patients with impending relapse. In order to enhance the GVL effect while limiting the known risk of GVHD post DLI, a recent pilot study investigated a repetitive schedule of low-dose DLIs every two months for at least 36 months and included 11 patients with high-risk ALL post allo-HCT. This innovative strategy was demonstrated to be safe and effective in reducing both relapse and GVHD rates in patients with high-risk acute leukemia (43). An alternative strategy involves a dose escalation schedule of DLI that similarly provides improved outcomes with lower rates of GVHD (44). In addition, DLI can be combined with blinatumomab in the post-transplant setting, allowing the infused donor T-cells to be redirected toward the CD19-positive leukemia cells. This combination was tested in a few retrospective studies that showed its tolerability, however with no definite added benefit (45, 46).

Blinatumomab is a recombinant murine monoclonal bispecific antibody that targets both CD19 antigen expressed by most B-cells and the CD3 antigen present on T cells leading to their engagement, activation of T cells and subsequent lysis of leukemia cells (47). Blinatumomab was granted the US Food and Drug Administration (FDA) approval in 2014 for adults and children with R/R B-ALL or those with persistent MRD positive ALL based on a multi-institutional randomized phase III trial that demonstrated superiority of blinatumomab over chemotherapy in regards to overall response rate (ORR) and OS in patients with R/R ALL (48). Despite the great enthusiasm, blinatumomab as a single agent in overt relapse offered a modest response rate of 40% and a median OS not exceeding 8 months (48). An exploratory analysis on 64 patients who had relapsed post allo-HCT and were treated with blinatumomab showed similar outcomes with an ORR of 45% and median OS of 8.5 months (49). More importantly, there were no increased rates of GVHD, nor infections. It was soon established that blinatumomab is more effective when the burden of disease is low. The BLAST clinical trial investigated blinatumomab in 113 patients in first or second CR with detectable MRD ≥10^-3, where 78% achieved a complete MRD response and 67% proceeded to allo-HCT (50). In patients with chemotherapy-resistant MRD, targeted immunotherapy with blinatumomab resulted in a substantial molecular response rate and improved long-term outcomes among responders, even those who were not transplanted (51).

To decrease the risk of relapse post-transplant by redirecting the unengaged donor T-cells before they mount a GVL response toward residual leukemic cells, Gaballa et al. investigated the use of maintenance blinatumomab post allo-HCT in high-risk B-ALL (13). In a phase II study conducted at The MD Anderson Cancer Center, four cycles of maintenance blinatumomab were administered every 3 months in the first year after allo-HCT. Patients at high risk of relapse other than those with persistent MRD pre and/or post allo-HCT were included such as complete hematologic remission beyond first CR at the time of allo-HCT, primary induction failure requiring more than one line of treatment, and/or high-risk cytogenetic or molecular profile defined as Ph-positive ALL, Ph-like ALL, KMT2A gene rearrangement, complex cytogenetics, or hypodiploid cytogenetics at diagnosis. Twenty-one patients were treated with at least one cycle of blinatumomab, and 57% completed all scheduled four cycles. The median follow-up was for 14.3 months with a cumulative incidence of relapse of 29% (95% confidence interval: 11%-49%). The 1-year OS and progression-free survival (PFS) were 85% and 71%, respectively (13). As reported previously, blinatumomab was not associated with increased risk of GVHD nor infections. Interestingly, this study highlighted some important mechanistic insights on predictors of response including the number of CD4 and CD8 T-cells with effector memory phenotype and the expression of some checkpoint inhibitors especially TIM-3. Despite the established safety of blinatumomab post allo-HCT, its additional benefit was not confirmed when compared to a matched cohort not treated with blinatumomab. Furthermore, blinatumomab could have a preferential benefit in patients with genomic loss of human leucocyte antigen expression after haplo-identical HCT where three out of four patients achieved CR with complete MRD response after 2 cycles of treatment, suggesting blinatumomab therapy as a potential strategy to restore a GVL effect (52). The mentioned data indicate a remarkable potential for blinatumomab as a promising agent to maintain remission and manage relapse after allo-HCT with the need for more randomized trials to optimize the standards. Additionally, there is also a rationale for combining blinatumomab with other agents like checkpoint inhibitors or DLI to further activate donor T-cells and increase efficacy; however, this approach might be limited by a substantial increase in the risk of acute life threatening GVHD.

Inotuzumab ozogamicin is a CD22 antibody drug conjugate bound to calicheamicin, a cytotoxic antitumor antibiotic, that was approved by the FDA in 2017 for the treatment of adult patients with R/R B-ALL based on the results of the INO-VATE trial (53). The trial included 326 R/R B-ALL patients and among those who achieved CR, the percentage with MRD negativity was significantly higher in the inotuzumab ozogamicin (78.4%) compared to the standard therapy group (28.1%) (54). In addition, consolidation with allo-HCT for patients who achieved CR in the inotuzumab group led to better OS besides other factors that improved survival such as best MRD status, hematological remission and the duration of first CR (55). The CR rate was also similar between patients with or without prior allo-HCT (76.5% versus 81.5%) (54). The main limitation with inotuzumab ozogamicin is hepatotoxicity and veno-occlusive disease in patients receiving allo-HCT, for which preventive measures should be considered such as the avoidance of double alkylators within the conditioning regimen and the limitation of number of cycles of inotuzumab to up to 2 cycles if allo-HCT is planned, in addition to a longer interval between the last dose and allo-HCT, preferably six to eight weeks (56). The use of inotuzumab ozogamicin as maintenance treatment post allo-HCT at lower doses of 0.3 and 0.4 mg/m² in four 28-days cycles was studied in a phase I trial which included eight patients with high-risk ALL. Four patients completed the first year of post-transplant follow-up, low-dose inotuzumab ozogamicin was well tolerated with only thrombocytopenia as a dose-limiting toxicity (14). The absence of disease recurrence in this small cohort of high-risk ALL patients warrants further investigation.

Chimeric antigen receptor (CAR) T-cell therapy has led to significant success in hematological malignancies especially in R/R B-ALL where autologous CD19 CAR T-cells have shown remarkable anti-leukemia effects and CR rates of 70 to 90% (57). This led to tisagenlecleucel being the first CAR T-cell therapy product to be approved by the FDA in 2017 followed by brexucabtagene autoleucel as a second autologous product for R/R B-ALL (58). CAR T-cell therapy in the R/R setting is usually limited by a relatively short disease-free survival, for which successful CAR T-cell therapy is commonly followed by allo-HCT. However, data on CAR T-cells for post-transplant relapse is limited to few studies where the source of CAR T-cells can be from the patient him/herself (autologous) or from the transplant donor (allogeneic) (59). Allogeneic CAR T-cells can be responsible for lethal GVHD in some preclinical studies. In addition, a retrospective study comparing autologous to allogeneic CAR T-cell therapy demonstrated the presence of chronic GVHD in patients who received the allogeneic form (60). Ding et al. conducted a study on twenty patients with R/R B-ALL after allo-HCT that showed satisfactory initial efficacy and safety of CAR T-cell therapy. Moreover, the incidence of acute GVHD was higher in patients who previously received haploidentical transplantation especially for those receiving allogeneic CAR T-cells (15).

A promising new product generated by the Center for Cell and Gene Therapy, Baylor College of Medicine, involved multiple leukemia antigen–specific T-cells that targeted the tumor-associated antigens PRAME, WT1, and survivin, which are frequently expressed on B-cell and T-cell ALL cells from all 15 donors of patients with ALL who were undergoing allo-HCT. Eleven of the 15 products were infused into patients within 6 months post-transplant. There was an increase in the frequency of T-cells responding to targeted tumor antigens that correlated with durable remissions. Interestingly, no cases of GVHD were encountered after the infusion of the products (61).