Post-transplant relapse of B-cell acute lymphoblastic leukemia still represents today a critical condition associated with high mortality rates. In this retrospective study, we investigated the efficacy and safety of blinatumomab, a CD3-CD19 bispecific antibody, combined or not with DLI in this specific indication.
Firstly, we showed that the use of blina, even as single agent is associated with good response rates. Here, 60% of patients receiving blina or blina and DLI obtained CR as best response. Thirty-two patients (44%) obtained CR after 2 cycles of blina. These results are consistent with Stein et al(16). who found a CR / CR with partial hematologic recovery of peripheral blood counts (CRh) rate of 45% after 2 cycles. Among the whole cohort presented here, OS was 49.3% and 32% at 1 and 2 years, respectively. In Stein’s study, 1-year OS was 36%. Both of these results appear better than those obtained with chemo- or radiation-based salvage therapy even in association with second allo or DLI(6). Thus, our data confirm that blina represents an effective option for salvage therapy after post-transplant relapse.
Secondly, we questioned the possibly of a synergy between blina and DLI. Indeed, blina is a T cell engager. By binding patient’s CD3-positive cytotoxic T cells, this bi-specific antibody allows them to recognize and finally eliminate CD19-positive ALL blasts(21–23). Consistent to that, baseline percentage of CD3 + CD8 + effector T cells has been shown to predict response to blina in refractory or relapsed B-ALL patients(24). Thus, effectiveness of blina probably depends on T cells recovery after transplant. As patients relapsing after transplant present a poorer immune reconstitution(25–27), optimizing this reconstitution is probably a key to enhance blina efficacy.
Here, the combination of DLI to blina did not seem to enhance its efficacy. Although, 81.8% of patients in the blina-DLI group obtained CR, DLI considered as a time dependent variable was not statistically associated with OS, PFS or relapse rates in multivariate analysis.
Only a few cases of such combination have been reported in the literature. Durer et al., described a 51-year-old woman who received 4 cycles of blina and 3 DLI. Because of an extramedullary associated disease, she also received subsequent chemotherapy(28). This combined treatment conferred her more than 14 months of complete remission. Ueda et al., reported the outcome of 4 patients treated concomitantly with blina and DLI. Two of them were still in complete remission after a respective follow up of 7 and 13 months(29).
Our study did not confirm a synergy between drugs. Nevertheless, it was conducted in a real-life manner and reflects various and inhomogeneous practices. Administration of DLI concomitantly to blina infusion is probably a clue to obtain synergy. Indeed, blina has a short elimination half-life(30)..
Thirdly, administration of blina in combination or not with DLI appears to be safe. Indeed, the most common AE were hematological, neurological, infectious and the induction of CRS. These AE are those classically reported in phase 2(31–33) and phase 3(15) trials evaluating blina in relapsed or refractory B-cell ALL. No grade 5 toxicity has been reported. These AE are also consistent with those described in Stein’s study(16). Considering GVHD, only a few data support its induction by blinatumomab. Khan and Gul reported a 61-year-old woman with no history of GVHD developing gut and liver GVHD after 2 cycles of blina. In the aftermath, she obtained a complete remission and a 100% positive donor chimerism(34). In Stein et al., 7 patients in 64 experienced GVHD after post-transplant blina(16). This rate was substantially lower than in our study. However, the study design in Stein’s trial systematically excluded patients with active GVHD or receiving systemic treatment for GVHD prior to blina and could explain the difference.
Interestingly, we did not observe any strong excess of toxicity in the blina-DLI group. Both aGVHD and extensive cGVHD rates were also low in the combined treatment group. Thus, considering toxicities, combination appears feasible.
In recent years, treatment of relapse of ALL dramatically changed thanks to several developments. Among them, CAR-T cell therapy is an exciting approach. Tisagenlecleucel shows remarkable efficacy in pediatric patients and young adults in clinical trials(35,36). After the ZUMA-3 phase 2 trial(37), brexucabtagene autoleucel (KTE-X19) also obtained FDA approval The broad use of CAR-T cells in adults is impeded by toxicities such as cytokine release syndrome or Imune effector cell-associated neurotoxicity syndrome (ICANS)(38). Clinicians must also think about economical and organizational issues related to this procedure(39). It is critical to consider that CAR-T cells are manufacturing products engineered for each individual patient. Thus, obtaining CAR-T cells depend on the quality of leukapheresis. This also induces a non-reducible manufacturing time which could be detrimental for patients and even result in death. For instance, in the ZUMA-3 phase 2 trial, the median time from leukapheresis to CAR-T manufacturing release was 13 days(37). In 71 enrolled patients, only 55 finally received the KTE-X19 CAR T cells. Thus, blina represents an interesting alternative in a subset of transplant patients who failed leukapheresis or are not responders to bridging therapy. As blina is an “off the shelf” therapy, its use appears easier and faster.
This study presents some limitations. Firstly, the low GVHD rates found in the DLI group must be mitigated by the fact that physicians preferentially proposed DLI to patients who did not show signs of GVHD or experienced severe GVHD in the past. Indeed, only 27% of patients presented acute GVDH before treatment in the blina-DLI group versus 44% in the blina group.
Secondly, due to its retrospective design we did not control treatment given prior to, after or in parallel with blina and DLI. This could lead to bias. However, due to the severity of post-transplant relapses, combining therapies are probably needed. For instance, the association of Tyrosine Kinase Inhibitors (TKI) in case of Ph-positive or Ph-like ALL is attractive and should be considered(40,41).
Thirdly, data were lacking about minimal residual disease (MRD) assessment after blina treatment.
Despite the limitations presented above, this study is one of the largest focusing on the use of blinatumomab in combination with DLI in B-ALL patients relapsing after allo-HCT. Its multicentric approach offers us a more representative picture in real life.
In conclusion, the use of blinatumomab in post-transplant relapse of B-ALL is safe and effective. Adding DLI between 1 month before and 100 days after start of blina does not seem to improve outcomes or toxicities. More studies are needed to determine if better combination modalities between blina and DLI or other T cell modulation approaches could enhance blina efficiency in this specific situation.