Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children, with a particularly poor prognosis in infants under one year of age. Infants with ALL have a higher risk of relapse and lower overall survival rates compared to older children [1]. Traditional chemotherapy approaches often fail to adequately treat these patients due to the toxicity of chemotherapy agents on developing organs. Hematopoietic stem cell transplantation (HSCT) is an effective therapy for relapsed or refractory ALL; however, relapse after HSCT remains a significant challenge [2]. Therefore, there is a growing need for targeted therapies that can effectively treat infant ALL while minimizing toxicity [3].

Blinatumomab is a bispecific T-cell engager antibody that links CD19-expressing B cells to CD3-expressing T cells, leading to T-cell-mediated cytotoxicity of the B cells. The efficacy and safety of blinatumomab have been demonstrated in relapsed or refractory B-cell precursor ALL in both adults and children [4]. Van der Sluis et al. suggest that incorporating blinatumomab into chemotherapy regimens for infants with acute lymphoblastic leukemia may lead to improved event-free survival and overall survival rates [5].

Many children cannot undergo HSCT because of serious adverse events from previous treatment. In this case report, we present the case of an infant with relapsed/refractory ALL who received blinatumomab as salvage therapy after a second haploidentical HSCT and remained in remission for 15 months without subsequent HSCT.

The patient was a 4-month-old male diagnosed with high-risk infant B-cell ALL with KMT2A/AFF1 translo-cation. He received induction chemotherapy according to the INTERFANT-06 protocol and achieved complete remission. He underwent 10/10 matched-sibling bone marrow transplantation conditioned with busulfan, fludarabine, and etoposide, but experienced an isolated marrow relapse 2 months post-transplant. KMT2A/AFF1 was detected as positive again (3.38%); there was no other mutational change. The patient received two cycles of salvage chemotherapy (FLAG-IDA, FLAG) followed by a second haploidentical HSCT (father) with a conditioning consisting of treosulfan, fludarabine, and thiotepa. Bone marrow aspiration on day +30 showed regenerating marrow with no blasts; KMT2A/AFF1 translocation was not detected, and full donor chimerism was achieved. At the 3rd month of follow-up, bone marrow was in morphological remission, but KMT2A/AFF1 translocation became positive (0.58%) (Fig. 1). And because of the molecular relapse, tacrolimus was discontinued. Subsequently, grade 2 graft versus host disease (GvHD) appeared in the patient as stage 3 only on the skin. The patient did not experience chronic GvHD. To take advantage of the graft-versus-leukemia (GvL) effect, it was followed without intervention. Unfortunately, frank relapse occurred in bone marrow four months after the second HSCT; there was minimal residual disease (MRD) positivity in the bone marrow by flow cytometry, and KMT2A/AFF1 translocation was positive (3.48%) with 75% chimerism.

Figure 1. KMT2A/AFF1 follow-up. *Nor--malyze copy number - Inter-national standart scale (LOD=NCN-IS 0.01%).

The patient was then treated with one cycle of blinatumomab at a dose of 5 mcg/m²/day on days 1-7, followed by 15 mcg/m²/day on days 8-28. Blinatumomab was administered as monotherapy by continuous intravenous infusion via a central line catheter without significant adverse events. The patient achieved complete remission after the first cycle of blinatumomab, which was confirmed by MRD negativity in the bone marrow by flow cytometry; chimerism increased to 100%, and KMT2A/AFF1 translocation turned negative.

Due to toxicity, the patient did not receive a third transplant but was followed up after blinatumomab without acute or chronic GvHD. And the patient remained in complete remission for 15 months after the blinatumomab therapy. KMT2A/AFF1 translocation is always negative, first every month and then at the 3-month follow-up. He had no significant adverse events during this time, and immune reconstruction was established ap-propriately.

The use of blinatumomab in the treatment of relapsed or refractory ALL has shown promising results in both adults and children. In this case, blinatumomab was used as a curative option rather than a salvage therapy in an infant with relapsed/refractory ALL after a second haploidentical HSCT.

The efficacy of blinatumomab in the treatment of relapsed/refractory ALL in both adults and children has been demonstrated in several clinical trials [6-8]. In infants, the experience with blinatumomab is limited. Van Der Sluis et al. evaluated 28 infant ALL patients in their phase 2 studies on the use of blinatumomab in infants with newly diagnosed KMT2A-r ALL, and as a result, they explain that there was a high rate of complete MRD response (89% after 2 cycles of blinatumomab) and that it was well tolerated [9]. Clesham et al., in a case series of eleven infants with relapsed or refractory B-cell precursor ALL treated with blinatumomab, reported nine complete responses and two patients with persistent disease. Only three patients had grade 1-2 cytokine release syndrome (CRS). The authors concluded that blinatumomab can be safely and effectively delivered to infants with relapsed or refractory B-ALL and suggested that the optimal dosing and duration of treatment of blinatumomab in infants with ALL should be further evaluated [10].

Infusion of blinatumomab with healthy donor T cells after HSCT has a beneficial effect in the treatment of recurrent ALL [11,12]. Alcharakh et al. presented a case study involving a patient with post-stem cell transplant-relapsed acute CD19-positive biphenotypic leukemia who was treated with blinatumomab, which induced donor T-cell activation and subsequently resulted in complete remission. Handgretinger et al. described three pediatric patients with post-transplant relapsed ALL who achieved complete remission after blinatumomab-induced donor T-cell activation. These findings support the notion that blinatumomab infusion with healthy donor T cells could be a valuable therapeutic approach for post-HSCT relapsed ALL. Similarly, the high rate of donor chimerism and healthy donor T cells provided a great advantage for our patient.

The combination of blinatumomab and donor lymphosyte infusions (DLIs) after chimeric antigen receptor T-cell (CAR-T) therapy demonstrates its potential as salvage therapy, particularly in patients who have exhausted other treatment options [13].

In our case, blinatumomab was used as a curative treatment option after a second haploidentical HSCT in an infant with relapsed/refractory ALL. Due to toxicity, the patient did not receive a third transplant and was followed up after blinatumomab treatment. The patient achieved complete remission and remained in remission for 15 months. The optimal dosing and duration of treatment of blinatumomab in infants with ALL remain uncertain, and further studies are needed to determine the safety and efficacy of blinatumomab in this population.

In conclusion, blinatumomab has shown promising results in treating relapsed or refractory ALL in both adults and children, but its use in infants remains limited. Although blinatumomab has been known as a bridging therapy, we suggest that blinatumomab could be a promising curative therapy option for patients who cannot receive further HSCT.

The authors have no conflict of interest to declare.