In this study, we described a patient with a second relapse of DS-ALL who maintained CR by regular administration of InO as a single-agent treatment. Patients with DS-ALL have a high incidence of TRM and relapse [1, 4]. Although allo-HCT is a potentially curative approach to manage relapsed or refractory ALL, given the high probability of post-transplant leukemic relapse and transplant-related mortality, the frequency of use of allo-HCT remains less in DS-ALL [2]. Although maintenance therapy is essential for curing ALL, post-remission maintenance therapies to mitigate subsequent relapse without allo-HCT have not been established for relapsed DS-ALL.

Prophylactic administration of InO has been investigated as a strategy to reduce ALL relapse after allo-HCT in adults with high risk of relapse [8]. Low-dose InO, when administered as a relapse prevention therapy after allo-HCT, offers a high one-year progression-free survival rate (89%), has a favorable safety profile, and is not associated with excess toxicity in clinical applications, with no observed SOS or graft failure [8]. Furthermore, lower doses of InO were used in adult patients with Philadelphia chromosome-positive or -negative ALL who did not achieve MRD negativity after frontline or salvage therapy resulting in favorable survival, MRD negativity rates, and safety profiles for patients with ALL and MRD-positive status [12]. Notably, Brivio et al. reported that one patient showed prolonged continuous CR for 15 months after two courses of InO without any additional treatment [13]. They also reported that two other patients were in continuous CR for 19 months after InO treatment followed by chemotherapy or blinatumomab, although they did not undergo allo-HCT [13]. Based on the impressive outcomes seen in relapsed or refractory setting and favorable toxicity profile of single-agent InO compared to intensive chemotherapy, we hypothesized that InO would be a feasible agent for subsequent relapse prevention in patients with BCP-ALL who were heavily pretreated and intolerant to allo-HCT. InO is administered at 1.8 mg/m2 per cycle, 0.8 mg/m2 on day 1 and 0.5 mg/m2 on days 8 and 15 of a 21- to 28-day cycle until CR is achieved [5]. After CR, subsequent cycles are given at 1.5 mg/m2 per cycle, 0.5 mg/m2 on days 1, 8 and 15 of a 28-day cycle; the patients receive treatment for up to six cycles [5]. Absolute neutrophil count > 1.0 × 109/L and a platelet count > 50 × 109/L for 7 days are required for InO administration. We intended to perform InO treatment according to schedule; however, because of its hematological toxicity, especially thrombocytopenia, we had to lengthen the interval between InO doses from 4 to 10 weeks (Fig. 2), resulting in a treatment approach similar to that for post-transplant relapse prevention trial using InO [8]. Although thrombocytopenia requires lengthening the InO dose interval, we plan to administer a maximum of 6 cycles of 3 doses per cycle, since long-term maintenance therapy is effective for preventing subsequent relapse. In contrast, since Metheny et al. reported that even low-doses InO can eliminate MRD [8], it is worth considering reducing the InO dose to 0.3 mg/m2/dose, given the prolonged thrombocytopenia in the patient induced by InO. Since the patient achieved PCR-MRD negative CR with two cycles of bortezomib-combined chemotherapy before the InO treatment, it is unclear whether the patient’s relapse-free status was due to the effect of InO treatment or of bortezomib-combined chemotherapy. However, considering that the patient would have relapsed early if post-induction therapy had not been administered, InO-mediated maintenance therapy was considered to help preventing subsequent relapse. In our case, CAR-T cell therapy or allo-HCT were not chosen because of the high therapeutic toxicity in ALL with DS. Therefore, it should be noted that InO-mediated maintenance therapy was tolerated well in this patient with second relapsed DS-ALL, and no adverse events beside prolonged thrombocytopenia were observed.

This study does not answer one critical question: what cycles, intervals, and doses of InO can safely and feasibly be given for relapse prevention? Although a maximum of six cycles are allowed, it is not clear a priori how many cycles and doses of InO would be safe and effective in reducing relapse in patients with relapsed or refractory BCP-ALL who cannot proceed to allo-HCT. To answer this question, a prospective large-scale study is needed to further investigate the most feasible and safe schedule for InO administration.

Our study demonstrated that regular InO administration may prevent and overcome subsequent relapse without allo-HCT in patients with relapsed or refractory DS-ALL, who require less toxic therapeutic strategies than other patients with ALL, to improve outcomes. Regular administration of InO with longer dosing intervals may be a good option to avoid subsequent relapse in patients with relapsed or refractory BCP-ALL who cannot proceed to intensive chemotherapy or allo-HCT.