Inotuzumab ozogamicin and donor lymphocyte infusion is a safe and promising combination in relapsed acute lymphoblastic leukemia after allogeneic stem cell transplant

Abstract

Despite progresses in the treatment of B‐cell acute lymphoblastic leukemia (B‐ALL), relapse after allogeneic Stem Cell Transplant (allo‐SCT) frequently occurs, and prognosis is dismal. Inotuzumab Ozogamicin (IO, a calicheamicin‐immunoconjugate anti‐CD22) and Blinatumomab (a B‐specific T‐cell Engaging (BiTE) antibody) have been approved as monotherapy for relapsed/refractory (R/R) B‐ALL, showing better outcomes in terms of overall survival (OS) and complete remission (CR) rates, when compared to standard chemotherapy. Nevertheless, after the achievement of such a deep response, a further consolidation strategy is required, since efficacy of these strategies is limited overtime, and a “bridge to SCT” option may offer the best long term outcome. Unfortunately, a further allo‐SCT may not always be feasible, due to patients’ frailty, comorbidities, or persistent transplant‐related adverse events. Moreover, results obtained with a second allo‐SCT in ALL are controversial and often unsatisfactory. Therefore, other consolidation approaches are warranted, and the use of donor lymphocyte infusion (DLI) might be an option in this setting, having historically demonstrated a not irrelevant efficacy. Intriguingly, combining antibodies with DLI may represent a valuable opportunity, in order to potentiate the graft versus leukemia (GvL) effect. The rationale to combine Blinatumomab and DLI is supported by the role of T‐cells as effectors for the antibody, which engages “fresh” donor T lymphocytes obtained with DLI. While pivotal but encouraging data have already been published on this regard and clinical trials are underway (NCT 03982992), no data are yet available on the combination of IO followed by DLI. We retrospectively analyzed patients relapsed after allo‐SCT treated with IO followed by escalating doses of DLI at three Italian Hematology Institutions. Patients signed an informed consent form for IO and DLI therapy and, patients alive at the time of data collection, signed an informed consent form for personal data collection. Response was defined as CR for bone marrow (BM) blasts ≤ 5% and no evidence of extramedullary (EM) disease, evaluated with Fluorodeoxyglucose Positron Emission Tomography (FDG‐PET) in PET positive patients pre‐IO therapy. MRD was evaluated with BCR‐ABL fusion transcript Real‐Time Quantitative Reverse Transcription PCR (q‐RT‐PCR), or V(D)J IgH/TCR disease‐ specific rearrangement on BM in Philadelphia (Ph) positive and Ph‐ negative patients, respectively. Relapse Free Survival (RFS) was calculated from CR to relapse/death, and OS was calculated from the start of IO therapy. Toxicity was graded according to CTCAE version. 4.03. Eight B‐ALL adult patients, 5 Ph‐negative and 3 Ph‐positive, relapsed after allo‐SCT, were treated with IO and DLI (Table 1). All patients had documented BM disease (six morphological relapse and two in Minimal Residual Disease, MRD, positivity status), two patients had extramedullary (EM) disease (skeletal and skin in one case; nodal sites above and below diaphragm muscle in the other one). Four patients were in salvage 2 (S2), 3 patients in S1, 1 patient in S3; half of the patients had previously received Blinatumomab; all Ph‐positive patients had failed 3 generation Tyrosine Kinase Inhibitor (TKI) Ponatinib. Patients received a median of 3 (range 2–6) courses of IO, at the standard dosage. Intrathecal (IT) prophylaxis was administered after each IO cycle. At the time of IO treatment, none of the patients presented graft versus host disease (GvHD). Three patients received IO and DLI in an alternate schedule and 5 patients sequentially after IO; patients received a median of 3 (range 2–4) DLI infusions at escalating dose. Treatment details and DLI escalating dosage were defined according to transplant center policy (Tables 2 and 3). Six out of eight patients were evaluable for morphological response and achieved CR after the first IO course. All patients were evaluable for MRD analysis, which was performed on BM, with a sensitivity of 10. Six out of eight patients (75%) obtained MRD negativity (MRD−) after the 2 course of IO; notably, 4/6 patients achieved MRD status already after the 1 course. The two PET‐positive patients achieved PET‐negativity after the 1 IO course. With a median follow‐up of 25.0 (IQR 11.0–36.0) months, six of 8 (75%) patients are alive. Four of 8 (50%) patients relapsed: one with morphological BM relapse, one with Central Nervous System (CNS) relapse and peripheral leucocytosis, and one CNS relapse associated to BM MRD. One patient experienced molecular relapse only (MRD+ after achievement of CR MRD−) and was shifted to Blinatumomab therapy on MRD+ setting. Of the two patients with CNS relapse, one had not successfully received CNS