Page 66 - Haematologica Vol. 107 - September 2022

ARTICLE - Outcome of r/r B-ALL with extramedullary disease S. Kayser et al.
is capable of inducing CR rates of 18% to 44% in patients with r/r B-ALL,7-13 antibody-based strategies using blinatu- momab or inotuzumab ozogamicin (INO) have been proven to be more effective.14,15 INO is a humanized anti-CD22 mono- clonal antibody conjugated to the potent cytotoxic agent calicheamicin, which was developed as a targeted therapy for B-cell malignancies.16,17 Upon binding to CD22 and inter- nalization, calicheamicin is off-set and binds to DNA, thereby leading to double-strand breaks and apoptosis.16,17
The phase III INO-VATE trial demonstrated that INO had su- perior efficacy compared to standard-of-care treatment for r/r B-ALL, inducing CR/CR with incomplete hematologic re- covery (CRi) in 80.7% and 29.4% of the patients, respectively (P<0.001).15 Additionally, the rate of negativity for measurable residual disease (0.01% marrow blasts assessed at a central laboratory by multicolor, multiparameter flow cytometry) in patients with CR/CRi was significantly higher after treatment with INO than after standard-of-care (78.4% vs. 28.1%; P<0.001). After INO treatment, 41% of patients proceeded di- rectly to allogeneic HSCT as compared to 11% after stan- dard-of-care (P<0.001). The median progression-free survival was significantly longer after INO than after standard-of- care (5.0 months vs. 1.8 months; P<0.001). The median over- all survival (OS) was 7.7 months after INO as compared to 6.2 months after standard-of-care, and the 2-year OS rates were 23% versus 10%, respectively.15 The most frequent grade 3 or higher non-hematologic adverse events after INO were liver-related. Veno-occlusive liver disease (VOD)/sinusoidal obstruction syndrome (SOS) of any grade occurred in 15 pa- tients (11%), who received INO and in one patient (1%) after standard-of-care therapy. In addition, ten of 48 (21%) pa- tients, who underwent allogeneic HSCT after INO treatment, developed VOD after transplantation; three of these ten pa- tients had received a second transplant.15 Deep remissions with negativity for measurable residual disease can be achieved with INO treatment in patients with r/r ALL. How- ever, the safety and efficacy of INO treatment in patients with r/r ALL and extramedullary disease (EMD) is currently unclear. Patients with central nervous system infiltration and/or isolated EMD were excluded from the phase III ran- domized INO-VATE trial.15 Of note, extramedullary relapses are common in r/r ALL patients following exposure to blina- tumomab, occurring in up to 40%.18,19
EMD in r/r B-ALL is characterized by a dismal outcome with no accepted standard therapeutic approaches.1 The objec- tives of our study were to characterize a series of adult r/r B-ALL patients with EMD and evaluate their outcome after treatment with INO.
Methods
Patients
Information on 31 adult patients (median age, 31 years; range,
19-81 years) with histologically confirmed r/r B-ALL and EMD, who were treated with INO between 2015 and 2021 within a compassionate use program (n=7) or in-label after approval by the Food & Drug Administration or the European Medical Agency (n=24) was collected from six institutions in the USA and Europe. All 31 patients were CD22-positive at relapse/progressive disease. Three (10%) of the 31 patients had been previously treated with tyrosine kinase inhibitors for chronic myeloid leukemia and progressed to BCR-ABL- positive blast cell crisis of B-lymphoid lineage. Bone marrow evaluation and immunophenotyping by flow cytometry re- vealed B-ALL in all three patients. The 31 patients were heavily pretreated having received intensive chemotherapy with or without a tyrosine kinase inhibitor, as well as blina- tumomab in 14, and local irradiation in five patients. In ad- dition, allogeneic HSCT had been performed in 18 patients (first-line or at relapse, n=9, each).
Participating centers were chosen upon network relation- ships of the first and last authors. Detailed case report forms (including information on baseline characteristics, chemotherapy, allogeneic HSCT, response, and survival) were collected from all participating centers. Inclusion criteria were adult patients with r/r ALL and EMD. All patients who fulfilled these criteria were included by the participating in- stitutions.
Chromosome banding was performed using standard tech- niques, and karyotypes were described according to the In- ternational System for Human Cytogenetic Nomenclature.20 Data collection and analyses were approved by the Institu- tional Review Boards of the participating centers.
Treatment
INO was administered at a dose of 0.8 mg/m2 body sur- face area as a continuous intravenous infusion over 1 h on day 1 and at 0.5 mg/m2 body surface area on days 8 and 15. Once the patients had achieved CR, the dose on day 1 of each consecutive cycle was reduced to 0.5 mg/m2 body surface area. Up to six INO cycles (≤2 cycles, n=19; 3-4 cycles, n=7; 5-6 cycles, n=5) were administered according to the previously approved regimen. The three patients with BCR-ABL-positive blast cell crisis of B-lymphoid line- age received a tyrosine kinase inhibitor in addition to INO. EMD response was assessed by computed tomography (CT) or positron emission tomography-computed tomog- raphy (PET-CT). VOD/SOS was assessed according to pre- viously defined clinical criteria and diagnosed by the treating investigator.15
Statistical analyses
Patients’ characteristics were compared with the Kruskal- Wallis rank sum test for continuous variables and the Fisher exact test for categorical variables. The median follow-up time was computed using the reverse Kaplan-Meier esti- mate.21 The Kaplan-Meier method was used to estimate the
Haematologica | 107 September 2022
2065