scholarly journals A Phase I study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study)

Blood ◽  
2020 ◽  
Author(s):  
Erica Brivio ◽  
Franco Locatelli ◽  
Marta Lopez-Yurda ◽  
Andrea Malone ◽  
Cristina Diaz de Heredia ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Phase I ◽  
Phase I Study ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Sinusoidal Obstruction Syndrome ◽  
Cell Transplant ◽  
Antibody Drug Conjugate ◽  
Inotuzumab Ozogamicin ◽  
Hematopoietic Stem

This Phase I study investigated the recommended Phase II dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple-relapsed/refractory (R/R) CD22-positive acute lymphoblastic leukemia (ALL). Patients (≥1-<18 years) received three InO doses (Days 1, 8, 15) per course. Dose-escalation was based on dose-limiting toxicities (DLT) during Course 1 . Dose level 1 (DL1)=1.4 mg/m2 (0.6-0.4-0.4 mg/m2); DL2=1.8 mg/m2 (0.8-0.5-0.5 mg/m2). Secondary endpoints included safety, anti-leukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLT) were enrolled. In Course 1, first cohort, 1/6 (DL1) and 2/5 (DL2) patients experienced DLTs; subsequent review considered DL2 DLTs to be non-dose-limiting. Dose was de-escalated to DL1 while awaiting protocol amendment to re-evaluate DL2 in a second cohort, where 0/6 (DL1) and 1/6 (DL2) patients had a DLT. Twenty-three patients experienced Grade 3-4 adverse events; hepatic sinusoidal obstruction syndrome was reported in two patients after subsequent chemotherapy. Overall response rate after Course 1 was 80% [95% CI: 59-93%] (20/25 patients; DL1=75% [43-95%], DL2=85% [55-98%]); 84% [60-97%] of responders obtained minimal residual disease-negative CR; 12-month overall survival was 40% [95% CI: 25-66%]. Nine patients received hematopoietic stem cell transplant or chimeric-antigen receptor T-cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating anti-leukemic activity in heavily pre-treated children with CD22-positive R/R ALL. RP2D was established as 1.8 mg/m2/course, as in adults.

scholarly journals Blinatumomab In pediatric relapsed/refractory B-cell acute lymphoblastic leukemia: RIALTO expanded access study final analysis

2022 ◽  
Author(s):  
Franco Locatelli ◽  
Gerhard Zugmaier ◽  
Noemi Mergen ◽  
Peter Bader ◽  
Sima Jeha ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adverse Events ◽  
B Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cell Transplant ◽  
Open Label ◽  
Hematopoietic Stem ◽  
Expanded Access ◽  
Molecular Abnormalities

The safety and efficacy of blinatumomab, a CD3/CD19-directed bispecific T-cell engager molecule, for treatment of pediatric relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R B-ALL) were examined in an open-label, single-arm, expanded access study (RIALTO). Children (>28 days, <18 years) with CD19+ R/R B-ALL received up to five cycles of blinatumomab by continuous infusion (cycle: 4 weeks on/2 weeks off). The primary endpoint was incidence of adverse events. Secondary endpoints included complete response (CR) and measurable residual disease (MRD) response within the first two cycles, relapse-free survival (RFS), overall survival (OS) and allogeneic hematopoietic stem cell transplant (alloHSCT) after treatment. At final data cutoff (1/10/20), 110 patients were enrolled (median age, 8.5 years; 88% ≥5% blasts at baseline). Blinatumomab treatment resulted in a low incidence of grade 3-4 cytokine release syndrome (n=2 [1.8%]) and neurologic events (n=4 [3.6%]). No blinatumomab-related fatal adverse events were reported. The probability of response was not affected by the presence of cytogenetic/molecular abnormalities. Median OS was 14.6 months (95%CI: 11.0─not estimable) and was significantly greater for MRD responders versus MRD non-responders (not estimable vs 9.3; HR 0.18, 95%CI: 0.08─0.39). One-year OS probability was higher for patients who received alloHSCT versus without alloHSCT post-blinatumomab (87% versus 29%). Median RFS for MRD responders (n=57) was 8.0 months (95%CI:3.4─10.1) versus 2.8 months (95%CI: 0.3─9.2) for MRD non-responders (n=10). Of patients achieving CR after 2 cycles, 73.5% (95%CI: 61.4%-83.5%) proceeded to alloHSCT. These findings support the use of blinatumomab as a safe and efficacious treatment for pediatric R/R B-ALL. (ClinicalTrials.gov identifier NCT02187354)

A registry-based, observational safety study of inotuzumab ozogamicin (InO) treatment in patients (pts) with B-cell precursor acute lymphoblastic leukemia (ALL) who proceeded to hematopoietic stem cell transplant (HSCT).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7017-7017
Author(s):  
Marcos J.G. De Lima ◽  
Partow Kebriaei ◽  
Francesco Lanza ◽  
Christina Cho ◽  
Sergio Giralt ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Clinical Status ◽  
Single Agent ◽  
Marrow Transplant ◽  
Sinusoidal Obstruction Syndrome ◽  
Cell Transplant ◽  
Antibody Drug Conjugate ◽  
Peripheral Blood Stem Cells ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct

7017 Background: InO is a CD22-directed antibody-drug conjugate indicated for treatment of relapsed/refractory (R/R) ALL. InO has been associated with hepatotoxicity and hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), particularly post-HSCT. Registry data (Center for International Blood and Marrow Transplant Research [CIBMTR]) was analyzed to assess toxicity in pts with ALL who received InO prior to HSCT. Methods: CIBMTR patient data are being collected for a 5-year period after US approval of InO (Aug 2017 – Aug 2022). Data from US pts age ≥18 y treated with InO who proceeded to allogeneic HSCT were included. Using interim data at 3 y, we evaluated post-HSCT outcomes, including clinical status, overall survival, transplant-related (non-relapse) mortality (NRM), relapse, death after relapse (time from HSCT to death after the first 28 d from any cause with prior relapse/progression post-HSCT), and investigator-defined adverse events, including hepatic VOD/SOS. All statistical analyses are descriptive. Results: Data accrued from 18 Aug 2017 to 17 Aug 2020 for 131 adult pts (median age 40 y) who proceeded to first allogeneic HSCT: 31% in first complete remission (CR1), 46% in CR2, 13% in ≥CR3, 5% in 1st relapse, 2% in ≥3rd relapse, and 3% in primary induction failure. A majority (70%) had transplants from peripheral blood stem cells, and 47% involved an HLA-identical sibling or other related donor. Nearly half received myeloablative conditioning regimens. Before HSCT, 36% of pts received 1 cycle of InO, 46% had 2 cycles, and 17% had ≥3 cycles. Half (48%) received InO as a single agent. Median time from last dose of InO to HSCT was 2.0 mo (range: 0.4–26.2). At time of data-lock (11 Nov 2020), post-transplant data were available for 131 pts. Outcomes for these pts are shown in the Table. Among a subgroup of adults with active R/R ALL (n = 91) at time of HSCT (median of 4 lines prior therapy), VOD/SOS incidence within 100 d of HSCT was 18%. Conclusions: Incidence of VOD/SOS after first HSCT in InO-treated pts with R/R ALL in this study was similar to the 18–19% reported in pooled analyses of 2 clinical trials among InO-treated pts with R/R ALL (Marks et al, Biol Blood Marrow Transplant 2019) and in the INOVATE study (Kantarjian et al, Lancet Haematol 2017). The NRM at 1 y of 21% (23% R/R ALL) is lower than the NRM at 1 y of 38% reported in the pooled analyses of R/R ALL InO recipients.[Table: see text]

scholarly journals Inotuzumab Ozogamicin Monotherapy as an Outpatient Salvage Treatment in Relapsed Refractory B-Cell Acute Lymphoblastic Leukemia: Compassionate Access

2021 ◽  
Vol 42 (02) ◽  
pp. 199-203
Author(s):  
Vivek S. Radhakrishnan ◽  
Ketan Modak ◽  
Saurabh J. Bhave ◽  
Jeevan Kumar ◽  
Mita Roychowdhury ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Salvage Therapy ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Complete Response ◽  
Sinusoidal Obstruction Syndrome ◽  
Inotuzumab Ozogamicin ◽  
Best Response

AbstractRelapsed and refractory (RR) acute lymphoblastic leukemia (ALL) poses unique and difficult challenges to a practicing clinician in India where access to novel immunotherapies is limited. Between 2017 and 2020, eight patients with B-cell ALL at our center received inotuzumab ozogamicin (IO) monotherapy on compassionate access, as salvage therapy after at least two lines of conventional therapy failure, and most often as outpatient infusion. Eight patients (21–60 years, three females) received IO. Three patients had morphologic relapse and five patients reported persistent measurable residual disease (MRD). The best response on IO therapy achieved was negative MRD in six of seven patients and complete response (CR) with persistent MRD in one. One patient died (intracranial hemorrhage) before completion of first cycle. All responding patients were transplant eligible and four patients (57%) underwent allogeneic hematopoietic cell transplantation (Allo-HCT). Median follow-up of this cohort is 9 months (4–29.6 months), four patients (57%) are alive as stable with negative MRD. No significant infusion reactions occurred during therapy. Three patients developed grades III and IV neutropenia, two patients showed grade III transaminitis, and two patients developed post-HCT severe sinusoidal obstruction syndrome (SOS). IO is a feasible outpatient based salvage therapy to improve the remission status in RR B-cell ALL.

scholarly journals Management of Recurrent Acute Lymphoblastic Leukemia With T-Cell Engagement: CAR T, BiTEs, and Beyond

2019 ◽  
Vol 17 (11.5) ◽  
pp. 1448-1450
Author(s):  
Jae Park
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Standard Of Care ◽  
Complete Response ◽  
Hematologic Malignancies ◽  
Cell Transplant ◽  
Inotuzumab Ozogamicin ◽  
Hematopoietic Stem ◽  
Evidence Based Treatment ◽  
Car T

Immunotherapies targeting CD19 (blinatumomab) and CD22 (inotuzumab ozogamicin) have demonstrated higher complete response rates and improved survival compared with chemotherapy in relapsed/refractory acute lymphoblastic leukemia (ALL), and are now standard of care in the relapsed setting. However, most adult patients still die of ALL despite these therapies, with or without hematopoietic stem cell transplant. At the NCCN 2019 Annual Congress: Hematologic Malignancies, Dr. Jae Park summarized clinical data from key trials of novel immunotherapies in ALL and reviewed evidence-based treatment approaches for adults with relapsed/refractory B‐cell ALL.

scholarly journals Successful treatment of relapsed/refractory B-Acute lymphoblastic leukemia with Inotuzumab ozogamicin after blinatumomab failure

2020 ◽  
Vol 9 (2) ◽  
pp. 67-70 ◽  
Author(s):  
Sergey N. Bondarenko ◽  
Anna G. Smirnova ◽  
Ivan S. Moiseev ◽  
Bella I. Ayubova ◽  
Elena V. Babenko ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Single Cycle ◽  
Inotuzumab Ozogamicin ◽  
Hematopoietic Stem ◽  
Cell Acute Lymphoblastic Leukemia

Blinatumomab, a bispecific T-cell engaging CD3-CD19 antibody, is highly effective in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (ALL) even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, patients who failed with Blina have a dismal outcome. Inotuzumab ozogamicin is one of the therapeutic options after blinatumomab failure. We report a young man who exhibited bone marrow (BM) relapse of B-ALL following haploidentical stem cell transplantation (haplo-HSCT). Remission was not achieved after Blinotumomab treatment, thus Inotuzumab was administered. A complete remission with no signs of minimal residual disease was achieved after a single cycle of Inotuzumab. The second haplo-HSCT from another donor was successful. Conclusion The present case demonstrate an opportunity of successful inotuzumab therapy after failure of allo-HSCT and blinotumomab treatment.

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