B-Cell Acute Lymphoblastic Leukemia: Update on Clinical Trials

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“Learning never exhausts the mind.”

—Leonardo da Vinci

To complement The ASCO Post’s continued comprehensive coverage of the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition, here are several abstracts selected from the meeting proceedings focusing on treatments under study in patients with newly diagnosed as well as resistant B-cell acute lymphoblastic leukemia (ALL). For full details of these study abstracts, visit

Syed Ali Abutalib, MD

Syed Ali Abutalib, MD

Jacob M. Rowe, MD

Jacob M. Rowe, MD

Older Adults With Newly Diagnosed B-Cell ALL

ABSTRACT 267: Phase II open label INITIAL-1 GMALL study: Efficacy and safety of inotuzumab ozogamicin for induction therapy followed by conventional chemotherapy-based consolidation and maintenance therapy in newly diagnosed patients (aged ≥ 56 years) with CD22 surface (≥ 20%) positive and BCR-ABL–negative ALL ( identifier NCT03460522).1

Background: Despite recent advances especially in younger patients, the prognosis for elderly patients with ALL remains dismal, with a 5-year survival rate of around 20%, even after intensive chemotherapy. Inotuzumab ozogamicin is an antibody-targeted intravenous chemotherapy agent composed of an anti-CD22 antibody linked to calicheamicin, a potent cytotoxic antitumor antibiotic. Inotuzumab ozogamicin was approved by the U.S. Food and Drug Administration in August 2017 for the treatment of adults with CD22 cell surface (different from cytoplasmic presence!)-expressing relapsed or refractory B-cell precursor ALL.2 In the INO-VATE phase III trial, which led to its approval, sinusoidal obstruction syndrome of any grade occurred in 15 patients (11%) who received inotuzumab ozogamicin and in 1 patient (1%) who received standard therapy. Inotuzumab ozogamicin is a better strategy relative to standard intensive chemotherapy to bridge patients to a more definitive therapy such as allogeneic hematopoietic cell transplant (allo-HCT) or cell therapy.

Methods: The primary endpoint is event-free survival at 12 months of follow-up. The first induction cycle consists of inotuzumab ozogamicin at 0.8 mg/m2 on day 1 and 0.5 mg/m2 on days 8 and 15, together with dexamethasone at 10 mg/m2 (days 7–8, 14–17) and one intrathecal injection of triplet therapy—methotrexate, cytarabine, and dexamethasone. The second and third induction cycles consist of inotuzumab ozogamicin at 0.5 mg/m2 on days 1, 8, and 15 plus intrathecal triplet therapy. Response evaluation is scheduled after each cycle. Patients achieving a complete remission are offered to receive five conventional consolidation therapies (three intermediate doses of methotrexate, asparaginase; two intermediate doses of cytarabine) and one reinduction therapy (idarubicin, cytarabine, cyclophosphamide, dexamethasone) in combination with rituximab (for CD20-positive ALL), followed by maintenance therapy with mercaptopurine and methotrexate.

Results: Due to suspected therapy-related liver toxicities, one patient received one induction cycle, and one patient received two induction cycles (both were in remission after the first induction). All other patients completed induction therapy and achieved complete remission, mainly after the first induction.

Results of minimal residual disease (MRD) measured by polymerase chain reaction are available for 23 patients, with 17 achieving MRD negativity after induction. So far, four events have been reported (two deaths in remission and one relapse of ALL in the first year of treatment; one relapsed in the second year).

With a median follow-up of 242 days, the probability of overall survival at 1 year is 82.4 %.

Two patients received an allo-HCT in ongoing first remission.

In regard to adverse events during the first, second, and third induction therapies, most common adverse events ≥ grade 3 reported were leukocytopenia (in 64%, 33%, and 13% of all cases, respectively), anemia (54%, 28%, 13%), thrombocytopenia (68%, 17%, 26%), and elevation of liver enzymes (31%, 22%, 20%).

Clinical Implications: Replacement of conventional induction chemotherapy by inotuzumab ozogamicin is feasible, results in promising remission rates, and may reduce the risk of early morbidity and lethality. Lower-intensity therapy in older adults is a much-needed approach but should be balanced with the increased association of sinusoidal obstruction syndrome with inotuzumab ozogamicin. Also, refer to Abstract 1014, which describes promising phase II results with inotuzumab ozogamicin in combination with mini–hyper-CVD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with or without blinatumomab, in older adults (aged ≥ 60 years) with newly diagnosed Philadelphia chromosome–negative ALL.3 Randomized phase III trials to evaluate the efficacy of these experimental combinations compared with the current standard of care are warranted.

ABSTRACT 614: Comparison of reduced-intensity conditioning allo-HCT (n = 418) and autologous HCT (auto-HCT; n = 142) for elderly (aged > 55 years) patients with ALL: A retrospective analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.4

Background: The outcomes of patients with ALL aged 55 and older treated with conventional-dose chemotherapy are poor. Due to the frequent presence of comorbidities, many patients are ineligible for curative myeloablative allo-HCT. The role of auto-HCT and reduced-intensity conditioning allo-HCT is not well established. The goal of this study was to analyze the results of these transplant options and to identify factors affecting outcomes.

Methods: Among allogeneic donors, 50% were HLA-matched sibling donors, and 50% were 8/8 HLA-matched unrelated donors. The median ages of patients given reduced-intensity conditioning allo-HCT and auto-HCT were 60 (range, 55–76 years) and 61 (range, 55–76 years), respectively. The proportion of Philadelphia chromosome–positive ALL was 71% and 63%, respectively. MRD-positive status at the time of transplant was reported in 35% and 21% patients, respectively (P = .002). Fludarabine plus busulfan was the most frequently used conditioning regimen in the setting of reduced-intensity conditioning allo-HCT (34%), whereas a combination of 12 Gy of total-body irradiation plus cyclophosphamide was the most frequent regimen in the auto-HCT group (33%).

Results: With a median follow-up of 57 months, the results of auto-HCT vs reduced-intensity conditioning allo-HCT follow:

The rates of leukemia-free survival and overall survival at 5 years were 39% vs 34% (P = .11) and 45% vs 42% (P = .23), respectively.

The incidence of relapse and nonrelapse mortality rates were 41% vs 51% (P = .22) and 25% vs 10% (P = .001), respectively.

In a multivariate model, using auto-HCT as a reference, the risk of nonrelapse mortality was increased for HLA-matched sibling donor–HCT (hazard ratio [HR] = 2.1, P = .02) and HLA-matched unrelated donor–HCT (HR = 3.08, P < .001), which for HLA-matched unrelated donor–HCT translated into a decreased chance of leukemia-free survival (HR = 1.55, P = .01) and overall survival (HR = 1.62, P = .008).

Clinical Implications: Results of auto-HCT for patients with ALL aged 55 and older in first complete remission and with MRD negativity pretransplant are encouraging. This option may be a valuable alternative to reduced-intensity conditioning allo-HCT and appears to be associated with improved overall survival compared with transplantations from matched unrelated donors. Indeed, these observations require verification in prospective trials in the context of currently available novel agents and technologies, including blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor (CAR) T-cell therapy.

Allogeneic CAR T-Cell Therapy in Adults With Resistant B-Cell ALL

ABSTRACT 163: Phase I BALLI-01 study: Preliminary results of UCART22 (allogeneic engineered T cells expressing anti-CD22 [≥ 90% by flow cytometry] CAR) in adults with relapsed or refractory CD22-positive B-cell ALL (NCT04150497).5

Background: UCART22 is a genetically modified T-cell product manufactured from non–HLA-matched healthy donor cells. Donor-derived T cells are transduced using a lentiviral vector to express anti-CD22 CAR (anti-CD22 scFv-41BB-CD3ζ) and are further modified using Cellectis’ TALEN® technology to disrupt the T-cell receptor alpha constant and CD52 genes. These modifications minimize the risk of graft-vs-host disease and allow the use of anti–CD52-directed drugs in lymphodepletion.

Methods: The purpose of this study is to evaluate the safety, tolerance, and clinical activity of UCART22 as well as to determine the maximum tolerated dose in adults with relapsed or refractory CD22-positive B-cell ALL. Protocol therapy includes lymphodepleting regimens of cyclophosphamide and fludarabine with or without alemtuzumab, followed by a single dose of UCART22 at one of four dose levels.

Results: Of six patients, five received UCART22 infusion (dose level 1: 1 × 105 cells/kg [n = 3], dose level 2: 1 × 106 cells/kg [n = 2]). One patient discontinued treatment prior to UCART22 administration due to an adverse event. The median number of prior therapies was three (range, 2–4). The median baseline marrow blasts percentage prior to lymphodepleting therapy was 35% (5%–78%).

A total of four patients experienced 10 treatment-related adverse events: Two patients experienced serious treatment-related adverse events: one patient had grade 3 febrile neutropenia and grade 3 perihepatic hematoma; one patient had grade 4 bleeding and grade 5 sepsis in the context of progressive disease. No patients had treatment-related, serious treatment-emergent adverse events, graft-vs-host disease, neurotoxicity, protocol-defined dose-limiting toxicity, or an adverse event of special interest.

Two patients at dose level 1 achieved best response at day 28 of complete remission with incomplete hematologic recovery. One patient at dose level 2 had initial significant reduction in marrow blasts (40% [day –1] to 13% [day 28]) and then experienced disease progression.

Correlative analysis of UCART22 expansion and persistence is ongoing.

Clinical Implications: UCART22 demonstrated no unexpected toxicities at doses of 1 x 105/kg and 1 x 106/kg with cyclophosphamide/fludarabine. Cytokine-release syndrome was observed in three patients, all grade 1 or 2, and was reported to be manageable. No patient had dose-limiting toxicity, graft-vs-host disease, or neurotoxicity. Two patients achieved complete remission with incomplete hematologic recovery. As host immune recovery was observed early, the addition of alemtuzumab to cyclophosphamide/fludarabine is now being explored in ongoing treatment cohorts to potentially achieve a deeper and more sustained T-cell depletion and promote expansion and persistence of UCART22. Enrollment is ongoing. 

Dr. Abutalib is Associate Director of the Hematology and BMT/Cellular Therapy Programs and the Director of the Clinical Apheresis Program at the Cancer Treatment Centers of America, Zion, Illinois; Associate Professor at Rosalind Franklin University of Medicine and Science; and Founder and Co-Editor of Advances in Cell and Gene Therapy. Dr. Rowe is Emeritus Professor at Technion, Haifa, Israel; Director of the Hematology Department at Shaare Zedek Medical Center, Jerusalem; and Editor-in-Chief of Haematologica.

DISCLOSURE: Dr. Abutalib has served on the advisory board for AstraZeneca. Dr. Rowe has served as a consultant or advisor to BioSight.


1. Stelljes M, Raffel S, Wäsch R, et al: First results of an open label phase II study to evaluate the efficacy and safety of inotuzumab ozogamicin for induction therapy followed by a conventional chemotherapy-based consolidation and maintenance therapy in patients aged 56 years and older with acute lymphoblastic leukemia (INITIAL-1 trial). 2020 ASH Annual Meeting & Exposition. Abstract 267. Presented December 5, 2020.

2. Kantarjian HM, DeAngelo DJ, Stelljes M, et al: Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 375:740-753, 2016.

3. Short NJ, Kantarjian HM, Ravandi F, et al: Reduced-intensity chemotherapy with mini-hyper-CVD plus inotuzumab ozogamicin, with or without blinatumomab, in older adults with newly diagnosed Philadelphia chromosome–negative acute lymphoblastic leukemia: Results from a phase II study. 2020 ASH Annual Meeting & Exposition. Abstract 1014. Presented December 5, 2020.

4. Giebel Sr S, Labopin M, Houhou  M, et al: Comparison of reduced intensity conditioning – allogeneic HCT and autologous HCT for elderly patients with acute lymphoblastic leukemia: An analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. 2020 ASH Annual Meeting & Exposition. Abstract 614. Presented December 7, 2020.

5. Jain N, Roboz GJ, Konopleva M, et al: Preliminary results of Balli-01: A phase I study of UCART22 (allogeneic engineered T cells expressing anti-CD22 chimeric antigen receptor) in adult patients with relapsed or refractory CD22+ B-cell acute lymphoblastic leukemia. 2020 ASH Annual Meeting & Exposition. Abstract 163. Presented December 5, 2020.