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Inotuzumab ozogamicin effective for the treatment of newly diagnosed older patients and pediatric patients with R/R BCP-ALL – results from two studies

May 14, 2021
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Inotuzumab ozogamicin (InO) is an antibody–drug conjugate composed of an anti-CD22 antibody linked to calicheamicin, a potent cytotoxic antitumor antibiotic. This binds to CD22-expressing tumor cells and induces cell cycle arrest and apoptotic cell death after endocytosis. InO was first licensed by the U.S. Food and Drug Administration (FDA) in August 2017, for the treatment of adults with relapsed or refractory B-cell precursor (BCP) acute lymphoblastic leukemia (ALL).

Presented at the 62nd American Society of Hematology Annual Meeting and Exposition, the use of InO has been explored in two phase II clinical trials for the treatment of ALL. Matthias Stelljes and colleagues presented their research on the efficacy and safety of InO in the induction treatment of older patients with ALL (INITIAL-1 trial NCT03460522),1 while following on from a phase I study recently published in Blood, Erica Brivio reported on the initial findings of using single agent InO in the treatment of pediatric patients with relapsed or refractory (R/R) CD22-positive ALL (ITCC-059). 2,3                           

InO for the treatment of patients ≥ 56 years old with newly diagnosed ALL1

Despite recent advances, ALL carries a poor prognosis in older patients, with a 2-year survival of approximately 30%. Furthermore, conventional chemotherapy induction treatment comes with an increased risk of toxicity, such as infection and cytopenia.

Study design

An open-label phase II study of the German Multicenter Study Group on Adult ALL, conducted in 14 centers across Germany.

Patients were eligible if they were > 55 years old, had newly diagnosed B-cell ALL with at least 20% CD22 expression on blast cells, and no previous ALL-specific treatment.

Endpoints

Primary endpoint: Event-free survival at 12 months.

Per the statistical plan, 42 evaluable patients are required to prove the hypothesis that InO induces an event rate of ≤ 40% at 12 months (type I error probability of ɑ = 0.05 and power of 80%)

Secondary endpoints: Complete hematological remission rates and MRD response at 42 days, relapse-free survival and overall survival at 2 years, molecular relapse, and death during induction and in complete remission.

Treatment

Induction Cycle 1:

  • InO 0.8 mg/m2 on Day 1, 0.5 mg/m2 on Days 8 and 15
  • Intrathecal central nervous system (CNS) prophylaxis with methotrexate, cytarabine, and dexamethasone

Induction Cycle 2 and 3:

  • InO 0.5 mg/m2 on Days 1, 8, and 15, plus intrathecal CNS prophylaxis with methotrexate, cytarabine, and dexamethasone

Patients achieving complete remission went on to receive conventional consolidation and maintenance treatment according to the treatment recommendations of the German ALL study group.

Results

At the time of analysis, 36 patients had been recruited to the study, of which 31 had received > 1 cycle of InO induction and were assessable for remission. 20 patients had been on the study for 12 months or more after inclusion. For patient characteristics see Table 1.

Table 1. Patient characteristics1

ALL, acute lymphoblastic leukemia.

Characteristics

Patients (N = 36)

Median age, years (range)

65 (56–80)

Common ALL, n

Pro-B lymphocyte ALL, n

25

4

Median CD22 expressions (range)

70% (21–99%)

Blasts > 20%/40-60%/> 60% positive for CD20, n

5/10/20

Blasts > 20% positive for CD20, n

17

Remission rates after at least one cycle of induction with InO were high (100%) and could be sustained for up to one year (see Table 2 for details).

Table 2. Efficacy1

allo-HSCT, allogeneic hematopoietic stem cell transplantation; CI, confidence interval; CR, complete remission; CRi, CR with incomplete hematologic recovery; EFS, event-free survival; MRD, measurable residual disease; OS, overall survival.

Response

Patients

Patients in CR/CRi after >1 induction cycle, n (%)

31 (100)

Early death within 3 months after treatment start, %

0

MRD-negative as best response, n (%)

21/27 (78%)

Hematological/molecular relapse, n/n

2/1

Allo-HSCT in remission/after relapse, n/n

3/1

OS at 12 months (n=31), %

87% (95% CI 70-100%)

EFS at 12 months (n=31), %

87% (95% CI 70-100%)

Safety data

Adverse events are presented in Table 3, considering Grade 3 and above AE during each of induction cycles 1, 2, and 3.

Table 3. Adverse events1

≥ Grade 3 adverse events (> 10% occurrence)

Induction Cycle

Cycle 1

Cycle 2

Cycle 3

Leukocytopenia

Anemia

Thrombocytopenia

Elevation of liver enzymes

Hyperphosphatemia

Hyperglycemia

60%

32%

52%

14%

12%

19%

15%

5%

5%

0%

0%

10%

13%

13%

6%

0%

0%

0%

Summary

InO is a promising and well-tolerated induction agent for the treatment of older patients with B-cell ALL, reducing the risk of treatment-related mortality and improving clinical outcomes and remission.

Single-agent InO for the treatment of CD22 positive relapsed or refractory ALL in children3

Study design

An open label, multicenter, pediatric phase I study across 13 European countries. InO was administered at the recommended phase II dose of 1.8 mg/m2/course.

Inclusion criteria

Patients aged 1–18 years, with R/R CD22-positive BCP-ALL with M2/M3 marrow, were included in the study. No liver or kidney dysfunction or veno-occlusive disease was permitted.

Endpoints

Primary endpoint: Overall response rate (ORR), including complete remission (CR), CR with incomplete hematological recovery (Cri) (ANC > 500/µL and/or PLT ≤ 50.000/µL) and CR with incomplete platelet counts (CRp).

The study was designed to reject the null hypothesis (H0) of an ORR < 30% based on data from 25 patients (80% power and ɑ = 0.05).

Secondary endpoints: Safety, MRD status, durability of response, and pharmacokinetics/pharmacodynamics.

Results

Of 32 patients enrolled, 28 patients were treated and 27 were evaluable. One patient discontinued early due to sinusoidal obstruction syndrome (SOS). Patient characteristics are shown in Table 1.

Table 4. Patient characteristics3

CAR, chimeric antigen receptor; HSCT, hematopoietic stem cell transplantation.

Characteristics

Patients (N = 32)

Number of patients

28 treated

Median age, years (range)

7.5 (1.7–17)

Male, n (%)

19 (68)

Primary refractory disease, n (%)

≥ 2 relapse, n (%)

First relapse post HSCT, n (%)

6 (21)

16 (57)

6 (21)

Previous HSCT, n (%)

Previous CAR T-cell therapy, n (%)

Previous blinatumomab, n (%)

14 (50)

3 (11)

7 (25)

Median CD22 blast, % (range)

96.7 (44–100)

Efficacy

Treatment and safety data is presented in Tables 5 and 6. At the time of analysis, 48 courses of InO had been prescribed (1.8 mg/m2/course), with a range of 14 courses per patient. The median follow up was 8.5 months and the median duration of treatment was 7 months (95% CI, 6.2NA). 14 patients proceeded to allogeneic hematopoietic stem cell transplant (allo-HSCT) as consolidation treatment, while three patients received CAR-T therapy. Primary and secondary outcomes are described in Table 5.

Table 5. Primary and secondary outcomes3

allo-HSCT, allogeneic hematopoietic stem cell transplantation; CAR, chimeric antigen receptor; CI, confidence interval; CR, complete remission; CRi, CR with incomplete hematological recovery; CRp, CR with incomplete platelet count; EFS, event-free survival; MRD, measurable residual disease; OS, overall survival.

Outcome

Patients

Overall response achieved in 27 patients, %

CR, n

CRp, n

Cri, n

81.5

14

1

7

MRD negativity, %

82% after Course 1

95% best response

Consolidation after CR/CRi/CRp

14/22 (63.6%) went on to receive allo-HSCT

3/22 (13.6%) went on to receive CAR T-cell therapy

Median follow-up, months

7.3

EFS at 12 months, % (95% CI)

23.1 (8.563.2)

OS at 12 months, % (95% CI)

46.5 (27.279.6)

Median duration of response, months (95% CI)

7 (6.21NA)

Safety

There were six cases of SOS, one during treatment with InO which completely resolved and 5 cases after allo-HSCT of which only two resolved. Severe toxicities seen in more than 10% of patients are described in Table 6.

Table 6. Grade 3-4 toxicities observed in > 10% of patients3

ALT, alanine transaminase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; SOS, sinusoidal obstruction syndrome

Grade 34 toxicity

Number of patients

%

Increased ALT

6/28

21.5

SOS

5/28

18

Increased AST

5/28

18

Febrile neutropenia

5/28

18

Tumor lysis syndrome

3/28

11

ANC decreased

24/27

88

Decreased platelets

17/27

63

Summary

InO shows remarkable activity (ORR 82.5%; MRD negativity 94%) meeting its primary endpoint in heavily pretreated pediatric patients with B-cell lymphoblastic leukemia, with 46.5% of patients alive at 1 year. However, six cases of SOS occurred, mostly after allo-HSCT. A phase I study testing InO in combination with chemotherapy in pediatric patients with R/R ALL is currently ongoing.

Conclusion

Beyond its approved use for treating adult patients with R/R BCP-ALL, InO has demonstrated its potential for treating pediatric patients with R/R BCP-ALL but also as first-line induction therapy for adult patients with BCP-ALL, both of whom are susceptible to treatment related morbidities, adverse events, and treatment-related mortality. InO offers a tolerable treatment option with potentially improved remission and survival in both populations. 

  1. Stelljes M, Raffel R, 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). Oral abstract #267. 62nd ASH Annual Meeting and Exposition; Dec 5, 2020; Virtual.

  2. Brivio E, Locatelli F, Lopez-Yurda M et al. A phase I study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study) Blood 2021:137(12):1582–1590. DOI: https://doi.org/10.1182/blood.2020007848
  3. Brivio E, Locatell Fi, Thano A, et al. A phase II study of single-agent inotuzumab ozogamicin in pediatric CD22-positive relapsed/refractory acute lymphoblastic leukemia: results of the ITCC-059 study. Oral abstract #164. 62nd ASH Annual Meeting and Exposition; Dec 5, 2020; Virtual.

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