Inotuzumab Ozogamicin in Pediatric Patients With Relapsed or Refractory B-Cell ALL

Précis

This review discusses the significance of the FDA-approved drug inotuzumab ozogamicin in pediatric patients with acute lymphocytic leukemia (ALL) and relapsed/refractory (R/R) ALL, and the evolving therapeutic options in R/R ALL.

Image credit: jarun011 | stock.adobe.com

Introduction

Acute lymphocytic leukemia (ALL) is a heterogenous disease characterized by the proliferation of immature lymphoid cells in the bone marrow, peripheral blood, and other organs.¹ ALL is recognized as a rare, genetically heterogenous disease with 6550 new diagnoses and 1330 deaths in 2024.^2,3 While ALL is not a common cancer, the majority of cases occur in children younger than 5 years. The risk declines after age 25 years and slowly rises after age 50 years, with most deaths occurring in adults with ALL.

The therapeutic options for pediatric patients and adults with ALL differ partly due to the nature and response of each population group with the disease.^2,3 The underlying mechanism of the disease involves multiple genetic mutations resulting in rapid cell division within the bone marrow. Hematopoietic cells of ALL consist of either the B-cell precursor (BCP-ALL) or T-cell lineages. Both immunophenotypes comprise various subtypes characterized by alterations in chromosomes. The World Health Organization states that categories of lymphoid neoplasm integrate genetic data, clinical features, cell morphology, and immunophenotype, which has importance in the prognosis and management of the disease.⁴

ALL is diagnosed by a complete blood count, which consists of differential count, peripheral blood smear, bone marrow examination, histochemical studies, cytogenetics, and immunophenotyping studies.⁴ Identification of blast cells of lymphoid origin (≥ 20% of the bone marrow cells or ≥ 20% of nonerythroid cells) when the erythroid component is greater than 50% helps determine the diagnosis of ALL.⁴ Further, Auer rods in the cytoplasm of the blast cells are never present in ALL as opposed to acute myeloid leukemia, in which they are present. Patients with ALL typically have between 25% and 95% of blast cells in the bone marrow.⁴

Immunophenotypic markers are critical for categorizing acute leukemias, with immunophenotyping studies including CD3 for lymphoid cells of T cells and CD19, CD20, and CD22 for lymphoid cells of B-cell origin. Cytogenetic abnormalities in ALL include but are not limited to t(9;22) in adults and t(12;21) in children, as shown in the Table.⁴

Ph+, Philadelphia chromosome positive.

Genetic and chromosomal studies have indicated that t(12;21)/ETV6-RUNX1 and high hyperdiploidy have favorable prognostic features, while t(9;22)/BCR-ABL-1 with a positive Philadelphia chromosome has poor prognostic features.^4,5 The common translocations in children with BCP-ALL are t(12;21) [ETV6-RUNX1], t(1;19) [TCF3-PBX1], t(9;11)[BCR-ABL1], and translocations that include the MLL gene.⁶ Further, 20% of newly diagnosed cases of BCP-ALL do not belong to any genotype subtypes and are referred to as B-other⁶; the various subtypes in ALL make diagnosis and treatment challenging for pediatric patients.

Research and clinical studies have suggested that genetic markers can predict a patient’s reaction to specific regimens. Pharmacokinetics (PK), pharmacodynamics (PD), and pharmacogenomics have shown different factors that contribute to various treatment responses among different patients, which can impact clinical outcomes.⁶ By monitoring the changes in mutation clearance during the initial induction therapy or observing the unfolding of mutations associated with relapse, it is possible to identify patients who could benefit from early modifications to their treatment plans.⁶ Furthermore, by exploring genomic analysis to predict relapses in ALL and by conducting clinical studies in pediatric patients with ALL, it is possible to gain a deeper understanding of the role of genetic markers in the disease, targets for therapeutic interventions, and effective treatments for a favorable clinical outcome.

Treatment Overview for Pediatric Patients With ALL

Treatment approaches for ALL are complex and require intensive cancer therapy. Although the specific treatment regimens, including the selection of drugs, dose schedules, and treatment duration, differ among the pediatric, adolescent, and young adult (AYA) and adult patient groups, as well as between the different subtypes of ALL, the basic treatment principles are similar.¹ For all groups, treatment phases are grouped into induction, consolidation, and maintenance.¹ The phases are broken further into induction 1A; induction 1B; central nervous system (CNS) phase; early intensification; delayed intensification continuation; consolidation 1A, 1B, 1C, and 2; and interim maintenance 1 and 2. All treatment regimens for ALL include CNS prophylaxis and/or treatment, with some treatment plans including targeted agents and hematopoietic stem cell transplant (HSCT).¹

Induction treatment plans are generally based on a foundation that includes vincristine, corticosteroids (eg, prednisone, dexamethasone), and asparaginase with or without anthracyclines (eg, daunorubicin, doxorubicin). The Berlin-Frankfurt-Munster and Children’s Oncology Group (COG) regimens are based on 4-drug induction regimens that include vincristine, an anthracycline, a corticosteroid, and asparaginase.¹ According to the COG, patients who are classified as having National Cancer Institute standard-risk disease are treated with a 3-drug induction that does not include anthracyclines.¹ Some studies from Cancer and Leukemia Group B have utilized a 5-drug regimen in AYA and adult patients, which adds cyclophosphamide to the 4-drug combination.¹ Treatment phases in the postinduction consolidation phase may involve 4 to 6 cycles of therapy and in some settings may occur for up to 8 months.¹

The consolidation phase is the phase most affected by risk stratification. Patients with lower-risk disease receive less intensive consolidation and patients with higher-risk disease receive more intensive consolidation.1 The following medications are often incorporated into consolidation/intensification regimens: high-dose methotrexate, cytarabine, 6-mercaptopurine (6-MP), cyclophosphamide, 6-thioguanine, vincristine, corticosteroids, and asparaginase.¹

The maintenance phase is mostly based on mainstay treatments of 6-MP and weekly methotrexate (typically with the addition of periodic vincristine and corticosteroids) for 2 to 3 years.¹ Additionally, CNS prophylaxis and/or treatment to prevent CNS disease or relapse is crucial to clearing leukemic cells within sites that cannot be accessed with systemic chemotherapy.¹

CNS prophylaxis is generally given to all patients throughout the course of ALL therapy. CNS therapy may include intrathecal therapy (eg, cytarabine and corticosteroid), cranial irradiation, and/or systemic chemotherapy (eg, dexamethasone, high-dose methotrexate, intermediate/high-dose cytarabine, and asparaginase).

Therapies targeted for hematologic malignancies and monoclonal antibodies to surface antigens such as CD19, CD20, CD22, and CD52, have been utilized in ALL therapy.¹ Targeted therapies used in ALL include unconjugated forms of monoclonal antibodies (eg, rituximab and epratuzumab), conjugated forms of immunotoxins or chemotherapeutic agents (eg, moxetumomab [Lumoxiti; AstraZeneca] and inotuzumab ozogamicin [Besponsa; Pfizer Inc]), and the bispecific antibody blinatumomab (Blincyto; Amgen).

Chimeric antigen receptor (CAR) T-cell therapies targeting CD19 have also demonstrated remissions in pediatric and AYA patients with R/R BCP-ALL.¹ Overall, the therapies used in induction, consolidation, and maintenance during the course of ALL therapy and in R/R ALL are based on, but not limited to, risk stratification (standard risk or high risk), gender, age, cytogenetics abnormalities, early BCP-ALL, pre–B-cell ALL, or T-cell ALL.

R/R in Pediatric B-Cell ALL

In recent years, treatment for R/R ALL has evolved for both T-cell and B-cell ALL. Blinatumomab, a bispecific T-cell engager, targets CD19 for B cells and CD3 for T cells. Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate (ADC). Both blinatumomab and inotuzumab ozogamicin have shown activity in the R/R setting.

The FDA approved inotuzumab ozogamicin for the treatment of adults with R/R BCP-ALL on August 17, 2017. On March 6, 2024, the FDA approved inotuzumab ozogamicin for pediatric patients 1 year and older with R/R CD22-positive BCP-ALL.³ The phase 3 clinical study that led to the new drug application submission was INO-VATE ALL (NCT01564784), which evaluated the efficacy of the drug in a multicenter, single arm, open-label study in 53 pediatric patients 1 year and older. The initial dose was 1.4 mg/m²/cycle in 12 patients and 1.8 mg per m² per cycle in 41 patients.³ Patients were premedicated with an antipyretic, methylprednisolone 1 mg/kg (maximum dose, 50 mg), and an antihistamine. A median of 2 cycles of therapy were administered to patients (range, 1 to 4 cycles).⁷

The efficacy outcome measures were complete remission (CR), duration of CR, and the proportion of patients with minimal residual disease (MRD)–negative CR. Complete remission was defined as less than 5% of blasts in the bone marrow and the absence of peripheral blood leukemia blasts, a full recovery of peripheral blood counts (platelets ≥ 100 × 109 and absolute neutrophil count ≥ 1 × 109/L), and resolution of any extramedullary disease. The MRD was defined by leukemic cells consisting of less than 1 × 10-4 (< 0.01%) of bone marrow nucleated cells by flow cytometry or by pathologic complete response (pCR).⁷

In all patients, 42% (95% CI; 28.1%-55.9%) achieved CR and the median duration of CR was 8.2 months (95% CI; 2.6 months-not evaluable). The undetectable MRD rate in patients with CR was 95.5% (95% CI; 77.2%-99.9%) based on flow cytometry, and 86.4% (95% CI; 65.1%-97.1%) based on real-time quantitative reverse transcriptase pCR. Common adverse events (AEs; ≥ 20%) included thrombocytopenia, pyrexia, anemia, vomiting, infection, hemorrhage, neutropenia, nausea, leukopenia, febrile neutropenia, increased transaminases, abdominal pain, and headache.⁷ The recommended dose for inotuzumab ozogamicin is 1.8 mg/m2 per cycle, administered as 3 divided doses on day 1 (0.8mg/m²), day 8 (0.5mg/m²), and day 15 (0.5mg/m²).⁷ Cycle 1 is 3 weeks in duration but may be extended to 4 weeks if the patient achieves CR or CR with incomplete hematologic recovery and/or to allow recovery from toxicity.⁷

The phase 2 study ITCC-059 (NCT02981628) of inotuzumab ozogamicin in pediatric patients with R/R ALL investigated the recommended phase 2 dose (RP2D) of inotuzumab ozogamicin, established at 1.8 mg/m², in pediatric patients with multiple R/R ALL.⁸ Of the patients with multiple R/R ALL, 85% reached CR after 1 course of single-agent inotuzumab ozogamicin at the RP2D, and 100% had MRD negativity.7 Patients (aged ≥ 1 year or <18 years) received 3 doses of inotuzumab ozogamicin on days 1, 8, and 15 per course. Dose escalation was based on dose-limiting toxicities (DLTs) during course 1. Dose level 1 (DL1) was 1.4 mg/m² and dose level 2 (DL2) was 1.8 mg/m².⁸ Secondary end points included safety, antileukemic activity, and PK.⁸ Among the 25 patients enrolled, 23 were evaluable for DLTs. The primary objective was determining the maximum tolerated dose of RP2D of intravenous (IV) inotuzumab ozogamicin monotherapy and secondary objectives included safety, response, and PK/PD.⁸ In the first cohort, 2 patients at DL2 experienced a DLT per protocol definition. A course of therapy included 3 doses of inotuzumab ozogamicin (IV infusion for 60 minutes) once per week on days 1, 8, and 15. A maximum of 6 courses, 2 or 3 courses only before HSCT, were permitted.⁷ Course 1 was planned to last 22 days, and all succeeding courses were planned to last 28 days, with delays up to 42 days.⁸

Patients were pretreated with methylprednisolone 1 mg/kg IV (maximum 50 mg) before each infusion of inotuzumab ozogamicin was recommended.⁸ In course 1, DL1 was 1.4 mg/m² administered in separate doses, with the day 1 dose to be 0.6mg/m2 and the following 2 doses to be 0.4 mg/m² due to high tumor burden at relapse.⁸ In courses 2 through 6, patients received a total dose per course of 1.2 mg/m². Preclinical studies indicated that lower doses of inotuzumab ozogamicin compared with a single-course high dose suggested improvement in overall ALL activity and reduced toxicities.

Inotuzumab ozogamicin was well tolerated with efficacy in children pretreated with R/R ALL. RP2D was significant at 1.8 mg/m² per course. The overall risk reduction was 80% with a 1-year overall survival (OS) probability of 40%.⁷ The response rate was higher for patients treated with DL2 (85%) compared with DL1 (75%) with no statistical difference due to the small sample size.⁸

The MRD negativity rate was 66% for DL1 and 100% for DL2. Of the 25 patients, 9 received consolidation therapy that included HSCT or CAR T-cell therapy. Additionally, 3 patients showed prolonged CR without subsequent HSCT or CAR-T cell therapy (2 patients received additional therapy) and 1 did not receive any treatment after inotuzumab ozogamicin.⁸ There were 2 cases of sinusoidal obstruction syndrome (SOS) following multiagent chemotherapy, and no patient given HSCT developed SOS.⁸

PK of inotuzumab ozogamicin was included in this study. The peak and trough concentrations of inotuzumab ozogamicin after single or multiple doses varied in children compared with data in typical adult patients with ALL. Inotuzumab ozogamicin plasma PK is comparable between pediatric and adult patients due to the lower or higher changes with data variability.⁸ Patients treated with DL1 and DL2 had comparable plasma levels, with the results indicative of higher activity at DL2 leading to the RP2D of 1.8 mg/m² per course.⁸

In this phase 2 study, inotuzumab ozogamicin was well tolerated and manifested antileukemic activity with high levels of MRD-negative response in children with R/R ALL. The dose of 1.8 mg/m² was established in the single-agent phase 2 cohort of this study during course 1. The dose of 1.5 mg/m² was established per course up to a maximum of 6 courses unless HSCT was planned.⁷ According to the PK analyses, PK of inotuzumab ozogamicin was unaffected by age and dose adjustment was not required for children.

Preliminary data were the first prospective data analysis of inotuzumab ozogamicin in pediatric patients and are consistent with initial observations recorded in retrospective studies of inotuzumab ozogamicin in children. According to the United States–European compassionate use program, the CR rate was reported to be 67% and in the same group of patients with CR, 71% achieved MRD negativity.⁸

Preliminary results from the COG AALL1621 phase 2 study (NCT02981628) investigating inotuzumab ozogamicin monotherapy in the pediatric population at the adult dose demonstrated a rate of CR or complete remission with incomplete count recovery of 58.3%; 19 of the patients had CR and 9 patients had complete response with incomplete count recovery after cycle 1. There was an MRD of less than 0.01% in approximately 65% of responders and minimal hepatic toxicity during inotuzumab ozogamicin therapy; however, 4 of 14 patients who received HSCT (30.7%) developed SOS.^8,9

Inotuzumab ozogamicin has been studied as a single agent and in combination with chemotherapy in pediatric patients with R/R ALL. For this single agent in a single-stage design, 25 patients needed to be recruited to achieve 80% power at 0.05 significance level. Thirty-two patients were enrolled, 28 were treated, and 27 were evaluated for response. The estimated overall relative risk was 81.5% (95% CI; 61.9%-93.7%), and 81.8% of the responding patients were MRD negative. One-year event-free survival (EFS) was 36.7% (95% CI; 22.2%-60.4%) and the OS was 55.1% (95% CI; 39.1%-77.7%). Eighteen patients received consolidation with HSCT and/or CAR T-cell therapy). SOS occurred in 7 patients and resolved in 5 patients. The occurrence of SOS was relevant in patients receiving inotuzumab ozogamicin treatment followed by HSCT.¹⁰ All 28 patients experienced 1 AE, most commonly a fever. Five patients experienced febrile neutropenia and 4 patients had thrombocytopenia grade 3/4 extended after day 42.10 In this single-agent, phase 2 trial, CD22 expression is essential for inotuzumab ozogamicin binding and efficacy was not dependent on CD22 expression levels. While CD22 expression is crucial for the binding of inotuzumab ozogamicin, high levels of CD22 expression on leukemic blasts, saturation of CD22 with inotuzumab ozogamicin, and internalization of inotuzumab ozogamicin do not appear to be crucial for clinical response to inotuzumab ozogamicin.¹⁰

Understanding Inotuzumab Ozogamicin

Inotuzumab ozogamicin is a CD22-directed monoclonal ADC. N-acetyl-gamma-calicheamicin is a small molecule and a cytotoxic agent that covalently attaches to the antibody by a linker. The binding of the ADC to CD22-expressing tumor cells leads to the anti-tumor effects after the ADC-CD22 is internalized and the N-acetyl-gamma-calicheamicin dimethylhydrazide is released intracellularly by hydrolytic cleavage of the linker.¹¹ The double-stranded DNA breaks due to the activation of N-acetyl-gamma-calicheamicin, thereby inducing cell cycle arrest and apoptotic death.¹¹ The PD response of inotuzumab ozogamicin is classified by the depletion of CD22+ leukemic blasts. After multiple doses were administered, a 5.3 times accumulation of inotuzumab ozogamicin was predicted by cycle 4.11 The total volume of distribution of inotuzumab ozogamicin was approximately 12 L. There was an approximate 30% increase in area under the blood concentration–time curve of inotuzumab ozogamicin in pediatric patients 1 year and older compared with adults.

Inotuzumab ozogamicin has a warning for hepatotoxicity, including veno-occlusive disease and increased risk of post-HSCT, nonrelapse mortality.¹² Inotuzumab ozogamicin is administered via IV infusion only and patients must be premedicated with a corticosteroid, antipyretic, and antihistamine prior to all infusions.¹² For patients with circulating lymphoblasts, cytoreduction with a combination of hydroxyurea steroids and/or vincristine to a peripheral blast count of less than or equal to 10,000/mm³ is recommended prior to the first dose.12

Warnings and precautions for inotuzumab ozogamicin include myelosuppression, infusion-related reactions (monitor during and for at least 1 hour after infusion ends), QT interval prolongation (obtain electrocardiograms and electrolytes at baseline and monitor during treatment; monitor frequently when using concomitant medications known to prolong QT interval), and embryo-fetal toxicity.¹³

Inotuzumab ozogamicin has found its place in the treatment of R/R BCP-ALL in both single-agent and combination chemotherapy regimens in both pediatric and adult populations. Given the complexity of ALL treatment regimens and supportive care measures, pediatric patients need to be treated at a specialized cancer center.¹³

However, treatment of R/R BCP-ALL is not limited to inotuzumab ozogamicin. There are other immunotherapy options such as blinatumomab and tisagenlecleucel (Kymriah; Novartis). Blinatumomab for pediatric use is supported by a single-arm, phase 1/2 study (NCT01471782) in pediatric patients with R/R ALL, with 39% of patients achieving CR within 2 cycles of blinatumomab and 52% achieving a complete MRD response. The levels are lower than those observed in the studies with inotuzumab ozogamicin.

Tisagenlecleucel is also approved for the treatment of patients 25 years or younger with R/R ALL. Other CD22-directed therapies are epratuzumab, which has shown limited activity. There have been early-phase studies published investigating CAR T cells in patients with R/R BCP-ALL; both CAR T and inotuzumab ozogamicin need soluble CD22 expression.¹⁴ The potential benefits of CAR T therapy compared with inotuzumab ozogamicin are lack of published evidence of SOS in the latter and the ability of CAR T cells to treat extramedullary disease.¹⁴

Ongoing Clinical Trials

There are ongoing trials by The University of Texas MD Anderson Cancer Center to combine inotuzumab ozogamicin with chemotherapy regimens for pediatric patients. The current trial is the phase 2 Study of Pedi-cRIB (NCT05645718), which looks to investigate whether cyclophosphamide, vincristine, and dexamethasone, a regimen also called mini-hyper-CVD, in combination with intrathecal chemotherapy that includes methotrexate, hydrocortisone, cytarabine, and cRIB (compressed rituximab, blinatumomab, and inotuzumab ozogamicin) can control the disease.¹⁵ The primary objective of the trial is CR and the secondary objectives are response rate, OS, EFS, and MRD negativity rate.¹⁵ While clinical trials of inotuzumab ozogamicin are ongoing in other ethnic groups and children with MRD positivity, the current clinical trial of inotuzumab ozogamicin with mini-hyper-CVD may help to further evaluate how pediatric patients can respond after relapse therapy and CR.

Conclusion and Future Directions

The overall management of ALL has significantly evolved in the past few years. Relapses, MRD, toxicities, genetic variations, and increasing costs of new treatments have posed new challenges for health care professionals and patients. However, the development of immunotherapy and molecularly targeted therapy has helped better manage the disease. The hope of ongoing clinical trials in pediatric patients will pave the way for new treatments in R/R ALL. Additionally, although inotuzumab ozogamicin is FDA approved for pediatric patients with R/R B-cell ALL, due to limited data of resistance and antigen loss of inotuzumab ozogamicin, further clinical trials are needed.

REFERENCES

1. NCCN. Clinical Practice Guidelines in Oncology. Acute lymphoblastic leukemia, version 2.2024. July 19, 2024. Accessed July 23, 2024. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf

2. DeAngelo DJ, Jabbour E, Advani A. Recent advances in managing acute lymphoblastic leukemia. Am Soc Clin Oncol Educ Book. 2020;40:330-342. doi:10.1200/EDBK_280175

3. Key statistics for acute lymphoblastic leukemia (ALL). American Cancer Society. Updated January 17, 2024. Accessed April 27, 2024. https://www.cancer.org/cancer/types/acute-lymphocyticleukemia/about/key-statistics.html

4. Emadi A, Law J. Acute lymphoblastic leukemia (ALL). Merck Manual. Updated October 2023. Accessed April 27, 2024. https://www.merckmanuals.com/professional/hematology-and-oncology/leukemias/acute-lymphoblastic-leukemia-all

5. Lanza F, Maffini E, Rondoni M, Massari E, Faini AC, Malavasi F. CD22 expression in B-cell acute lymphoblastic leukemia: biological significance and implications for inotuzumab therapy in adults. Cancers (Basel). 2020;12(2):303. doi:10.3390/cancers12020303

6. Ekpa QL, Akahara PC, Anderson AM, et al. A review of acute lymphocytic leukemia (ALL) in the pediatric population: evaluating current trends and changes in guidelines in the past decade. Cureus. 2023;15(12):e49930. doi:10.7759/cureus.49930

7. FDA approves inotuzumab ozogamicin for pediatric patient with acute lymphoblastic leukemia. FDA. March 6, 2024. Accessed April 30, 2024. https://www.fda.gov/drugs/resources-information-approveddrugs/fda-approves-inotuzumab-ozogamicin-pediatric-patients-acutelymphoblastic-leukemia

8. Brivio E, Locatelli F, Lopez-Yurda M, et al. A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study). Blood. 2021;137(12):1582-1590. doi:10.1182/blood.2020007848

9. O’Brien MM, Ji L, Shah NN, et al. Phase II trial of inotuzumab ozogamicin in children and adolescents with relapsed or refractory B-cell acute lymphoblastic leukemia: Children’s Oncology Group Protocol AALL1621. J Clin Oncol. 2022;40(9):956-967. doi:10.1200/JCO.21.01693

10. Pennesi E, Michels N, Brivio E, et al. Inotuzumab ozogamicin as single agent in pediatric patients with relapsed and refractory acute lymphoblastic leukemia: results from a phase II trial. Leukemia. 2022;36(6):1516-1524. doi:10.1038/s41375-022-01576-3

11. Besponsa clinical pharmacology. Pfizer. 2024. Accessed April 30, 2024. https://www.pfizermedicalinformation.com/besponsa/clinical-pharmacology

12. Besponsa. Prescribing information. Pfizer; 2024. Accessed April 30, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761040s003lbl.pdf

13. NCCN. Clinical Practice Guidelines in Oncology. Pediatric acute lymphoblastic leukemia, version 1.2025. August 28, 2024. https://www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf

14. Rubinstein JD, O’Brien MM. Inotuzumab ozogamicin in B-cell precursor acute lymphoblastic leukemia: efficacy, toxicity, and practical considerations. Front Immunol. 2023;14:1237738. doi:10.3389/fimmu.2023.1237738

15. McCall D, Jabbour E, Roth M, Nunez C, Cuglievan B. Mini-hyper CVD + CRIB (condensed rituximab, inotuzumab ozogamicin, and blinatumomab) for refractory pediatric B-acute lymphoblastic leukemia. Pediatr Blood Cancer. 2023;70(1):e29939. doi:10.1002/pbc.29939

The author has nothing to disclose.