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CCCG Relapsed Acute Lymphoblastic Leukemia 2017 Study in Children

Primary Purpose

Acute Lymphoblastic Leukemia, in Relapse

Status

Completed

Phase

Phase 2

Locations

Hong Kong

Study Type

Interventional

Intervention

Bortezomib Injection

rituximab injection

About this trial

This is an interventional treatment trial for Acute Lymphoblastic Leukemia, in Relapse focused on measuring Relapsed ALL

Eligibility Criteria

3 Months - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Age at relapse less than 21 years and the age at initial diagnosis of ALL of Pre-B or T-lineage less than 18 years.
Confirmed diagnosis of relapse of leukemia according to definition as below:

Definitions of Relapse

RELAPSE: Any recurrence of disease whether in marrow or extramedullary.
(1) ISOLATED Bone Marrow Relapse: Patients with an M3 marrow (>25% blast) at any point after achieving remission without involvement of the CNS and/or testicles and/or other extramedullary sites. Relapsed should be confirmed by morphology, flow cytometry, FISH and/or cytogenetics. M2 marrow should have a repeat of bone marrow in 1-2 weeks to confirm M3 status unless the original cytogenetic clone reappears.
(2) CNS Relapse: Positive cytomorphology and WBC ≥ 5/μL OR clinical signs of CNS leukemia such as facial nerve palsy, brain/eye involvement, or hypothalamic syndrome that are compatible with recurrent CNS leukemia than to alternative causes (e.g., viral infection with facial nerve palsy or chemotherapy toxicity). If any CSF evaluation shows positive cytomorphology and WBC < 5/μL, a second CSF evaluation is recommended within 2 - 4 weeks. While identification of a leukemic clone in CSF by flow cytometry (TdT, CD19, CD10, etc.) or FISH for diagnostic karyotypic abnormality may be useful, definitive evidence of CNS involvement (i.e. WBC ≥ 5/μL OR clinical signs of CNS leukemia) is required for the diagnosis of a CNS relapse.
(3) TESTICULAR Relapse: Must be documented by testicular biopsy, if not associated with a marrow relapse.
(4) ISOLATED Extramedullary (IEM) relapse: CNS and/or testicular relapse and/or other extramedullary sites such as skin with an M1 marrow. The presence of MRD in the bone marrow does NOT exclude IEM.
(5) COMBINED Relapse: M2 or M3 marrow at any time after achieving remission with concomitant CNS and/or testicular relapse.

CNS Status:

CNS 1: In cerebral spinal fluid (CSF), absence of blasts on cytospin preparation, regardless of the number of white blood cells (WBCs).

CNS 2: In CSF, presence < 5/μL WBCs and cytospin positive for blasts, or ≥ 5/μL WBCs but negative by Steinherz/Bleyer algorithm:

CNS 2a: < 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts; CNS 2b: ≥ 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts; and CNS 2c: ≥ 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts but negative by Steinherz/Bleyer algorithm (see below).

CNS3: In CSF, presence of ≥ 5/μL WBCs and cytospin positive for blasts and/or clinical signs of CNS leukemia:

CNS 3a: < 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts; CNS 3b: ≥ 10/μL RBCs, ≥ 5/μL WBCs and positive by Steinherz/Bleyer algorithm (see below); CNS 3c: Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye involvement or hypothalamic syndrome).

Method of Evaluating Initial Traumatic Lumbar Punctures:

If the patient has leukemic cells in the peripheral blood and the lumbar puncture is traumatic and contains ≥ 5 WBC/μL and blasts, the following algorithm should be used to distinguish between CNS 2 and CNS 3 disease: CSF WBC > 2X Blood WBC CSF RBC Blood RBC

Exclusion Criteria:

Mature B ALL,
Poor Karnosky score

Sites / Locations

Hong Kong Children's Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

rituximab and bortezomib

Arm Description

to test whether adding rituximab in CD20 positive patients will have improvement in remission rate. (this arm terminated in October 2020) to add bortezomib in high risk patients at Induction to improve remission rate.

Outcomes

Primary Outcome Measures

remission rate

bone marrow blast count < 5% and MRD <0.01%

Secondary Outcome Measures

event-free survival rates

survive without relapse or death or second cancer, with or without HSCT

overall survival

survive without death event

Full Information

NCT ID

NCT04224571

First Posted

January 8, 2020

Last Updated

August 29, 2023

Sponsor

Chinese University of Hong Kong

Collaborators

Shanghai Children's Medical Center

1. Study Identification

Unique Protocol Identification Number

NCT04224571

Brief Title

CCCG Relapsed Acute Lymphoblastic Leukemia 2017 Study in Children

Official Title

Chinese Children Cancer Group Relapsed Acute Lymphoblastic Leukemia 2017 Study

Study Type

Interventional

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Completed

Study Start Date

September 14, 2018 (Actual)

Primary Completion Date

February 15, 2023 (Actual)

Study Completion Date

February 15, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Chinese University of Hong Kong

Collaborators

Shanghai Children's Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Relapsed acute lymphoblastic leukaemia (ALL) has a poorer outcome than newly diagnosed ALL patients with only about 40% overall survival after re-treatment. The study CCCG Relapsed ALL 2017 study will adopt the UK R3 study stratification and treatment backbone with two new agents added. There will be a 4-week induction, followed by two consolidation courses. High-risk patients will receive allogeneic stem cell transplant. While intermediate and standard risk groups will continue maintenance treatment for another 2 years or one year. New agents will be added aiming at improving survival outcome. Study of adding anti-CD20 antibody (rituximab) with chemotherapy: CD20 is found to be expressed in 40-50% of B-lineage ALL, and rituximab has been studied in adult ALL with superior survival (75% vs 47%,). There is little experience of using rituximab in pediatric ALL thus a CCCG Relapsed ALL 2017 Study will perform the study assessing the remission rate and MRD response of CD20+ ALL treated with rituximab. Six doses of rituximab and will be monitored the week 5 MRD and relapse rate as study outcome. (This arm was terminated in October 2020 after interim analysis showing lack of efficacy) Adding bortezomid during the induction: The very early or early bone marrow relapse has low remission rate. Previous case studies showed that Bortezomib, a proteasome inhibitor, may achieve remission in refractory ALL, 80% remission in B-ALL with combination of chemotherapy and bortezomib. Thus adding bortezomib, may improve the remission rate, thus bridging to allogeneic stem cell transplant. Adding bortezomib in the relapsed chemotherapy protocol may increase the toxicity and even treatment related mortality. In this protocol, we suggested to add during the induction therapy.

Detailed Description

Acute Lymphoblastic Leukemia (ALL) is now having over 80% event-free survival after frontline chemotherapy treatment. There is still 15-20% of patients having a relapse after initial control. Relapsed ALL is associated with lower second remission rate and also high chance of further relapse. Currently there are only a few large scale studies targeting this challenging disease. BFM Relapsed ALL studies have been organized since 1990s and have identified several important prognostic factors, including timing and site of relapse and also immunophenotyping. COG has performed several studies on relapsed ALL (AALL02P2, AALL0433, ADVL04P2) but the results are rather fragmented. Recently UK group conducted a nationwide randomized study, ALL R3 study, testing the type of anthracycline and prognostic value of minimal residual disease after induction therapy. T-ALL relapse is having poor prognosis except for the late isolated extramedullary relapse. Long-term survival of T-ALL bone marrow relapse treated with chemotherapy is less than 10%, thus allogeneic stem cell transplant is always indicated. Whereas B-ALL has been better studied and the risk stratification of relapsed ALL is better defined. According to previous studies, patients can be stratified into Standard, Intermediate and High-Risk groups based on site of relapse, time of relapse from first diagnosis and immunophenotyping. Early bone marrow relapse at less than 18-36 months from diagnosis is having the worst prognosis and is classified as HR. Those with late relapse at >36 months from diagnosis is in general having a better prognosis. Bone marrow relapse is having a poorer outcome as compared to isolated extramedullary relapse (IEM). Somehow combined marrow and extramedullary relapse appear to have a better prognosis than isolated bone marrow relapse. Early B-ALL marrow relapse was only having 15-30% long-term survival, and early B-ALL IEM around 30-50% survival. Late B-ALL marrow relapse has a higher second remission rate of around 95% and also better long term survival of 50-60%. Late B-ALL IEM is having a better prognosis of up to 70-80% survival. Based on the above criteria, several study groups including BFM, UK and COG also adopted similar strategies of stratifying patients and delivered risk-adapted treatment, with some minor variation among these groups.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Lymphoblastic Leukemia, in Relapse

Keywords

Relapsed ALL

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Model Description

Prospective and Non-randomized controlled trial

Masking

None (Open Label)

Allocation

N/A

Enrollment

208 (Actual)

8. Arms, Groups, and Interventions

Arm Title

rituximab and bortezomib

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Bortezomib Injection

Other Intervention Name(s)

Velcade

Intervention Description

Bortezomib: patients with BM relapsed, add for 4 doses on D1,4,7, 11 in induction; dosage 1.3 mg/m2/dose as per parenteral;

Intervention Type

Drug

Intervention Name(s)

rituximab injection

Other Intervention Name(s)

Mab Thera

Intervention Description

Add rituximab in patients with CD20 positive ALL, rituximab: 6 doses of on D8,11of induction, D1,15 of consolidation1 and 2 with dosage 375 mg/m2 as parenteral (Terminated in Oct 2020)

Primary Outcome Measure Information:

Title

remission rate

Description

bone marrow blast count < 5% and MRD <0.01%

Time Frame

week 5 MRD and relapse rate

Secondary Outcome Measure Information:

Title

event-free survival rates

Description

survive without relapse or death or second cancer, with or without HSCT

Time Frame

2-year

Title

overall survival

Description

survive without death event

Time Frame

5 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

3 Months

Maximum Age & Unit of Time

21 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age at relapse less than 21 years and the age at initial diagnosis of ALL of Pre-B or T-lineage less than 18 years. Confirmed diagnosis of relapse of leukemia according to definition as below: Definitions of Relapse RELAPSE: Any recurrence of disease whether in marrow or extramedullary. (1) ISOLATED Bone Marrow Relapse: Patients with an M3 marrow (>25% blast) at any point after achieving remission without involvement of the CNS and/or testicles and/or other extramedullary sites. Relapsed should be confirmed by morphology, flow cytometry, FISH and/or cytogenetics. M2 marrow should have a repeat of bone marrow in 1-2 weeks to confirm M3 status unless the original cytogenetic clone reappears. (2) CNS Relapse: Positive cytomorphology and WBC ≥ 5/μL OR clinical signs of CNS leukemia such as facial nerve palsy, brain/eye involvement, or hypothalamic syndrome that are compatible with recurrent CNS leukemia than to alternative causes (e.g., viral infection with facial nerve palsy or chemotherapy toxicity). If any CSF evaluation shows positive cytomorphology and WBC < 5/μL, a second CSF evaluation is recommended within 2 - 4 weeks. While identification of a leukemic clone in CSF by flow cytometry (TdT, CD19, CD10, etc.) or FISH for diagnostic karyotypic abnormality may be useful, definitive evidence of CNS involvement (i.e. WBC ≥ 5/μL OR clinical signs of CNS leukemia) is required for the diagnosis of a CNS relapse. (3) TESTICULAR Relapse: Must be documented by testicular biopsy, if not associated with a marrow relapse. (4) ISOLATED Extramedullary (IEM) relapse: CNS and/or testicular relapse and/or other extramedullary sites such as skin with an M1 marrow. The presence of MRD in the bone marrow does NOT exclude IEM. (5) COMBINED Relapse: M2 or M3 marrow at any time after achieving remission with concomitant CNS and/or testicular relapse. CNS Status: CNS 1: In cerebral spinal fluid (CSF), absence of blasts on cytospin preparation, regardless of the number of white blood cells (WBCs). CNS 2: In CSF, presence < 5/μL WBCs and cytospin positive for blasts, or ≥ 5/μL WBCs but negative by Steinherz/Bleyer algorithm: CNS 2a: < 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts; CNS 2b: ≥ 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts; and CNS 2c: ≥ 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts but negative by Steinherz/Bleyer algorithm (see below). CNS3: In CSF, presence of ≥ 5/μL WBCs and cytospin positive for blasts and/or clinical signs of CNS leukemia: CNS 3a: < 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts; CNS 3b: ≥ 10/μL RBCs, ≥ 5/μL WBCs and positive by Steinherz/Bleyer algorithm (see below); CNS 3c: Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye involvement or hypothalamic syndrome). Method of Evaluating Initial Traumatic Lumbar Punctures: If the patient has leukemic cells in the peripheral blood and the lumbar puncture is traumatic and contains ≥ 5 WBC/μL and blasts, the following algorithm should be used to distinguish between CNS 2 and CNS 3 disease: CSF WBC > 2X Blood WBC CSF RBC Blood RBC Exclusion Criteria: Mature B ALL, Poor Karnosky score

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Chi Kong LI, Professor

Organizational Affiliation

Chinese University of Hong Kong

Official's Role

Principal Investigator

Facility Information:

Facility Name

Hong Kong Children's Hospital

City

Hong Kong

ZIP/Postal Code

852

Country

Hong Kong

12. IPD Sharing Statement

Plan to Share IPD

Citations:

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21220611

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CCCG Relapsed Acute Lymphoblastic Leukemia 2017 Study in Children

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