UMIN-CTR Clinical Trial

Public title

A Phase II Study of Risk Directed Therapy for Infants with Acute Lymphoblastic Leukemia (MLL-10)

Acronym

JPLSG MLL-10

Scientific Title

A Phase II Study of Risk Directed Therapy for Infants with Acute Lymphoblastic Leukemia (MLL-10)

Scientific Title:Acronym

JPLSG MLL-10

Region

Japan

Condition

Infants with newly diagnosed acute lymphoblastic leukemia (ALL) less than 1 year of age at the time of diagnosis without prior history of treatment; for neonates less than 30 days of life, patients must be > 36 weeks gestational age at the time of diagnosis. Patients with acute mixed lineage leukemia (AMLL), acute undifferentiated leukemia (AUL), or acute bilineal leukemia are eligible, provided the morphology and immunophenotype are predominately lymphoid or non T-lineage. Patients with mature B-cell ALL, T-ALL, AMLL with T-ALL criteria, or acute myeloid leukemia (AML) are NOT eligible.

Classification by specialty

Hematology and clinical oncology

Pediatrics

Classification by malignancy

Malignancy

Genomic information

NO

Narrative objectives1

To introduce a new risk-stratification system using MLL-gene status of leukemic cells, age, and central nervous system (CNS) involvement at diagnosis, and evaluate the efficacy and safety of risk-directed therapy for infants with ALL. Objectives of each subgroup are as follows:
1. Low Risk (LR): MLL germline (MLL-G)
To describe the outcome of infants with MLL-G ALL treated with MLL96/98 chemotherapy backbone.
2. Intermediate Risk (IR): MLL-rearranged (MLL-R) AND age 180 days or older AND no CNS disease
To evaluate the efficacy and safety of intensive combination chemotherapy without hematopoietic stem cell transplantation (HSCT) in 1st remission.
3. High Risk (HR): MLL-R either with age <180 days OR with CNS disease
To evaluate the efficacy and safety of intensive combination chemotherapy followed by HSCT in 1st remission.

Basic objectives2

Others

Basic objectives -Others

In this study, infants with ALL who are not eligible to be treated according to the protocol are registered so that any selection bias can be determined.

Trial characteristics_1

Confirmatory

Trial characteristics_2

Developmental phase

Phase II

Primary outcomes

3-year event-free survival (EFS) of infants with MLL-R ALL

Key secondary outcomes

1. Complete remission (CR) rate, and bone marrow response after the 1st induciton course.
2. 1-, 3-, and 5-year EFS and overall survival (OS)
3. Feasibility of the protocol therapy for IR/HR patients, and rate of HSCT recieved for HR patients
4. To evaluate relations between Busulphan pharamacokinetics and transplant-related toxicities.
5. To evaluate toxicities with CTCAE ver.3.0
6. Three- or 5-year EFS and OS for all registered patients.
*Prognostic factors including MLL status, risk groups, predonisolone response, minimal residual disease (MRD), CR rate, age, WBC, translocation partners in MLL-R group, immunophenotype will be evaluated

Study type

Interventional

Basic design

Single arm

Randomization

Non-randomized

Randomization unit

Blinding

Open -no one is blinded

Control

Uncontrolled

Stratification

YES

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

1

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

Combination chemotherapy.
Allogeneic hematopoietic stem cell transplantation for High Risk patients.

Interventions/Control_2

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

Not applicable

Age-upper limit

1

years-old

>

Gender

Male and Female

Key inclusion criteria

Patients should meet all the criteria listed below:
1. Patients must be newly diagnosed with acute lymphoblastic leukemia (ALL), acute mixed lineage leukemia (AMLL), acute undifferentiated leukemia (AUL), acute bilineal leukemia, provided the morphology and immunophenotype are predominately lymphoid and non T-lineage. Patients with Mature B-cell ALL, T-ALL, the presence of t(9;22)(q34;q11), t(8;14)(q24;q32), t(2;8)(p13;q24), and t(8;22)(q24;q11), Down syndrome, AMLL with T-ALL criteria, or acute myeloid leukemia (AML) are NOT eligible.
2. Patients must be less than 1 year old at the time of diagnosis.
3. All patients and/or their parents or legal guardians must sign a written informed consent.

Key exclusion criteria

Patients should be excluded if either of the below criteria is met:
1. Neonates younger than 30 days AND less than 36 weeks gestational age at the time of diagnosis.
2. Patients whose performance status (PS) score is 4.
3. Patients with organ dysfunction that is inappropriate for the protocol therapy:
3-1. uncontrollable heart failure
3-2. uncontrollable renal failure
3-3. respiratory disease requiring mechanichal ventilation
3-4. severe CNS hemorrhage
4. Patients with uncontrollable infection.
5. Patients with congenital disease or complications that is inappropriate for the protocol therapy.
6. Patients with other malignant disease.
7. Patients with prior history of chemotherapy, radiation therapy, using systemic steroids within 1 week.
8. Patients without signed informed consent legal guardians.
9. Patients whose local physician decided not eligible for the study entry.

Target sample size

55

Name of lead principal investigator

1st name	Daisuke
Middle name
Last name	Tomizawa

Organization

National Center for Child Health and Development

Division name

Division of Leukemia and Lymphoma, Children's Cancer Center

Zip code

1138519

Address

2-10-1 Okura, Setagaya-ku, Tokyo

TEL

03-3416-0181

Email

tomizawa-d@ncchd.go.jp

Name of contact person

1st name	Daisuke
Middle name
Last name	Tomizawa

Organization

National Center for Child Health and Development

Division name

Division of Leukemia and Lymphoma, Children's Cancer Center

Zip code

1138519

Address

2-10-1 Okura, Setagaya-ku, Tokyo

TEL

03-3416-0181

Homepage URL

Email

tomizawa-d@ncchd.go.jp

Institute

Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)

Institute

Department

Personal name

Organization

Grant-in aid for cancer research and a grant for clinical cancer research from the Ministry of Health, Labor and Welfare, Japan

Organization

Division

Category of Funding Organization

Japanese Governmental office

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

IRB of the National Center for Child Health and Development

Address

2-10-1 Okura, Setagaya-ku, Tokyo

Tel

03-3416-0181

Email

rinken@ncchd.go.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Date of disclosure of the study information

2011

Year

01

Month

01

Day

URL releasing protocol

http://jplsg.jp/

Publication of results

Published

URL related to results and publications

https://ashpublications.org/blood/article/136/16/1813/461277/A-risk-stratified-therapy-for-infants-w

Number of participants that the trial has enrolled

90

Results

1) Primary Endpoint
3-year EFS of the patients with MLL-rearranged ALL (n=75) 66.2% (SE, 5.6%)

2) Secondary endpoints (key results only)
3-year EFS and OS rates
･All (n=90): EFS 70.9% (4.9%), OS 86.6% (3.6%)

･MLL status:
germline (n=15) EFS 93.3% (6.4%), OS 100%
rearranged (n=75) EFS 66.2% (5.6%), OS 83.9% (4.3%)

･Risk groups:
low (n=15) EFS 93.3% (6.4%), OS 100%
intermediate (n=19) EFS 94.4% (5.4%), OS 94.7% (5.1%)
high (n=56) EFS 56.6% (6.8%), OS 80.2% (5.4%)

Results date posted

2021

Year

09

Month

02

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

2020

Year

10

Month

15

Day

Baseline Characteristics

Refer to the publication (Tomizawa D. 2020 Oct 15;136(16):1813-1823. doi: 10.1182/blood.2019004741).

Participant flow

Refer to the publication (Tomizawa D. 2020 Oct 15;136(16):1813-1823. doi: 10.1182/blood.2019004741).

Adverse events

Refer to the publication (Tomizawa D. 2020 Oct 15;136(16):1813-1823. doi: 10.1182/blood.2019004741).

Outcome measures

The primary end point of the study was 3-year EFS rate for patients with MLL-r ALL.
The secondary end points regarding efficacy were CR rate, bone marrow status at the end of initial induction, and EFS and overall survival (OS) rates in the total study cohort and among subgroups.
The secondary end points regarding toxicity were grade 3 or greater adverse events, feasibility of regimen B for IR or HR patients, and correlation between busulfan pharmacokinetics and HSCT-related adverse events for HR patients.

Plan to share IPD

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2010

Year

10

Month

19

Day

Date of IRB

2010

Year

12

Month

24

Day

Anticipated trial start date

2011

Year

01

Month

01

Day

Last follow-up date

2018

Year

12

Month

24

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

Registered date

2010

Year

12

Month

27

Day

Last modified on

2021

Year

09

Month

02

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000005714