CCCG Relapsed Acute Lymphoblastic Leukemia 2017 Study in Children

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. 1. 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) 2. 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.

Sex

All

Minimum age

3 Months

Maximum age

21 Years

Inclusion Criteria:

1. 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.
2. 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:

1. Mature B ALL,
2. Poor Karnosky score

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