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.

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.

Eligibility Criteria:
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