CCCG Relapsed Acute Lymphoblastic Leukemia 2017 Study in Children
Condition: Acute Lymphoblastic Leukemia, in Relapse
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Study type: Interventional
Phase: Phase 2

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.

        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.
    

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.
    

Intervention name(s): Bortezomib Injection; rituximab injection
Intervention type(s): Drug; Drug
Intervention description(s): 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;; 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)
Other intervention name(s): Velcade; Mab Thera
Intervention MeSH terms: Rituximab; Bortezomib
Intervention model: Single Group Assignment
Intervention model description: Prospective and Non-randomized controlled trial
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Relapsed ALL