Intensified Conditioning Regimen With High-Dose-Etoposide for Allo-HSCT for Adult Acute Lymphoblastic Leukemia
Condition: Acute Lymphoblastic Leukemia; Stem Cell Transplantation, Hematopoietic
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Evolving paradigms in the treatment of adult ALL include the application of intense pediatric
      regimens to the treatment of adolescents and young adults (AYA) and the optimization of
      allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the cure of patients. The
      Cancer and Leukemia Group B (CALGB) and the Children's Cancer Group (CCG) first asked whether
      AYA between the ages of 16 and 20 fared differently whether they were treated on pediatric
      protocols. The results of this study demonstrated that although the complete remission rates
      were identical for the AYAs treated on the CALGB and CCG trials, the AYAs had a 63%
      event-free survival (EFS) and 67% OS at 7 years on the CCG trials compared with 34% and 46%,
      respectively, on the CALGB trials.

      High relapse and transplantation-related-mortality still remains great challenge for HSCT of
      adult ALL, which both range between 25% and 30%. Recently, risk-adapted indication and
      optimization of conditioning regimen are highlighted, which aiming to reduce TRM and relapse
      rate, respectively.City of Hope National Medical Center studied the substitution of etoposide
      (VP-16) for CY in the treatment of ALL patients receiving HCT. The result suggested that
      etoposide and TBI are associated with a decreased relapse rate following transplantation for
      ALL, compared with those receiving CY and TBI. Japanese and Germany reports pronounced the
      advantage of VP-16 in intensified regimen for adult ALL. On the same time, the investigators
      previous researches have confirmed the effect and safety of FA-intensified conditioning
      regimen on relapse and refractary leukemia.

      Based on mentioned above, the investigators speculate that VP-16-intensified conditioning
      regimen could improve the outcome for adult ALL. The potential mechanism will be attributed
      to reduce MRD and promote GVL effect via providing enough time-window for
      immuno-reconstitution by high-dose preparative regimen.
    

Detailed description: 
      In the first decade of the new millennium, multiple studies have begun to change our thinking
      about the treatment of adults with acute lymphoblastic leukemia (ALL). In pediatric patients
      cure rates in the range of 80% to 90% are now attainable. While adult patients with ALL now
      have a 90% complete remission (CR) with modern chemotherapy, most patients will relapse, and
      leukemia-free survival with 3 to 7 years of follow-up in large series is only in the range of
      30% to 40%. The poor outcome of chemotherapy in adults with ALL as compared to children
      relates to multiple factors, including poor tolerance of intensive courses of chemotherapy
      and a higher incidence of poor prognostic subtypes of ALL such as Philadelphia
      chromosome-positive ALL and a lower incidence of favorable subtypes such as the t (12; 21).

      Evolving paradigms in the treatment of adult ALL include the application of intense pediatric
      regimens to the treatment of adolescents and young adults (AYA) and the optimization of
      allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the cure of patients. Adult
      regimens are typically less intense than pediatric regimens. The Cancer and Leukemia Group B
      (CALGB) and the Children's Cancer Group (CCG) first asked whether AYA between the ages of 16
      and 20 fared differently whether they were treated on pediatric protocols. The results of
      this study demonstrated that although the complete remission rates were identical for the
      AYAs treated on the CALGB and CCG trials, the AYAs had a 63% event-free survival (EFS) and
      67% OS at 7 years on the CCG trials compared with 34% and 46%, respectively, on the CALGB
      trials. These results have prompted new studies where pediatric ALL regimens have been
      adapted to the treatment of younger adults. With short follow-up, GRAALL-2003 reports suggest
      EFS and OS outcomes in the range of 60%. This improved outcome was more pronounced in the
      standard-risk patients with a donor who had an OS at 5 years of 69%. On the same time, our
      previous researches have confirmed the effect and safety of FA-intensified conditioning
      regimen on relapse and refractary leukemia.

      Based on mentioned above, we speculate that VP-16-intensified conditioning regimen could
      improve the outcome for adult ALL. The potential mechanism will be attributed to reduce MRD
      and promote GVL effect via providing enough time-window for immuno-reconstitution by
      high-dose preparative regimen.
    

Intervention name(s): TBI+CY+VP-16; FA+TBI+CY+VP-16
Intervention type(s): Drug; Drug
Intervention description(s): CR Cohort will receive conditioning regimen of TBI+CY+VP-16: TBI: 4.5Gy/d, -5d, -4d; CY: 60mg/kg/d, -3d, -2d; VP-16: 15mg/kg/d, -3d, -2d; NR Cohort will receive conditioning regimen of FA+TBI+CY+VP-16: Flu: 35mg/m2/d: -10~-6d; AraC: 1g/m2/d, -10d~-6d; TBI: 4.5Gy/d, -5d,-4d; CY:60mg/kg/d, -3d, -2d; VP-16: 15mg/kg, -3d, -2d
Intervention MeSH terms: Etoposide; Etoposide phosphate
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Acute Lymphoblastic leukemia; Hematopoietic Stem Cell Transplantation