Donor-specific Allogeneic Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia (ALL)

Study Overview
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Brief Summary
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[Study Objectives] To evaluate the efficacy of allogeneic hematopoietic cell transplantation (HCT) in patients with acute lymphoblastic leukemia (ALL) in the first or second complete remission (CR). The efficacy of the treatment will be measured in terms of the frequency of relapse and duration of remission (the primary endpoints). The secondary end points of the study include; engraftment, donor chimerism, secondary graft failure, acute and chronic graft-versus-host disease (GVHD), immune recovery, infections, transplantation-related mortality, leukemia free survival, and overall survival.

Detailed Description
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1.0 STUDY OBJECTIVES 1.1. To evaluate the efficacy of allogeneic hematopoietic cell transplantation (HCT) in patients with acute lymphoblastic leukemia (ALL) either who have achieved complete remission (CR) after induction chemotherapy or who experienced recurrent leukemia then achieved second CR after salvage chemotherapy. The efficacy of the treatment will be measured in terms of the frequency of relapse after HCT and the duration of remission (the primary endpoints). 1.2. The secondary end points of the study include; engraftment (absolute neutrophil count over 500/㎕, unsupported platelet count over 20,000/㎕), donor chimerism at 2 and 4 weeks after HCT, secondary graft failure, acute and chronic graft-versus-host disease (GVHD), lymphocyte subset recovery at 1, 2, 3, 6, and 12 months, cytomegalovirus (CMV) reactivation/CMV disease, Epstein-Barr virus (EBV) reactivation/post-transplant lymphoproliferative disorder, transplantation-related mortality (100 day, 1 year), leukemia free survival, and overall survival. 1. 3. The hematopoietic cell donors in the study will include; HLA-matched sibling donors, HLA-matched unrelated donors, and HLA-mismatched family members, so that the majority of patients who achieve CR after induction or salvage chemotherapy will undergo allogeneic HCT as a part of consolidation therapy. 2.0 BACKGROUND INFORMATION 2.1. ALL is a malignant disorder characterized by the rapid proliferation of immature lymphocytes, which results in the accumulation and infiltration of neoplastic lymphocytes in the blood/bone marrow and other tissues. Allogeneic HCT is a curative therapeutic modality for a significant proportion of patients with ALL. Allogeneic HCT from HLA-matched sibling donors can produced long-term leukemia free survival in patients with ALL in high-risk first CR or second CR.(1) In adults with standard-risk ALL, the greatest benefit is achieved from a matched sibling allogeneic transplantation when compared to autologous transplantation or consolidation/maintenance therapy in the first CR status.(2) 2.2. Wider application of allogeneic HCT in patients with ALL, however, is impeded by limited donor availability. Less than a third of patients who need allogeneic HCT will have a HLA-matched sibling who can donate hematopoietic cells. For those patients who do not have an HLA-matched donor in the family, provided that they do not carry rare or private HLA-haplotype, HLA-matched unrelated donor can be found.(3) The chance of finding a willing unrelated donor in Korea is about 50%. On the other hand, nearly all patients who are in the need of allogeneic HCT have at least one HLA-haploidentical familial member, who is most willing to give hematopoietic cells immediately, not only for the initial transplantation, but also for the subsequent additional donations, if those became necessary. Early attempts to transplant allogeneic hematopoietic cells across the barriers of HLA-haplotype difference was met with high frequencies of engraftment failure and severe graft-versus-host disease (GVHD).(4, 5) Depletion of donor T cells from the graft before HCT decreased the frequency and severity of GVHD. However, it resulted in increased graft failure, delayed immune reconstitution, and increased fatal infections.(6-8) Further efforts to improve the outcomes of HLA-mismatched familial donor HCT included use of polyclonal(9, 10) or monoclonal antibodies(11, 12) against T cell as a part of conditioning regimen (in vivo-T cell depletion) and incorporation of the concept of feto-maternal immune tolerance in the donor selection process among several available HLA-haploidentical family members.(13) 2.3. In addition to aforementioned approaches, use of RIC in the setting of HLA-mismatched familial donor HCT has been explored. Various RIC regimens, utilizing total body irradiation (TBI),(14, 15) busulfan,(16, 17) or melphalan,(18) along with fludarabine, have been shown to be effective in achieving successful engraftment with less transplantation-related mortality (TRM), especially in elderly patients and in patients with organ dysfunctions, in the setting of HLA-matched donor HCT. These findings showed that under adequate immunosuppression, but not necessarily myeloablation, of the patients, donor hematopoietic cells can engraft and complete donor hematopoietic chimerism can be achieved. There are data that suggest the same principle may be extended to HLA-mismatched HCT settings as well. Successful engraftment of allogeneic hematopoietic cells across HLA-haplotype difference has been well-documented after RIC in animal models,(19-21) and in infants with severe combined immunodeficiency syndrome.(22, 23) In adult patient with hematologic malignancies, several studies involving small number of patients showed feasibility of successful engraftment of hematopoietic cell graft from HLA-haploidentical familial donor after RIC.(24-27) 2.4. Data generated in our hospital enhance the evidence of feasibility of hematopoietic engraftment across the HLA-haplotype barrier in adult patients after RIC.(28) Between April 2004 and February 2008, 31 patients (including 21 patients with acute leukemia) underwent HLA-haploidentical HCT after RIC of busulfan, fludarabine, and ATG and all 28 evaluable patients achieved engraftment with absolute lymphocyte count (ANC) over 500/㎕ on median day 16.5. As early as 2 weeks after HCT, 22 of 24 evaluated patients showed complete donor chimerism of 95% or over. None of the patients in the study experienced secondary graft failure. While achieving consistent and durable donor cell engraftment, the cumulative incidences of grades 2-4 acute and chronic GVHD were 19%, and 20%, respectively. 2.5. Between May 2008 and May 2009, 31 additional patients with acute leukemia were treated with HLA-mismatched HCT using the same treatment strategy as in the aforementioned study. As such, the data of 52 patients are now available. There were 24 male and 28 female with median age of 39.5 years (range, 16-70). Thirty-seven patients had AML, 13 ALL, and 2 acute mixed lineage leukemia. Ten patients were in first CR status, 15 in second or third CR status, and 27 had refractory disease. The donors were either offsprings (n=23), mothers (n=16), or siblings (n=13) of the patients and their median age was 37 years (range, 3-68). The conditioning regimen for HCT included busulfan in reduced-dose, fludarabine, and antithymocyte globulin. GVHD prophylaxis was given with cyclosporine and methotrexate. Other than 4 patients who experienced leukemia progression within 30 days of HCT or died early, all the rest 48 patients achieved donor cell engraftment with absolute neutrophil count (ANC) >500/㎕ on median 14.5 days (range, 10-27). One patient experienced secondary graft failure subsequently. Cumulative incidence rates for acute GVHD grade 2-4 and chronic GVHD were 10% (95% CI, 4%-23%) and 33% (95% CI, 22%-51%), respectively. Cumulative incidence rates of leukemia progression/recurrence were 13%, 41%, and 77% for patients in CR1, CR2-3, and refractory leukemia at the time of HCT. In all, five patients in the series died without leukemia progression/recurrence giving transplantation-related mortality (TRM) rate of 12% (95% CI, 5%-29%). Kaplan-Meier event-free survival and overall survival rates were 44% and 50% for patients in CR1 at HCT, 40% and 23% for patients in CR2-3, and 10% and 15% for patients with refractory leukemia. These results showed that HCT from an HLA-mismatched family member can be performed in patients with acute leukemia successfully without increased GVHD or TRM. 2.6. In our current prospective study, we try to integrate HLA-mismatched HCT in overall care of patients with ALL in the first or second CR. In the past, those patients without an HLA-matched donor in the family or unrelated donor registry were not offered allogeneic HCT. The outcomes of HCT will be analyzed according to several clinical variables such as patient, disease, and donor characteristics.

Official Title
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Allogeneic Hematopoietic Cell Transplantation for Patients With Acute Lymphoblastic Leukemia in Remission Using HLA-matched Sibling Donors, HLA-matched Unrelated Donors, or HLA-mismatched Familial Donors-A Phase 2 Study

Conditions
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Acute Lymphoid Leukemia

Intervention / Treatment
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* Procedure: alloHCT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with ALL who achieve CR after induction chemotherapy. Patients with recurrent ALL that went into second CR after salvage chemotherapy, except those who had undergone allogeneic HCT previously. Patients should be 15 years of age or more, and 75 years of age or less. The performance status of the patients should be 70 or over by Karnofsky performance scale. Patients should have adequate hepatic function (bilirubin less than 2.0 mg/dl, AST less than three times the upper normal limit). Patients must have adequate renal function (creatinine less than 2.0 mg/dl). Patients must have adequate cardiac function (ejection fraction > 40% on MUGA scan). Patients must sign informed consent. Exclusion Criteria: Presence of significant active infection Presence of uncontrolled bleeding Any coexisting major illness or organ failure Patients with psychiatric disorder or mental deficiency severe as to make compliance with the treatment unlike, and making informed consent impossible Nursing women, pregnant women, women of childbearing potential who do not want adequate contraception Patients with a diagnosis of prior malignancy unless disease-free for at least 5 years following therapy with curative intent (except curatively treated nonmelanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia)

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: alloHCT<br>alloHCT arm: For HLA-matched sibling HCT, if a patient is 55 years old or less and without co-morbidity, the patient will receive Bu-Cy conditioning therapy and be transplanted with bone marrow cells. Patients who are older than 55 years or with co-morbidity will receive Bu-Flu-ATG conditioning and be transplanted with mobilized peripheral blood hematopoietic cells. For HLA-matched unrelated donor or HLA-mismatched familial donor HCT, the patient will receive Bu-Flu-ATG conditioning and well be transplanted with mobilized peripheral blood hematopoietic cells. | Procedure: alloHCT<br>* [ alloHCT arm ] Bu-Cy conditioning; Busulfan (Bu) 3.2 mg/kg*/day iv daily on days -7 and -4. Cyclophosphamide (Cy) 60 mg/kg* in D5W 200 mL iv over 1-2 hours daily on days -3 and -2. BuFluATG conditioning; Bu 3.2 mg/kg*/day iv daily on days -7 and -6. Fludarabine (Flu) 30 mg/m2/day in D5W 100 ml iv over 30 minutes starting at 4 pm daily on days -7, -6, -5, -4, -3, and -2. Anti-thymocyte globulin (ATG, Thymoglobulin, Genzyme Transplant, Cambridge, MA, USA) 1.5 mg/kg/day (for HLA-matched sibling HCT) or 3.0 mg/kg/day (for HLA-matched unrelated donor HCT or HLA-mismatched familial donor HCT) in N/S 500-800 ml (less than 4 mg/ml) iv over 4 hours starting at 8 am daily on days , -3, -2 and -1.<br>* Other names: allogeneic hematopoietic stem cell transplantation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of relapse |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| leukemia free survival |  | 3 years | 
| engraftment rate |  | 100 days | 
| donor chimerism |  | 1year, 2year, 3year | 
| secondary graft failure rate |  | 100days, 1year | 
| Incidence & severity of acute GVHD |  | 100 days | 
| incidence and severity of chronic GVHD |  | 1year, 2year, 3year | 
| degree of immune recovery |  | 6 months, 1year | 
| cumulative incidence and severity of infection |  | 3years | 
| transplantation-related mortality rate |  | 3 years | 
| overall survival rate & median survival time |  | 3 years | 
| duration of remission |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute lymphoid leukemia, primary complete remission, secondary complete remission, postremission therapy, allogeneic hematopoietic cell transplantation