Allogeneic Stem Cell Transplantation in Relapsed/Refractory T-, NK/T-cell Lymphomas

Study Overview
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Brief Summary
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Relapsed and refractory T-cell lymphomas have been reported to have dismal outcomes. The role of allogeneic stem cell transplantation have been demonstrated in these patients. This clinical trial is studying the efficacy and safety of busulfan plus fludarabine as conditioning therapy followed by allogeneic stem cell transplantation (Allo-SCT) in T- and NK/T-cell lymphoma patients who have relapsed or are refractory to previous chemotherapies including autologous transplantation.

Detailed Description
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Conditioning therapy Busulfan (Busulfex®; Patheon Manufacturing Services LLC, Greenville, NC 27834) 3.2 mg/kg + 5% DW (the diluent quantity should be 10 times the volume of Busulfan, so that the final concentration of busulfan becomes approximately 0.5 mg/mL), intravenously for 3 hours once daily for 3 days (days -7 to -5) Fludarabine (Fludarabine®, Zydus Hospira Oncology Private Ltd., Ahmedabad, India) 30 mg/m2 + 5% DW 100㎖, intravenously for over 1 hour once daily for 6 days (days -8 to -3) Busulfan should be infused as soon as completion of fludarabine infusion Primary objective of this study I. To determine the 2-year progression-free survival of this reduced toxicity conditioning in relapsed or refractory T- and NK/T-cell non-hodgkin lymphoma patients. Secondary endpoints I. To evaluate the response rate, engraftment rate and time to engraftment, 2-year overall survival, 100-days treatment-related mortality, regimen-related toxicities by CTCAE version 4.03, post-transplantation complications (HVOD, acute/chronic graft-versus-host disease (GVHD), cytomegalovirus (CMV) infection,CMV disease) of this reduced toxicity conditioning in relapsed or refractory T- and NK/T-cell non-hodgkin lymphoma patients.

Official Title
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Allogeneic Stem Cell Transplantation With 3-days Busulfan Plus Fludarabine as Conditioning in Patients With Relapsed or Refractory T-, NK/T-cell Lymphomas

Conditions
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T-cell Non-Hodgkin Lymphoma, Lymphoma, Extranodal NK-T-Cell

Intervention / Treatment
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* Drug: Busulfan
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 19 - 65 Histologically confirmed T or NK cell lymphomas : anaplastic large cell lymphoma angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, NOS NK/T-cell lymphoma Relapsed after or refractory to one or more of previous chemotherapy including frontline autologous HSCT. At least one measured lesion using conventional CT or PET CT at the time of relapse after or refractory to one or more of previous chemotherapy and before salvage chemotherapy Complete or Partial response after short cycles of salvage chemotherapy Patients who have HLA full-match (8/8 in HLA-A, B, C, DR by DNA high-resolution technique) or one-locus mismatch (7/8) sibling, or unrelated bone marrow or peripheral blood or cord blood stem cell donors ECOG performance status ≤ 2 Charlson Comorbidity Index (CCI) before HSCT ≤ 3 Adequate renal function : serum creatinine level < 2.0 mg/dL Adequate liver function : Transaminase (AST/ALT) < 3 X upper normal value (or < 5 x ULN in the presence of lymphoma involvement of the liver) Total bilirubin < 2 X upper normal value (or < 5 x ULN in the presence of NK/T involvement of the liver) Cardiac ejection fraction ≥ 50 % as measured by MUGA or 2D ECHO without clinically significant abnormality No clinically significant infection No clinically significant bleeding symptoms or sign Patients who decided to participate in this study and signed for a written consent Exclusion Criteria: Adult T cell leukemia/lymphoma, Lymphoblastic lymphoma, Primary cutaneous CD30+ T cell disorders Mycosis fungoides, Sezary SD Patients who have previously performed Allo-HSCT T cell lymphoma with primary central nervous system (CNS) Involvement. ** However, patients who have only had prophylactic intrathecal or intravenous chemotherapy against CNS disease are eligible. Patients with a known history of HIV seropositivity or HCV (+). ** Patients with HBV are eligible. However, primary prophylaxis using antiviral agents is recommended for HBV carrier or prevent HBV reactivation during whole treatment period. Any other malignancies within the past 5 years ** Except curatively treated non-melanoma skin cancer or in situ carcinoma of cervix uteri Ejection fraction < 50% by a echocardiography FEV1 <60% or DLCO <60% by a pulmonary function test ECOG performance status 3 or 4 Combined serious medical problem or disease Serious or unstable heart disease although proper treatment Myocardial infarction in recent 3 months Underlying serious neurologic or psychiatric disease including dementia or seizure Active uncontrolled infection including hepatitis B and C Serious other medical problems observed by the doctors in charge of the patient Pregnant or lactating women, women of childbearing potential not employing adequate contraception

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Experimental Arm<br>Conditioning chemotherapy: Fludarabine and Busulfan followed by Allogeneic stem cell transplantation | Drug: Busulfan<br>* intravenous, 3.2 mg/kg + 5% DW (the diluent quantity should be 10 times the volume of Busulfan, so that the final concentration of busulfan becomes approximately 0.5 mg/mL), once daily for 3 hours for 3 days (days -7 to -5)<br>* Other names: Busulfex;Drug: Fludarabine<br>* intravenous, 30 mg/m2 + 5% DW 100㎖, over 1 hour once daily for 6 days (days -8 to -3)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year progression-free survival | 2 year progression-free survival rate from the date of allogeneic stem cell transplantation. Estimated using the Kaplan-Meier method. Median value will be provided. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | Response will be measured after 3 months of the date of allogeneic stem cell transplantation. Mean value will be provided. | 3-months | 
| Time to neutrophil engraftment | Summarized using standard descriptive statistics along with corresponding 95% confidence intervals. | Day 30 | 
| Time to platelet engraftment | Summarized using standard descriptive statistics along with corresponding 95% confidence intervals. | Day 30 | 
| 2-year overall survival | 2 year overall survival rate from the date of allogeneic stem cell transplantation. Estimated using the Kaplan-Meier method. Median value will be provided. | 2 years | 
| 100-days treatment-related mortality | Summarized using standard descriptive statistics. | Days 100 | 
| Rate of regimen-related toxicities | Toxicity according to CTCAE version 4.03. Summarized using standard descriptive statistics. | Day 30 | 
| Rate of hepatic venoocclusive disease (HVOD) | Summarized using standard descriptive statistics. | Day 30 | 
| Acute graft-versus-host disease (GVHD) grades I-IV | Summarized using standard descriptive statistics. | Day 100 | 
| Chronic GVHD grades I-IV | Summarized using standard descriptive statistics. | 2 year | 
| Rate of cytomegalovirus (CMV) infection | Summarized using standard descriptive statistics. | 2 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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T-cell Non-Hodgkin Lymphoma, NK/T-cell Non-Hodgkin Lymphoma, Relapsed, refractory, Conditioning, Allogeneic stem cell transplantation