Busulfan and Cyclophosphamide Followed By ALLO BMT

Study Overview
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Brief Summary
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This is a treatment guideline to allow routine clinical data to be collected and maintained in Oncore (clinical database) and the University of Minnesota Blood and Marrow Database as part of the historical database maintained by the department.

Detailed Description
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This is a single arm trial to evaluate the efficacy of busulfan and cyclophosphamide followed by an allogeneic hematopoietic stem cell transplant (HSCT) in the treatment of hematological malignancies. The intent of this study is to provide a protocol that will use unmanipulated allogeneic hematopoietic stem cells from related and unrelated donors after a common preparative regimen.

Official Title
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Busulfan and Cyclophosphamide Followed By Allogeneic Hematopoietic Cell Transplantation In Patients With Hematological Malignancies

Conditions
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Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: Allopurinol
* Drug: Keppra
* Drug: Busulfan
* Drug: Cyclophosphamide
* Drug: Tacrolimus
* Drug: Mycophenolate mofetil
* Biological: Allogeneic hematopoietic stem cell transplant
* Biological: Filgrastim
* Biological: antithymocyte globulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and current in complete remission meeting one of the following: <45 years of age who are at least 6 months after initial hematopoietic stem cell transplant (HSCT) <45 years of age and have received sufficient radiation treatment to be ineligible for total body irradiation (TBI) containing preparative therapy Karnofsky performance status >70% or if <16 years of age, a Lansky play score >50 Adequate major organ function including: cardiac: left ventricular ejection fraction >45% by echocardiogram (ECHO/MUGA) renal: creatinine clearance >40 mL/min/1.73m^2 hepatic: no clinical evidence of hepatic failure (e.g., coagulopathy, ascites) An acceptable source of stem cells according to current University of Minnesota Bone Marrow Transplant program guidelines. Acceptable stem cell sources include: HLA-matched related or unrelated donor bone marrow (6/6 or 5/6 antigen match) HLA-matched related or unrelated donor peripheral blood stem cells related or single or double unrelated donor umbilical cord blood (6/6, 5/6 or 4/6 match) Women of childbearing age must have a negative pregnancy test and all sexually active participants must agree to use effective contraception during study treatment Written consent (adult or parent/guardian) Exclusion Criteria: eligible for TBI containing preparative regimen active uncontrolled infection within one week of study enrollment pregnant or lactating female

Ages Eligible for Study
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Maximum Age: 44 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: Allogeneic Hematopoietic Stem Cell Transplant<br>Patients treated with Allopurinol, Keppra, Busulfan, Cyclophosphamide, Filgrastim, antithymocyte globulin, Tacrolimus, Mycophenolate mofetil and allogeneic hematopoietic stem cell transplant infusion. | Drug: Allopurinol<br>* Day -8 (prior to transplant): Per institutional guidelines<br>* Other names: Zyloprim;Drug: Keppra<br>* Day -8 (prior to transplant): Per institutional guidelines<br>* Other names: Levetiracetam;Drug: Busulfan<br>* Days -7 through -4 (prior to transplant): given intravenously (IV) infusion over 2 hours every 6 hours following dose, administration and pharmacokinetic monitoring per University of Minnesota institutional guidelines.<br>* Other names: Myleran;Drug: Cyclophosphamide<br>* Days -3 and -2 (prior to transplantation): given as a 2 hour intravenous infusion with a high volume fluid flush and mesna per institutional guidelines. Dosing is based on actual body weight.<br>* Other names: Cytoxan;Drug: Tacrolimus<br>* All patients (regardless of allograft source) will receive tacrolimus therapy beginning on day -3. Dosing will be monitored and altered as clinically appropriate per institutional pharmacy guidelines. Dose adjustments will be made on the basis of toxicity and/or low tacrolimus levels. Taper at day +100 for matched sibling donor (MSD) recipients, and day +180 for non-MSD recipients. Taper to zero by 10% weekly dose reduction over approximately 10 weeks.<br>Drug: Mycophenolate mofetil<br>* Day -3 (prior to transplant): Recipients of umbilical cord blood will given a dose of 3 gm/day every 8 or 12 hours (> or = 40 kg) or 15 mg/kg 3 times per day (< 40 kg) for up to 30 days unless no engraftment.<br>* Other names: MMF;Biological: Allogeneic hematopoietic stem cell transplant<br>* Day 0 (or Day+1/+2 to accommodate weekdays): Infusion of cells from related or unrelated donor bone marrow or single or double unrelated donor umbilical cord blood.<br>Biological: Filgrastim<br>* Beginning Day +1: Intravenously (IV) 5 mcg/kg once daily and continuing until the absolute neutrophil count is >2500 x 10^9/L or per institutional guidelines.<br>* Other names: Granulocyte-colony stimulating factor;Biological: antithymocyte globulin<br>* Administered per institutional guidelines for recipients of umbilical cord blood transplant.<br>* Other names: ATG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Counts of Participants With Disease Free Survival | The length of time after treatment ends that a patient survives without any signs or symptoms of that cancer or any other type of cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works. Patients with leukemia involving the BM and myelodysplastic syndrome will have this assessed by BM biopsy and additional special studies such as cytogenetics or flow cytometry as appropriate. Patients will also have radiology studies such as plain X-rays or CT scans and/or other studies such as blood tumor markers to document presence or absence of disease as clinically indicated. | 2 Years | 
| Count of Participants With Disease Free Survival | The length of time after treatment ends that a patient survives without any signs or symptoms of that cancer or any other type of cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works. Patients with leukemia involving the BM and myelodysplastic syndrome will have this done by BM biopsy and additional special studies such as cytogenetics or flow cytometry as appropriate. Patients will also have radiology studies such as plain X-rays or CT scans and/or other studies such as blood tumor markers to document presence or absence of disease as clinically indicated. | 5 Years | 
| Count of Participants With Disease Free Survival | The length of time after treatment ends that a patient survives without any signs or symptoms of that cancer or any other type of cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works. Patients with leukemia involving the BM and myelodysplastic syndrome will have this done by BM biopsy and additional special studies such as cytogenetics or flow cytometry as appropriate. Patients will also have radiology studies such as plain X-rays or CT scans and/or other studies such as blood tumor markers to document presence or absence of disease as clinically indicated. | 7 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Count of Participants Who Achieved Neutrophil Engraftment | Neutrophil engraftment is defined as the first day of three consecutive days where the neutrophil count (absolute neutrophil count) is 500 cells/mm^3 (0.5 x 10^9/L) or greater. | By Day 42 | 
| Percentage of Participants With Acute Graft-Versus-Host Disease by Grade | Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host. Patients will be staged weekly between days 0 and 100 after transplantation using standard criteria used for staging. Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level. The stages of individual organ involvement are combined to produce an overall grade. Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening. | Day 100 | 
| Percentage of Participants With Chronic Graft-Versus-Host Disease | Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cells into a foreign host. Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level. The stages of individual organ involvement are combined to produce an overall grade. Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening. | 6 Months | 
| Percentage of Participants With Chronic Graft-Versus-Host Disease | Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cells into a foreign host. Patients will be staged weekly between days 0 and 100 after transplantation using standard criteria used for staging. Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level. The stages of individual organ involvement are combined to produce an overall grade. Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening. | 1 Year | 
| Percentage of Participants With Treatment-Related Toxicity | In the field of transplantation, toxicity is high and all deaths without previous relapse or progression are usually considered as related to transplantation. | 6 Months | 
| Percentage of Participants With Treatment-Related Toxicity | In the field of transplantation, toxicity is high and all deaths without previous relapse or progression are usually considered as related to transplantation. | 1 year | 
| Percentage of Participants With Relapse | The return of disease after its apparent recovery/cessation. Patients with leukemia involving the BM and myelodysplastic syndrome will have this assessed by BM biopsy and additional special studies such as cytogenetics or flow cytometry as appropriate. Patients will also have radiology studies such as plain X-rays or CT scans and/or other studies such as blood tumor markers to document presence or absence of disease as clinically indicated. | 1 Year | 
| Percentage of Participants With Relapse | The return of disease after its apparent recovery/cessation. Patients with leukemia involving the BM and myelodysplastic syndrome will have this assessed by BM biopsy and additional special studies such as cytogenetics or flow cytometry as appropriate. Patients will also have radiology studies such as plain X-rays or CT scans and/or other studies such as blood tumor markers to document presence or absence of disease as clinically indicated. | 2 Years | 
| Percentage of Participants With Engraftment Failure | Graft failure is defined as not accepting donated cells. The donated cells do not make the new white blood cells, red blood cells and platelets. | Day 42 | 
| Number of Participant Who Were Alive at 2 Years Post Transplant | Overall survival will be defined as time from date of enrollment to date of death or censored at the date of last documented contact for patients still alive. | 2 Years | 
| Number of Participant Who Were Alive at 5 Years Post Transplant | Overall survival will be defined as time from date of enrollment to date of death or censored at the date of last documented contact for patients still alive. | 5 Years | 
| Number of Participant Who Were Alive at 7 Years Post Transplant | Overall survival will be defined as time from date of enrollment to date of death or censored at the date of last documented contact for patients still alive. | 7 Years |