Busulfan/Clofarabine + Allogeneic Stem Cell Transplantation

Study Overview
=================
Brief Summary
-----------------
This research is a phase II clinical trial. Phase II clinical trials test the effectiveness of an investigational intervention to learn whether it works in treating a specific cancer. Investigational means that the study intervention is still being studied and that research doctors are trying to find out more about it. It also means that the FDA has not yet approved this study intervention for your type of cancer. All participants on this study are treated in an identical manner. The investigators are doing this study because there continues to be a significant risk of relapse of disease after reduced intensity transplantation. In studies which have compared transplants using high-doses of chemotherapy and/or radiation versus reduced intensity transplants, patients undergoing reduced intensity transplants appear to have higher rates of relapse, but lower rates of toxicity and complication. This study attempts to utilize clofarabine, a newer chemotherapy agent shown to be quite active in AML, ALL, and MDS, to increase the anti-tumor effects of the conditioning regimen without accumulating unacceptable toxicity. The reduced intensity allogeneic stem cell transplantation procedure involves giving you chemotherapy in relatively less intense doses to suppress your immune system. This is followed by an infusion of healthy blood stem cells from a matched related donor or a matched unrelated volunteer donor. It is hoped that these donor cells can eventually then attack any cancer cells which remain. In this research study, the investigators are looking to see how well this new combination of busulfan and clofarabine works in reduced intensity allogeneic stem cell transplantation. By works the investigators mean to analyze safety, ability of donor cells to engraft (take hold), as well as measures of complications including toxicity, infections, graft-vs-host disease (GVHD), and relapse.

Detailed Description
-----------------
You will start the conditioning regimen, which is also called the preparative regimen. Conditioning is done to kill more cancer cells which may remain as well as prepare your body for transplant. You will receive the conditioning drugs into a vein. The conditioning regimen consists of the following drugs: Busulfan and Clofarabine. While you are in the hospital you will have regular physical exams and you will be asked specific questions about any problems that you might be having. You will also have blood tests every day to look at how your bone marrow is recovering, to give possible transfusional support, and how to see how your liver and kidneys are functioning. You will receive the following drugs before and after the allogeneic stem cell transplant: Neupogen (G-CSF) injections, drugs to prevent infections, Tacrolimus to prevent GVHD and Methotrexate. You will have routine and regular follow-up in the transplant clinic after discharge from the hospital. The following will be performed at each visit: Physical exam to monitor your health and check for signs of GVHD, infections and any side effects you may be having; Blood draw for routine blood tests to measure your blood cell count and chemistry; Blood tests to see if the transplanted stem cells are being accepted and are growing in the body (engraftment); Bone marrow biopsy to see the status of the underlying disease (to be done around 100 days after the stem cell transplant). You will be asked to return to the clinic, at a minimum, for follow-up visits at 6 months, 9 months, 12 months, 18 months and 24 months after your stem cell transplant.

Official Title
-----------------
Phase II Study of Reduced Intensity Conditioning With Busulfan/Clofarabine Followed by Allogeneic Stem Cell Transplantation

Conditions
-----------------
Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndrome

Intervention / Treatment
-----------------
* Drug: Busulfan
* Drug: Clofarabine
* Procedure: Allogeneic Stem Cell Infusion


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Must have well-matched adult donor willing to donate peripheral blood stem cells with well-matched defined as 8/8 matched related or unrelated donor Adequate organ functioning Exclusion Criteria: Pregnant or breastfeeding Psychiatric disease severely impairing the compliance of the patient to participate in the study and/or give informed consent Evidence of prior exposure to HIV or HCV

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BuClo RIC + SCT<br>Busulfan and Clofarabine (BuClo) reduced intensity conditioning (RIC) followed by allogeneic stem cell Transplantation (SCT) | Drug: Busulfan<br>* Busulfan as part of reduced intensity conditioning prior to allogeneic stem cell transplantation<br>Drug: Clofarabine<br>* Clofarabine as part of reduced intensity conditioning prior to allogeneic stem cell transplantation<br>Procedure: Allogeneic Stem Cell Infusion<br>* Allogeneic stem cell transplantation after reduced intensity conditioning with busulfan / clofarabine chemotherapy<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Donor Stem Cell Engraftment: ANC Count | Patients are considered to have achieved donor cell engraftment if they have an absolute neutrophil count (ANC) of at least 500 cells/uL of blood for 3 consecutive measurements and at least 75% of hematopoietic elements are donor-derived as determined by chimerism assays from peripheral blood prior to day +40 after Busulfan/Clofarabine (BuClo) reduced intensity allogeneic stem cell transplantation | 1, 2, 3, and 4 weeks after transplantation | 
| Donor Stem Cell Engraftment: Platelet Count | Platelet recovery was defined as having a platelet count of at least 20,000 platelets/uL of blood on 2 consecutive measurements without transfusional support prior to day +100 after BuClo RIC HSCT. | 1, 2, 3, 4, 8, and 14 weeks post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Incidence of Non-relapse Mortality | The percentage of participants that experienced non-relapse mortality (NRM) at day 100 and 1 year after BuClo RIC SCT. Non-relapse mortality is any mortality that is not associated with or proceeded by disease progression of prior cancers. | 100 days, 1 year | 
| Progression-Free and Overall Survival | The 1-year and 2-year progression-free and overall survival measured from the time of stem cell transplantation. Progression is the recurrence or increase in the number of cancer cells found in the body. | 1 year, 2 years | 
| Cumulative Incidence and Severity of Acute GVHD Within 100 Days Post Transplant | The percentage of participants who experienced grades 2-4 and grades 3-4 acute graft-versus-host disease (GVHD) by 100 days post transplantation. GVHD is a condition that can occur following an allogenic stem cell transplantation when the donated bone marrow or peripheral stem cells view the recipients body as foreign and the donated cell/marrow attack the body. Acute GVHD is generally observed within the first 100 days post transplant. Acute GVHD is associated with increased treatment related morbidity and mortality. Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening. The grade of the GVHD is determined by grading GHVD associated adverse events. Associated adverse events were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4 which uses the same mild, moderate, severe, life threatening grading system as the overall GHVD assessment. | 100 days | 
| Cumulative Incidence of Chronic GVHD at One Year | The percentage of participants who experienced chronic Graft Versus Host Disease (GVHD) by one year. GVHD is a condition that can occur following an allogenic stem cell transplantation when the donated bone marrow or peripheral stem cells view the recipients body as foreign and the donated cell/marrow attack the body. Chronic GVHD normally occurs after the first 100 days post transplantation. Chronic GVHD can adversely influence long term survival. | 1 year | 
| Incidence of Hepatic Veno-occlusive Disease | The number of participants that experienced hepatic veno-occlusive disease (VOD). VOD is a condition in which some of the small veins in the liver are obstructed. | 2 years | 
| Grade 3 or 4 Toxicities | The number of participants that experienced the specified grade 3 and 4 non-hematological toxicities during treatment and follow-up as assessed by Common Terminology Criteria for Adverse Events version 4(CTAE v 4.0). Grade 3 toxicity is considered to be severe and grade 4 is considered to be life threatening. | 2 years | 
| Infection-related Complications | The number of patients with infection-related complications | 2 years |