Reduced Intensity Preparative Regimen Followed by Stem Cell Transplant (FAB)

Reduced-Intensity Preparative Regiment With Fludarabine, Busulfan, And Alemtuzumab (Campath 1H) Followed By Allogeneic Hematopoietic Stem Cell Transplant For Malignant And Non-Malignant Hematological Diseases

Blood disorders such as leukemia or lymphoma or hemoglobinopathies can benefit from receiving an allogeneic (meaning that the cells are from a donor) stem cell transplant. Stem cells are created in the bone marrow. They grow into different types of blood cells that the body needs, including red blood cells, white blood cells, and platelets. In a transplant, the body's stem cells would be killed and then replaced by stem cells from the donor. Usually, patients are given very high doses of chemotherapy (drugs which kill cancer cells) prior to receiving a stem cell transplant. However, patients that are older, have received several prior treatments, or have other organ diseases are at a high risk of getting life-threatening treatment-related side effects from high doses of chemotherapy. Over the past several years, some doctors have begun to use lower doses of chemotherapy for preparing patients for a stem cell transplant.

A condition that can occur after a stem cell transplant from a donor is Graft Versus Host Disease (GVHD). It is a rare but serious disorder that can strike persons whose immune system is suppressed and have received either a blood transfusion or a bone marrow transplant. Symptoms may include skin rash, intestinal problems similar to inflammation of the bowel and liver dysfunction.

This research study uses a combination of lower-dose chemotherapy agents that is slightly different from those that have been used before.

The medicines that will be used in this study are Fludarabine, Busulfan, both chemotherapy medicines, and Campath. Campath is a monoclonal antibody (a type of substance produced in the laboratory that binds to cancer cells). It helps the immune system see the cancer cell as something that needs to be destroyed.

This research study will help us learn if using Fludarabine, Busulfan and Campath prior to an allogeneic stem cell transplant can provide treatment for blood disorders while decreasing the incidence of side effects.

Study Overview

• Status: Terminated
• Conditions: Lymphoproliferative Disorders; Hematologic Diseases; Multiple Myeloma; Acute Lymphoblastic Leukemia; Acute Myelogenous Leukemia; Chronic Myelogenous Leukemia; Plasma Cell Dyscrasia; Myelodysplastic and Myeloproliferative Disorders
• Intervention / Treatment: Drug: Campath; Drug: Busulfan; Drug: Fludarabine; Procedure: Hematopoietic stem cell infusion; Drug: FK-506

Detailed Description

Allogeneic stem cell transplantation with high-dose chemotherapy affords a better chance of cure of malignant and non-malignant hematological diseases compared to autologous transplantation, because of the lack of stem cell contamination and the immune mediated graft vs. leukemia effect. Unfortunately, high-dose chemotherapy and allogeneic stem cell transplantation has a substantial treatment related mortality, that is particularly high in older patients (greater than 50 yrs of age), or in those with co-morbidities such as congestive heart disease and pulmonary disease. Patients who have pre-existing infections or who have had multiple relapses with prior chemotherapy are also at high risk. In all these groups, treatment related mortality may exceed 50%, making them ineligible for high-dose chemotherapy and allogeneic stem cell transplantation.

Recently interest has increased in using less toxic chemotherapy protocols that are termed submyeloablative. The intent is to allow partial engraftment of a donor immune and hemopoietic systems with subsequent progressive replacement of the host's own hemopoiesis and immunity. As the donor immune system becomes established, patients may develop full donor chimerism, without passing through the period of prolonged aplasia associated with conventional conditioning regimens, and with less of the associated toxicity. Preliminary results in high-risk patients have shown treatment related mortality (TRM) of 15-20%, versus 50% expected, with an overall survival rate of 70-80% at 1-2 years post transplant.

As might be anticipated, the major problem with sub-ablative conditioning is that the graft failure rate is increased, with published figures of 5-30% versus 1-5% predicted in fully ablated patients. The incorporation of lymphodepleting antibodies in the preliminary conditioning regimen may allow these rejection rates to be diminished. Moreover, a highly efficient lymphodepleting MAb or MAb combination might be successfully substituted in part or in whole for cytotoxic and immunosuppressive drugs, further increasing the safety and efficacy of the subablative approach to stem cell transplantation. Our own data using the crude polyclonal mixture of antibodies in ATG as a component of pre-transplant conditioning revealed an improvement in engraftment during matched unrelated donor transplantation.The lymphodepleting monoclonal antibody Campath IH has many of the properties desired for this application, and we propose to incorporate it in our conditioning regimen. Since CAMPATH1H persists after infusion, we would expect it to have additional anti-GvHD effector function, further reducing treatment related mortality (TRM).

The following preparative regimen will be delivered to all patients:

1. Busulfan 3.2 mg/kg/day IV daily for 2 days, infused over 3 hours, on Day -5 and Day -4
2. Fludarabine 30mg/m2/day IV daily for 4 days on Day -5 to D -2
3. Campath 10 mg/day IV daily for 3 days on days -6 to D-4.

Because CAMPATH-1H infusions will provide a persisting level of antibody over the transplant period, it will contribute to anti-GvHD activity. Additional Graft vs. host disease prophylaxis will consist of FK506 administered from Day-2.

The stem cells will be infused on day 0.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • The Methodist Hospital
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Diagnosis of myelodysplastic and myeloproliferative disorders, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, multiple myeloma, plasma cell dyscrasia, lymphoproliferative disorders (non-Hodgkin lymphoma, hairy cell leukemia, chronic lymphocytic leukemia, and Hodgkin's disease) and non malignant hematologic diseases considered treatable with an allogeneic transplant including but not limited to bone marrow failure syndrome, hemoglobinopathy and severe immunodeficiency states.
2. Performance status 0-2 on Zubrod scale
3. Ejection fraction > 30%
4. AST/ALT and bilirubin not > 4 times normal
5. FEV1 greater than 1.0 and diffusion capacity > 40%
6. Age birth to 70 years of age

7. Conditions that increase treatment related mortality (need more than one to be eligible):

   • Age > 35 years
   • EF of less than 45%
   • DLCO less than 50% or FEV1 50-75% of predicted value
   • Diabetes mellitus
   • Renal insufficiency, defined by increase in serum creatinine level of 1.5 times ULN or decrease in GFR by 25%
   • Prior recent history of systemic fungal infection
   • 3rd or greater remission of AML or ALL
   • More than 1 year of diagnosis (CML or myeloma patients only)
   • Multiple types of treatment regimens (equal to or more than 3)
   • Prior autologous or allogeneic stem cell transplantation
   • Significant Grade III or IV neurologic or hepatic toxicity as defined by NCI CTC toxicity from previous treatment
   • No matched sibling donor

8. Available healthy donor without any contraindications for donation

   • 5/6 or 6/6 related
   • 5/6 or 6/6 unrelated (molecular typing for DRB1)
9. Patient and/or responsible person able to understand and sign consent
10. For women of childbearing potential, negative pregnancy test

Exclusion Criteria:

1. Pregnant and lactating women or women unwilling to use contraception.
2. HIV positive patient.
3. Uncontrolled intercurrent infection.
4. Refractory AML or ALL.
5. Untreated blast crisis for CML.
6. Uncontrolled high-grade lymphoproliferative disease/lymphoma.
7. Unstable angina and uncompensated congestive heart failure (Zubrod of 3 or greater).
8. Severe chronic pulmonary disease requiring oxygen (Zubrod of 3 or greater).
9. Hemodialysis dependent.
10. Active Hepatitis or cirrhosis with total bilirubin, SGOT, and SGPT greater than 3 x normal.
11. Serum creatinine >2x ULN.
12. Unstable cerebral vascular disease and recent hemorrhagic stroke (less than 6 months).
13. Active CNS disease from hematological disorder.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HLA-identical sibling transplant; Recipients of HLA identical sibling stem cell transplants	Drug: Campath; 10 mg/day IV daily for 3 days on days -6 to D-4. Campath may be omitted from the conditioning regimen for patients with malignant diseases and matched related donor transplants; Other Names: Alemtuzumab; Drug: Busulfan; 3.2 mg/kg/day IV daily for 2 days, infused over 3 hours, on Day -5 and Day -4; Drug: Fludarabine; 30mg/m2/day IV daily for 4 days on Day -5 to D -2; Procedure: Hematopoietic stem cell infusion; Peripheral blood stem cells when possible. Bone marrow cells will be used if peripheral blood cells are insufficient or unavailable.; Drug: FK-506; FK-506 at a dose of 0.03 mg/kd/day will be administered via continuous infusion over 24 hours from 4pm on Day -2 until engraftment or when the patient is able to take PO, then 0.03 mg/kg PO every 12 hours.; Other Names: Tacrolimus
Experimental: Unrelated Matched or Single Antigen Mismatched transplant; Recipients of unrelated matched or single antigen mismatched donor stem cell transplant or single antigen mismatched family donor stem cell transplants	Drug: Campath; 10 mg/day IV daily for 3 days on days -6 to D-4. Campath may be omitted from the conditioning regimen for patients with malignant diseases and matched related donor transplants; Other Names: Alemtuzumab; Drug: Busulfan; 3.2 mg/kg/day IV daily for 2 days, infused over 3 hours, on Day -5 and Day -4; Drug: Fludarabine; 30mg/m2/day IV daily for 4 days on Day -5 to D -2; Procedure: Hematopoietic stem cell infusion; Peripheral blood stem cells when possible. Bone marrow cells will be used if peripheral blood cells are insufficient or unavailable.; Drug: FK-506; FK-506 at a dose of 0.03 mg/kd/day will be administered via continuous infusion over 24 hours from 4pm on Day -2 until engraftment or when the patient is able to take PO, then 0.03 mg/kg PO every 12 hours.; Other Names: Tacrolimus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Successful Donor Engraftment	Each patient will be classified as a success or failure. A success will be defined as engraftment of at least 35% of cells 100 days after transplant.	100 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of Patients With Treatment Related Grade III or IV Non-hematological Toxicity	100 days

Collaborators and Investigators

• Sponsor: Baylor College of Medicine
• Collaborators: The Methodist Hospital Research Institute; Center for Cell and Gene Therapy, Baylor College of Medicine
• Investigators: Principal Investigator: Rammurti T Kamble, MD, Baylor College of Medicine

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (Actual): February 1, 2009
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: December 19, 2007
• First Submitted That Met QC Criteria: December 20, 2007
• First Posted (Estimate): December 21, 2007

Study Record Updates

• Last Update Posted (Estimate): May 4, 2016
• Last Update Submitted That Met QC Criteria: March 29, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: Multiple Myeloma; Acute Lymphoblastic Leukemia; Hematologic Diseases; Fludarabine; Acute Myelogenous Leukemia; Alemtuzumab; Campath; Busulfan; Chronic Myelogenous Leukemia; Lymphoproliferative disorders; allogeneic stem cell transplant; Myelodysplastic and Myeloproliferative Disorders; Plasma Cell dyscrasia
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Blood Protein Disorders; Disease; Multiple Myeloma; Neoplasms, Plasma Cell; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Hematologic Diseases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphoproliferative Disorders; Myeloproliferative Disorders; Paraproteinemias; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Calcineurin Inhibitors; Fludarabine; Tacrolimus; Busulfan; Alemtuzumab
• Other Study ID Numbers: 19386; FAB