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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

Phase 1/Phase 2
70 Years
Not Enrolling
Myelodysplastic and Myeloproliferative Disorders, Acute Myelogenous Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, Multiple Myeloma, Plasma Cell Dyscrasia, Lymphoproliferative Disorders, Hematologic Diseases

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Trial Information

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

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.

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

- 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

11. Serum creatinine >2x ULN.

12. Unstable cerebral vascular disease and recent hemorrhagic stroke (less than 6

13. Active CNS disease from hematological disorder.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of Patients With Successful Donor Engraftment

Outcome Description:

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.

Outcome Time Frame:

100 days

Safety Issue:


Principal Investigator

Rammurti T Kamble, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Baylor College of Medicine


United States: Institutional Review Board

Study ID:




Start Date:

June 2007

Completion Date:

October 2010

Related Keywords:

  • Myelodysplastic and Myeloproliferative Disorders
  • Acute Myelogenous Leukemia
  • Acute Lymphoblastic Leukemia
  • Chronic Myelogenous Leukemia
  • Multiple Myeloma
  • Plasma Cell Dyscrasia
  • Lymphoproliferative Disorders
  • Hematologic Diseases
  • Myelodysplastic and Myeloproliferative Disorders
  • Acute Myelogenous Leukemia
  • Acute Lymphoblastic Leukemia
  • Chronic Myelogenous Leukemia
  • Multiple Myeloma
  • Plasma Cell dyscrasia
  • Lymphoproliferative disorders
  • Hematologic Diseases
  • Fludarabine
  • Busulfan
  • Campath
  • Alemtuzumab
  • allogeneic stem cell transplant
  • Hematologic Diseases
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Lymphoproliferative Disorders
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Myeloproliferative Disorders
  • Paraproteinemias



Texas Children's Hospital Houston, Texas  
The Methodist Hospital Houston, Texas  77030