Chemotherapy Followed by Allogeneic Stem Cell Transplantation for Hematologic Malignancies

NCT ID: NCT00741455

Last Updated: 2020-11-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2004-06-30
• Study Completion Date: 2020-05-01

Brief Summary

The purpose of this study is to determine disease-free survival, overall survival, time to progression, regimen-related toxicity and/or treatment-related mortality in patients with hematologic malignancies treated with non-myeloablative chemotherapy followed by allogeneic stem cell transplant.

Detailed Description

Allogeneic bone marrow transplantation (BMT) became feasible in the 1960s after elucidation of the Human Leukocyte Antigen (HLA) complex. Since then, the therapy has evolved into an effective treatment for many hematologic disorders. Otherwise incurable malignancies are frequently cured by this approach, with the likelihood of cure ranging from 10% to 85%, depending on the disease and the disease status. The treatment strategy incorporates very large doses of chemotherapy and often radiation to eliminate cancer cells and to immunosuppress the recipient to allow the engraftment of donor cells. Donor cells give rise to hematopoiesis within two to three weeks, rescuing the patient from the effects of high dose therapy. In the ideal situation, immune recovery and recipient-specific tolerance occurs over the following 6-18 months, and the patient is cured of their underlying malignancy, off immunosuppression, with a functionally intact donor-derived immune system. However, complications are common and include fatal organ damage from the effects of high dose chemotherapy, infection, hemorrhage, and, in particular, graft-versus-host disease (GvHD). A realistic estimate of transplant-related mortality in the standard HLA-matched sibling setting is approximately 25%. The risk of treatment-related mortality limits the success and certainly precludes its use in older patients. Thus, new strategies in transplantation are needed.

With the growing understanding that much of the curative potential of allogeneic bone marrow or stem cell transplant (SCT) is from an immune anti-tumor effect of donor cells, known as graft-versus-leukemia (GvL) or graft-versus-tumor (GvT), a new strategy is being employed that shifts the emphasis from high-dose chemo-radiotherapy to donor-derived, immune-mediated anti-tumor therapy. In this approach, patients receive preparative regimens that, while having some anti-tumor activity, are mainly designed to be immunosuppressive enough to allow engraftment of donor stem cells and lymphocytes. Engrafted lymphocytes then mediate a GvL effect; if the GvL effect of the initial transplant is not sufficient, then additional lymphocytes may be infused (achievement of engraftment allows additional lymphocytes to "take" in the recipient without requiring any additional conditioning of the recipient). The lower intensity of the preparative regimen lessens the overall toxicity by minimizing the doses of chemo-radiotherapy. In addition, less intensive preparative regimens may be associated with less GvHD, as much evidence suggests that high-dose therapy contributes to the syndrome of GvHD by causing tissue damage, leading to a cytokine milieu which enhances activation of graft-versus-host (GvH) effector cells. Thus, such an approach may allow the safer use of allogeneic transplants in standard populations and may allow extension of allogeneic transplantation to patients who could not receive standard (myeloablative) transplants because of age or co-morbidities. This protocol investigates a non-myeloablative transplant approach, using fludarabine and cyclophosphamide, to allow engraftment of allogeneic cells, which may then mediate anti-tumor effects.

Conditions

Hematologic Malignancies

Keywords

Non-myeloablative transplant; Chronic Myelogenous Leukemia; Acute Myelogenous Leukemia; Acute Lymphoblastic Leukemia; Multiple Myeloma; Non-Hodgkin's Lymphoma; Myelodysplastic syndrome; Chronic Lymphocytic Leukemia; Hodgkin's Disease

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Study Treatment

Chemotherapy, stem cell transplantation, HLA-Matched related allogeneic stem cell transplantation, leukapheresis, G-CSF, peripheral blood stem cell transplant, fludarabine, cyclophosphamide, donor lymphocyte infusion, cyclosporine, methotrexate

Group Type: EXPERIMENTAL

Stem Cell Transplant

Intervention Type: PROCEDURE

Donor: Prior to mobilization, leukapheresis to collect CD3+ cells. The donor will then receive G-CSF (10 mcg/kg/day) with leukapheresis collection of peripheral blood stem cells on days 5, 6 and 7 as needed. Goal of leukapheresis will be > 5 x 106 CD34+cells/kg of recipient.

Patient: Peripheral Blood Stem Cell (PBSC) Transplant. Fludarabine 25mg/m2/d IV over 30 minutes on days -6 to -2, followed by cyclophosphamide 1g/m2/d IV on days -3 and -2. This will be followed by allogeneic stem cell infusion 48 hours later.

Donor Lymphocyte Infusion (DLI) and Adjustment of Immunosuppression: Cyclosporine (CSA) and methotrexate (MTX) will be used for GvHD prophylaxis with target CSA levels of 200-400 ng/ml.

G-CSF

Intervention Type: DRUG

10 mcg/kg/day on days 5, 6, and 7

Fludarabine

Intervention Type: DRUG

25 mg/m2/d IV over 30 minutes on days -6 to -2

cyclophosphamide

Intervention Type: DRUG

1 g/m2/d IV on days -3 and -2

Cyclosporine

Intervention Type: DRUG

used for GvHD prophylaxis with target CSA levels of 200-400 ng/ml

Methotrexate

Intervention Type: DRUG

used for GvHD prophylaxis with target CSA levels of 200-400 ng/ml

Interventions

Stem Cell Transplant

Donor: Prior to mobilization, leukapheresis to collect CD3+ cells. The donor will then receive G-CSF (10 mcg/kg/day) with leukapheresis collection of peripheral blood stem cells on days 5, 6 and 7 as needed. Goal of leukapheresis will be > 5 x 106 CD34+cells/kg of recipient.

Patient: Peripheral Blood Stem Cell (PBSC) Transplant. Fludarabine 25mg/m2/d IV over 30 minutes on days -6 to -2, followed by cyclophosphamide 1g/m2/d IV on days -3 and -2. This will be followed by allogeneic stem cell infusion 48 hours later.

Donor Lymphocyte Infusion (DLI) and Adjustment of Immunosuppression: Cyclosporine (CSA) and methotrexate (MTX) will be used for GvHD prophylaxis with target CSA levels of 200-400 ng/ml.

Intervention Type: PROCEDURE

G-CSF

10 mcg/kg/day on days 5, 6, and 7

Intervention Type: DRUG

Fludarabine

25 mg/m2/d IV over 30 minutes on days -6 to -2

Intervention Type: DRUG

cyclophosphamide

1 g/m2/d IV on days -3 and -2

Intervention Type: DRUG

Cyclosporine

used for GvHD prophylaxis with target CSA levels of 200-400 ng/ml

Intervention Type: DRUG

Methotrexate

used for GvHD prophylaxis with target CSA levels of 200-400 ng/ml

Intervention Type: DRUG

Other Intervention Names

HLA-Matched Related Allogeneic Stem Cell Transplantation

Eligibility Criteria

Inclusion Criteria

• Age: 18-75 years
• Diseases

1. Chronic myelogenous leukemia (CML)

• First chronic phase or later
• Accelerated phase

2. Acute myelogenous or lymphoblastic leukemia (AML or ALL)

• Second or subsequent remission
• Patients who have failed an autologous PBSC transplant
• First remission with poor risk features, including, but not limited to: For AML- complex chromosome karyotype, abnormalities of chromosome 5 or 7, 12p-, 13+, 8+, t(9;22), t(11;23) For ALL- t(9;22), t(4;11), t(1;19), myeloid antigen coexpression

3. Myelodysplastic syndrome (MDS)

4. Multiple myeloma - high risk myeloma (poor responders, relapse after autologous PBSCT, chromosome 13 abnormalities)

5. Hodgkin's disease

• Primary refractory disease
• Relapsed disease (first relapse or later)
• Patients who have failed an autologous PBSC transplant

6. Non-Hodgkin's lymphoma Low grade (by Working Formulation)

• Relapsed, progressive disease after initial chemotherapy
• Primary refractory disease or failure to respond (>PR) to initial chemotherapy
• Patients who have failed an autologous PBSC transplant Intermediate grade (by Working Formulation)
• Relapsed disease
• Primary refractory disease or failure to respond (>PR) to initial chemo
• Mantle cell lymphoma
• Patients who have failed an autologous PBSC transplant

7. Chronic lymphocytic leukemia (CLL)

• Patients newly diagnosed with poor prognostic factors, including CD38 expression, Chromosome 11 or 17 abn
• T-CLL/PLL
• Relapsed or progressive disease, or refractory after Fludarabine
• Patients who have failed an autologous PBSC transplant
• Donor Availability: Six of six matched HLA A, B and DR identical sibling (or parent or child) or 5/6 related donor with single mismatch at Class I antigen (A or B)
• Karnofsky performance status of >70%
• Serum bilirubin <2x upper limit of normal; transaminases <3x normal (unless due to disease)
• 24 hr urine creatinine clearance of >40 ml/min.
• DLCO >50% predicted
• Left ventricular ejection fraction >35%
• No active infection
• Non-pregnant female
• Signed informed consent
• No major organ dysfunction or psychological problems that preclude compliance and completion of the clinical trial.

Exclusion Criteria

• Major organ dysfunction
• Pregnant or lactating female
• Active infection
• Psychological problems that preclude compliance and completion of the clinical trial
• Any other condition, that in the judgement of the investigator, affects participant safety or overall participation

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Dartmouth-Hitchcock Medical Center

OTHER

Sponsor Role: lead

Responsible Party

John M. Hill, Jr., MD

Director, Allogeneic Bone Marrow Transplant Program

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

John M Hill, MD

Role: PRINCIPAL_INVESTIGATOR

Dartmouth-Hitchcock Medical Center

Kenneth R Meehan, MD

Role: PRINCIPAL_INVESTIGATOR

Dartmouth-Hitchcock Medical Center

Locations

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

D0345

Identifier Type: -

Identifier Source: org_study_id