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Chemotherapy Followed by Allogeneic Stem Cell Transplantation for Hematologic Malignancies

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ClinicalTrials.gov Identifier: NCT00741455
Recruitment Status : Active, not recruiting
First Posted : August 26, 2008
Last Update Posted : March 26, 2018
Sponsor:
Information provided by (Responsible Party):
John M. Hill, Jr., MD, Dartmouth-Hitchcock Medical Center

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.

Condition or disease Intervention/treatment Phase
Hematologic Malignancies Procedure: Stem Cell Transplant Drug: G-CSF Drug: Fludarabine Drug: cyclophosphamide Drug: Cyclosporine Drug: Methotrexate Not Applicable

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 22 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Non-Myeloablative Chemotherapy Followed by HLA-Matched Related Allogeneic Stem Cell Transplantation for Hematologic Malignancies
Study Start Date : June 2004
Estimated Primary Completion Date : January 2023
Estimated Study Completion Date : December 2023


Arm Intervention/treatment
Experimental: 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
Procedure: 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.

Other Name: HLA-Matched Related Allogeneic Stem Cell Transplantation
Drug: G-CSF
10 mcg/kg/day on days 5, 6, and 7
Drug: Fludarabine
25 mg/m2/d IV over 30 minutes on days -6 to -2
Drug: cyclophosphamide
1 g/m2/d IV on days -3 and -2
Drug: Cyclosporine
used for GvHD prophylaxis with target CSA levels of 200-400 ng/ml
Drug: Methotrexate
used for GvHD prophylaxis with target CSA levels of 200-400 ng/ml



Primary Outcome Measures :
  1. Bone marrow engraftment [ Time Frame: Within 30 days of bone marrow transplant ]
    Rates of successful engraftment.


Secondary Outcome Measures :
  1. Donor chimerism [ Time Frame: Post-transplant days +30, +60, +100, +180 and +365 ]
    Complete donor chimerism

  2. Graft-versus-host disease [ Time Frame: Post-transplant procedure through death ]
    Collect the number of incidents of acute and chronic graft-versus-host disease

  3. Overall survival [ Time Frame: Post-transplant procedure through death ]
    Mortality rates in subjects after successful completion of a bone marrow transplant

  4. Collection of adverse events [ Time Frame: Until the 6th Bone Marrow Transplant performed in subjects on study ]
    Determine the level of toxicity experienced by subjects who receive protocol treatment and bone marrow transplant

  5. Assess disease response [ Time Frame: Post-transplant procedure through death ]
    Review and assess the tumor response rate



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00741455


Locations
United States, New Hampshire
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire, United States, 03756
Sponsors and Collaborators
Dartmouth-Hitchcock Medical Center
Investigators
Principal Investigator: John M Hill, MD Dartmouth-Hitchcock Medical Center
Principal Investigator: Kenneth R Meehan, MD Dartmouth-Hitchcock Medical Center

Responsible Party: John M. Hill, Jr., MD, Director, Allogeneic Bone Marrow Transplant Program, Dartmouth-Hitchcock Medical Center
ClinicalTrials.gov Identifier: NCT00741455     History of Changes
Other Study ID Numbers: D0345
First Posted: August 26, 2008    Key Record Dates
Last Update Posted: March 26, 2018
Last Verified: March 2018

Keywords provided by John M. Hill, Jr., MD, Dartmouth-Hitchcock Medical Center:
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

Additional relevant MeSH terms:
Neoplasms
Cyclophosphamide
Methotrexate
Fludarabine phosphate
Cyclosporins
Cyclosporine
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors
Antifungal Agents
Anti-Infective Agents
Calcineurin Inhibitors