Alemtuzumab, Busulfan, and Cyclophosphamide Followed By a Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer

A Prospective Trial to Evaluate the Role of In Vivo T Cell Depletion by Campath® (Alemtuzumab) in Reduction of Transplant Related Mortality in Transplantation From HLA-Class I or Class II Mismatched, Unrelated Donors

RATIONALE: Monoclonal antibodies, such as alemtuzumab, can find cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Giving chemotherapy drugs, such as busulfan and cyclophosphamide, before a donor stem cell transplant helps stop the growth of cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving tacrolimus and methotrexate after the transplant may stop this from happening.

PURPOSE: This phase I/II trial is studying the best dose of alemtuzumab when given together with busulfan and cyclophosphamide followed by a donor stem cell transplant and to see how well it works in treating patients with hematologic cancer.

Study Overview

• Status: Terminated
• Conditions: Myelodysplastic Syndromes; Leukemia; Myelodysplastic/Myeloproliferative Diseases; Graft Versus Host Disease
• Intervention / Treatment: Drug: cyclophosphamide; Drug: methotrexate; Procedure: allogeneic hematopoietic stem cell transplantation; Drug: busulfan; Procedure: peripheral blood stem cell transplantation; Biological: alemtuzumab; Drug: tacrolimus

Detailed Description

OBJECTIVES:

Primary

• Identify the lowest dose of alemtuzumab that is associated with day 180 transplant-related mortality ≤ 45%.

Secondary

• Determine the incidence of life-threatening infection in patients receiving this treatment.
• Determine the incidence of grades III-IV acute graft-vs-host disease (GVHD) in patients receiving this treatment.
• Determine the survival at 1 year in patients receiving this treatment.
• Determine the incidence of disease relapse at 1 year in patients receiving this treatment.
• Determine the incidence of extensive chronic GVHD at 1 year in patients receiving this treatment.
• Determine the incidence of graft failure at day 100 in patients receiving this treatment.

OUTLINE:

• Chemotherapy: Patients receive alemtuzumab IV over 2 hours on days -10 to -6, busulfan IV over 3 hours on days -7 to -4, and cyclophosphamide IV on days -3 and -2.
• Peripheral blood stem cell (PBSC) transplantation: Patients undergo allogeneic filgrastim (G-CSF)-mobilized PBSC transplantation on day 0.
• Graft-vs-host disease prophylaxis: Patients receive tacrolimus IV continuously or orally twice daily on days -1 to 50 and methotrexate IV on days 1, 3, 6, and 11.

After completion of study therapy, patients are followed periodically.

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

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109-1023
      • Seattle Cancer Care Alliance
    • Seattle, Washington, United States, 98104-1024
      • Fred Hutchinson Cancer Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 50 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Confirmed diagnosis of one of the following:

  • Primary acute myeloid leukemia (AML) meeting any of the following criteria:

    • First complete remission (CR; defined as < 5% blasts in marrow) with high-risk features as defined by failure to achieve remission by day 21 after induction chemotherapy, or the presence of chromosomal abnormalities involving any of the following:

      • -5/del(5q)
      • -7/del(7q)
      • Inversion 3q
      • Abnormalities of 11q23, 20q, 21q, del(9q),
      • Translocation 6;9
      • Translocation 9;22
      • Abnormalities of 17p
      • Complex karyotype with ≥ 3 abnormalities
    • Second CR or subsequent in remission
    • Refractory or relapsed disease
  • Secondary AML in remission or relapse

  • Chronic myelogenous leukemia (CML) in accelerated or blast phase meeting the following criteria:

    • Accelerated phase is defined by any one of the following:

      • Blasts 10% to 19% of peripheral blood white cells or bone marrow cells
      • Peripheral blood basophils ≥ 20%
      • Persistent thrombocytopenia (< 100,000/mm³) unrelated to therapy, or persistent thrombocytosis (> 1,000,000/mm³) unresponsive to therapy
      • Increasing spleen size and increasing WBC count unresponsive to therapy
      • Cytogenetic evidence of clonal evolution (i.e., the appearance of an additional genetic abnormality that was not present in the initial specimen at the time of diagnosis of chronic phase CML)

    • Blast phase is defined by any of the following:

      • Blasts ≥ 20% of peripheral blood white cells or bone marrow cells
      • Extramedullary blast proliferation
      • Large foci or clusters of blasts in bone marrow biopsy
  • Primary myelodysplastic syndromes (MDS) with an IPSS score > 1.5
  • Secondary MDS with any IPSS score

  • Primary acute lymphoblastic leukemia meeting any of the following criteria:

    • First CR (< 5% blasts in marrow) with high-risk features as defined by 1 of the following:

      • Failure to achieve remission after first induction chemotherapy
      • Presence of chromosomal abnormalities including hypodiploidy or abnormalities of 11q23 or translocation 9;22
    • Second CR or subsequent in remission
    • Refractory or relapsed disease
• No patients for whom a suitable HLA genotypically identical sibling or fully matched HLA-A, -B, -C, and -DRB1 unrelated donor is available
• No active CNS involvement with disease

• Donors must meet the following criteria:

  • Unrelated volunteer donors who are mismatched for more than one HLA-class I alleles or antigens or for one HLA-class I antigen, but matched by high-resolution typing at HLA-DRB1 and -DQB1, OR who are mismatched for one or more HLA-class II alleles or antigens, but matched by high-resolution typing at HLA-A, -B, and -C

    • No two-antigen mismatch at a single HLA-A, -B, or -C locus
    • No mismatching of class I and class II HLA
    • Matching must be based on results of high-resolution typing at HLA-A, -B, -C, - DRB1, and -DQB1

PATIENT CHARACTERISTICS:

• Karnofsky performance status 50-100%
• No symptomatic coronary artery disease or symptomatic congestive heart failure
• No hepatic disease with transaminases or bilirubin > 2 times upper limit of normal except for isolated hyperbilirubinemia attributed to Gilbert's syndrome
• No severe hypoxemia with room air P_AO_2 < 70, supplemental oxygen-dependence, or DLCO < 60% predicted
• No impaired renal function with creatinine > 2 times upper limit of normal or creatinine clearance < 50% normal
• Not HIV seropositive
• Not pregnant or breast-feeding
• Fertile patients must use effective contraception
• No active infections that are untreated or failing to respond to appropriate therapy

PRIOR CONCURRENT THERAPY:

Inclusion criteria:

• See Disease Characteristics

Exclusion criteria:

• Prior allogeneic or autologous bone marrow, peripheral blood stem cell, or umbilical cord blood transplantation using a high-dose total-body irradiation regimen

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Alemtuzumab; Alemtuzumab given together with busulfan and cyclophosphamide followed by a donor stem cell transplant.	Drug: cyclophosphamide; Drug: methotrexate; Procedure: allogeneic hematopoietic stem cell transplantation; Drug: busulfan; Procedure: peripheral blood stem cell transplantation; Biological: alemtuzumab; Drug: tacrolimus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lowest Dose of Alemtuzumab Associated With Transplant-related Mortality	Lowest dose of alemtuzumab associated with transplant-related mortality at day 180	Up to day 180

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Life-threatening Infection		Up to 180 days
Grades III-IV Acute Graft-vs-host Disease (GVHD)		Up to 100 days
Overall Survival	Count of surviving participants at 1 year	Up to 1 year
Disease Relapse	Count of participants with disease relapse at 1 year	Up to 1 year
Extensive Chronic GVHD	Count of participants with extensive chronic GVHD at 1 year	Up to 1 year
Graft Failure	Count of participants with graft failure at day 100	Up to day 100

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Ann E. Woolfrey, MD, Fred Hutchinson Cancer Center

Study record dates

Study Major Dates

• Study Start: September 1, 2007
• Primary Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: November 6, 2007
• First Submitted That Met QC Criteria: November 6, 2007
• First Posted (Estimate): November 7, 2007

Study Record Updates

• Last Update Posted (Actual): May 24, 2017
• Last Update Submitted That Met QC Criteria: April 17, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: de novo myelodysplastic syndromes; secondary myelodysplastic syndromes; adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(15;17)(q22;q12); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22); secondary acute myeloid leukemia; childhood acute lymphoblastic leukemia in remission; childhood acute myeloid leukemia in remission; chronic phase chronic myelogenous leukemia; childhood chronic myelogenous leukemia; childhood myelodysplastic syndromes; recurrent adult acute myeloid leukemia; adult acute myeloid leukemia in remission; adult acute megakaryoblastic leukemia (M7); adult acute monoblastic leukemia (M5a); adult acute monocytic leukemia (M5b); adult acute myeloblastic leukemia with maturation (M2); adult acute myeloblastic leukemia without maturation (M1); adult acute myelomonocytic leukemia (M4); adult erythroleukemia (M6a); adult pure erythroid leukemia (M6b); blastic phase chronic myelogenous leukemia; relapsing chronic myelogenous leukemia; recurrent adult acute lymphoblastic leukemia; recurrent childhood acute lymphoblastic leukemia; accelerated phase chronic myelogenous leukemia; adult acute lymphoblastic leukemia in remission; recurrent childhood acute myeloid leukemia; childhood acute megakaryocytic leukemia (M7); childhood acute promyelocytic leukemia (M3); adult acute promyelocytic leukemia (M3); graft versus host disease; childhood acute myeloblastic leukemia without maturation (M1); childhood acute myeloblastic leukemia with maturation (M2); childhood acute myelomonocytic leukemia (M4); childhood acute monoblastic leukemia (M5a); childhood acute monocytic leukemia (M5b); myelodysplastic/myeloproliferative diseases
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Leukemia; Preleukemia; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Graft vs Host Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Calcineurin Inhibitors; Cyclophosphamide; Methotrexate; Tacrolimus; Busulfan; Alemtuzumab
• Other Study ID Numbers: 1981.00; P30CA015704 (U.S. NIH Grant/Contract); FHCRC-1981.00; CDR0000574145 (Registry Identifier: PDQ)