Combination Chemotherapy, Bone Marrow Transplant, and Post Transplant Cyclophosphamide for Hematologic Cancer

• ClinicalTrials.gov Identifier: NCT00134017
• Recruitment Status: Completed
• First Posted: August 24, 2005
• Results First Posted: August 31, 2018
• Last Update Posted: August 31, 2018
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Description

Brief Summary:

RATIONALE: Giving chemotherapy before a donor bone marrow transplant helps stop the growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting the donor's stem 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 cyclophosphamide, mycophenolate mofetil, or tacrolimus after transplant may stop this from happening.

PURPOSE: This clinical trial is studying how well giving combination chemotherapy together with tacrolimus and mycophenolate mofetil works in treating patients who are undergoing a donor bone marrow transplant for hematologic cancer.

Condition or disease	Intervention/treatment	Phase
Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes	Drug: Busulfan; Drug: Cyclophosphamide	Phase 2

Detailed Description:

OBJECTIVES:

Primary

• Determine the optimal dose of post-transplant immunosuppression comprising high-dose cyclophosphamide, tacrolimus, and mycophenolate mofetil administered after myeloablative conditioning chemotherapy comprising busulfan and cyclophosphamide followed by allogeneic bone marrow transplantation in patients with high-risk hematologic malignancies.
• Determine the incidence and severity of acute graft-versus-host disease in patients treated with this regimen.
• Determine other toxic effects of this regimen in these patients.

Secondary

• Determine immune reconstitution in patients treated with this regimen.
• Determine disease control in patients treated with this regimen.

OUTLINE: This is a pilot study. Patients are stratified according to age (≤ 19 years old vs > 19 years old).

• Myeloablative conditioning chemotherapy: Patients receive busulfan IV or orally 4 times daily on days -7 to -4 OR days -6 to -3 and cyclophosphamide IV over 1 hour once daily on days -3 to -1 OR days -2 and -1.
• Allogeneic bone marrow transplantation: Patients undergo allogeneic bone marrow transplantation on day 0.
• Immunosuppression therapy: Patients receive high-dose cyclophosphamide IV over 1 hour on days 3 and 4.

After completion of study transplantation, patients are followed at 30 and 60 days, 6 months, 1 year, and then annually thereafter.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 142 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: HLA Matched Related and Unrelated Bone Marrow Transplantation With Busulfan/Cyclophosphamide and Post Transplantation Cyclophosphamide for Hematological Malignancies
• Actual Study Start Date: June 2004
• Actual Primary Completion Date: February 2010
• Actual Study Completion Date: February 2010

Arms and Interventions

Arm	Intervention/treatment
Experimental: Bone marrow transplant; Myeloablative bone marrow transplant with a busulfan (Bu), cyclophosphamide (Cy), preparative regimen and post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis	Drug: Busulfan; Days -7 to -4: 4 mg/kg PO daily OR 3.2 mg/kg IV daily OR 160 mg/m^2 daily (for pediatric recipients); Other Names: Myleran; Busulfex; Drug: Cyclophosphamide; Days -3, -2, +3, +4: 50 mg/kg IV daily; Other Names: Cytoxan; CTX

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants Who Develop Acute Graft-versus-host Disease (GVHD) [ Time Frame: Day 100 ]
   Percentage of participants who developed grades II-IV and grades III-IV acute GVHD. Acute GVHD is defined by the Przepiorka criteria, which stages the degree of organ involvement in the skin, liver, and gastrointestinal (GI) tract, based on severity, with Stage 1+ being least severe and stage 4+ being the most severe. Grading of acute GVHD is as follows: Grade I (skin involvement stages 1+ to 2+, with no liver or GI involvement), Grade II (skin involvement stages 1+ to 3+, liver 1+, GI tract 1+), Grade III (skin involvement stages 2+ to 3+, liver 1+, GI tract 2+ to 4+), Grade IV (skin involvement stages 4+, Liver 4+).

Secondary Outcome Measures :

1. Days to Engraftment [ Time Frame: Up to one year ]
   Median number of days to neutrophil and platelet engraftment.
2. Chimerism [ Time Frame: Day 30, Day 60 ]
   Number of patients who achieved 100% donor chimerism.
3. Non-relapse Mortality [ Time Frame: Day 100, 2 years ]
   Percentage of participants who died for BMT-related reasons.
4. Relapse [ Time Frame: 2 years ]
   Percentage of participants who developed relapse or progressive disease.

Eligibility Criteria

• Ages Eligible for Study: 6 Months to 65 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following hematologic malignancies:

  • Acute myeloid leukemia (AML), meeting 1 of the following criteria:

    • AML beyond first complete remission (CR1)
    • Refractory AML
    • AML arising from myelodysplastic syndromes (MDS)
    • Secondary AML

  • MDS

    • Refractory anemia with excess blasts with > 10% blasts in bone marrow

  • Acute lymphoblastic leukemia (ALL), meeting 1 of the following criteria:

    • ALL in CR1 with 1 of the following high-risk features:

      • Philadelphia chromosome (Ph)-positive disease
      • Less than 1 year of age at diagnosis
      • Cytogenetic abnormalities involving chromosome 11q23
    • ALL beyond CR1
    • Refractory ALL
  • Chronic myeloid leukemia beyond first chronic phase
  • Chronic myelomonocytic leukemia

  • Chronic lymphocytic leukemia

    • Stage III-IV disease
    • Does not meet criteria for other bone marrow transplantation (BMT) studies

  • Myeloproliferative disorders

    • Ph-negative disease

  • Hodgkin's or non-Hodgkin's lymphoma

    • Chemotherapy-resistant disease
  • Paroxysmal nocturnal hemoglobinuria with life-threatening thrombosis

  • Multiple myeloma

    • Stage II or III disease

• Very high-risk disease

  • Having an unrelated donor is considered a high-risk condition
• Meets medical criteria for myeloablative BMT for the Sidney Kimmel Comprehensive Cancer Center

• Bone marrow donor available, meeting 1 of the following criteria:

  • Genotypically HLA-identical sibling
  • Phenotypically matched first-degree relative
  • Unrelated donor molecularly matched at HLA-A, -B, -C, -DRB1, and -DQB1

PATIENT CHARACTERISTICS:

Age

• 6 months to 65 years

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• See Disease Characteristics

Hepatic

• Not specified

Renal

• Not specified

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• See Disease Characteristics

Endocrine therapy

• No concurrent dexamethasone as an antiemetic during immunosuppression therapy

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• No concurrent immunosuppressants until ≥ 24 hours after the completion of cyclophosphamide (post-transplantation)

Contacts and Locations

Locations

United States, Maryland

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States, 21231-2410

Sponsors and Collaborators

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Leo Luznik, MD; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

More Information

Publications of Results:

Luznik L, Bolaños-Meade J, Zahurak M, Chen AR, Smith BD, Brodsky R, Huff CA, Borrello I, Matsui W, Powell JD, Kasamon Y, Goodman SN, Hess A, Levitsky HI, Ambinder RF, Jones RJ, Fuchs EJ. High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Blood. 2010 Apr 22;115(16):3224-30. doi: 10.1182/blood-2009-11-251595. Epub 2010 Feb 2.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT00134017
• Other Study ID Numbers: J0373; P01CA015396 ( U.S. NIH Grant/Contract ); P30CA006973 ( U.S. NIH Grant/Contract ); NA_00034100 ( Other Identifier: JHMIRB )
• First Posted: August 24, 2005
• Results First Posted: August 31, 2018
• Last Update Posted: August 31, 2018
• Last Verified: August 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:

adult acute myeloid leukemia in remission; refractory anemia with excess blasts; 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); childhood acute myeloid leukemia in remission; recurrent adult acute myeloid leukemia; recurrent childhood acute myeloid leukemia; secondary acute myeloid leukemia; de novo myelodysplastic syndromes; adult acute lymphoblastic leukemia in remission; childhood acute lymphoblastic leukemia in remission; recurrent adult acute lymphoblastic leukemia; recurrent childhood acute lymphoblastic leukemia; accelerated phase chronic myelogenous leukemia; blastic phase chronic myelogenous leukemia; childhood chronic myelogenous leukemia; chronic phase chronic myelogenous leukemia; relapsing chronic myelogenous leukemia; stage III chronic lymphocytic leukemia; stage IV chronic lymphocytic leukemia; chronic eosinophilic leukemia; chronic idiopathic myelofibrosis; chronic neutrophilic leukemia; stage III adult Hodgkin lymphoma; stage IV adult Hodgkin lymphoma; stage II multiple myeloma; stage III multiple myeloma

Additional relevant MeSH terms:

Lymphoma; Leukemia; Multiple Myeloma; Neoplasms, Plasma Cell; Preleukemia; Myelodysplastic Syndromes; Myeloproliferative Disorders; Syndrome; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease; Pathologic Processes; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Bone Marrow Diseases; Precancerous Conditions; Cyclophosphamide; Busulfan; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs