Clinical trial NCT01118013: Donor Stem Cell Transplant in Treating Patients With Relapsed Hematologic Malignancies or Secondary Myelodysplasia Previously Treated With High-Dose Chemotherapy and Autologous Stem Cell Transplant
Official title: Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation as Second Transplantation for Patients With Disease Relapse or Myelodysplasia After Prior Autologous Transplantation
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Leukemia
Lymphoma
Lymphoproliferative Disorder
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Neoplasms
Keywords: 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)
juvenile myelomonocytic leukemia
prolymphocytic leukemia
recurrent adult acute myeloid leukemia
recurrent adult T-cell leukemia/lymphoma
recurrent childhood acute myeloid leukemia
refractory chronic lymphocytic leukemia
recurrent adult Hodgkin lymphoma
recurrent adult Burkitt lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult grade III lymphomatoid granulomatosis
recurrent adult immunoblastic large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent childhood grade III lymphomatoid granulomatosis
recurrent childhood large cell lymphoma
recurrent childhood lymphoblastic lymphoma
recurrent childhood small noncleaved cell lymphoma
recurrent cutaneous T-cell non-Hodgkin lymphoma
recurrent mycosis fungoides/Sezary syndrome
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
recurrent marginal zone lymphoma
recurrent small lymphocytic lymphoma
recurrent/refractory childhood Hodgkin lymphoma
childhood diffuse large cell lymphoma
childhood grade III lymphomatoid granulomatosis
childhood immunoblastic large cell lymphoma
childhood nasal type extranodal NK/T-cell lymphoma
post-transplant lymphoproliferative disorder
stage I multiple myeloma
stage II multiple myeloma
stage III multiple myeloma
refractory multiple myeloma
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
childhood myelodysplastic syndromes
recurrent childhood anaplastic large cell lymphoma
adult acute myelomonocytic leukemia (M4)
childhood acute myelomonocytic leukemia (M4)
adult acute minimally differentiated myeloid leukemia (M0)
childhood acute minimally differentiated myeloid leukemia (M0)
adult acute myeloblastic leukemia without maturation (M1)
childhood acute myeloblastic leukemia without maturation (M1)
adult acute myeloblastic leukemia with maturation (M2)
childhood acute myeloblastic leukemia with maturation (M2)
adult acute promyelocytic leukemia (M3)
childhood acute promyelocytic leukemia (M3)
adult acute monoblastic leukemia (M5a)
adult acute monocytic leukemia (M5b)
childhood acute monoblastic leukemia (M5a)
childhood acute monocytic leukemia (M5b)
adult erythroleukemia (M6a)
adult pure erythroid leukemia (M6b)
childhood acute erythroleukemia (M6)
adult acute megakaryoblastic leukemia (M7)
childhood acute megakaryocytic leukemia (M7)
childhood Burkitt lymphoma
atypical chronic myeloid leukemia, BCR-ABL1 negative
chronic myelomonocytic leukemia
cutaneous B-cell non-Hodgkin lymphoma
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma
myelodysplastic/myeloproliferative neoplasm, unclassifiable
Lead sponsor: Alliance for Clinical Trials in Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2010-05-06
Enrollment: 6
Sex: ALL
Maximum age (years): 69
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Giving chemotherapy, such as busulfan and fludarabine phosphate, before a peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving methotrexate, tacrolimus, and antithymocyte globulin before and after the transplant may stop this from happening. Once the donated stem cells begin working, the patient's immune system may see the remaining cancer cells as not belonging in the patient's body and destroy them (called graft-versus-tumor effect). Giving an infusion of the donor's white blood cells (donor lymphocyte infusion) may boost this effect.

PURPOSE: This phase II trial is studying how well donor stem cell transplant works in treating patients with relapsed hematologic malignancies or secondary myelodysplasia previously treated with high-dose chemotherapy and autologous stem cell transplant .

Detailed description: OBJECTIVES:

Primary

* To demonstrate the efficacy of performing reduced-intensity conditioning allogeneic hematopoietic cell transplantation in patients with relapsed hematologic malignancies or secondary myelodysplasia after completion of prior high-dose chemotherapy and autologous hematopoietic stem cell transplantation.
* To compare the strategy of this regimen with the strategy used in CALGB-100002.

Secondary

* To describe the response rate at 6 and 12 months in patients treated with this regimen.
* To describe the time-to-progression in patients treated with this regimen.
* To determine the ability to use pharmacokinetic-directed busulfan to achieve AUC within 20% of target AUC in \> 80% of patients.
* To determine percent of donor chimerism in T-cell, myeloid and B-cell populations achieved with this regimen compared with CALGB-100002.
* To determine the risk of acute and chronic graft-versus-host disease and other toxicities of this regimen in these patients.
* To describe the overall survival and disease-free survival of patients treated on this regimen.
* To determine the rate of viral, bacterial, and fungal opportunistic infections occurring in the first year after transplantation compared with CALGB-100002.

OUTLINE: This is a multicenter study.

* Preparative Regimen:

  * Busulfan test dose: Patients receive busulfan IV over 45 minutes once during days -14 and -9.
  * Busulfan treatment dose: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and busulfan IV over 3 hours on days -6 to -3.
* Graft-vs-Host Disease (GVHD) Prophylaxis:

  * HLA-identical donor: Patients receive antithymocyte globulin IV over 6-10 hours on days -6 to -5; oral tacrolimus twice daily on days -2 to 90 followed by a taper\* as tolerated until day 150 or 180; and methotrexate IV on days 1, 3, and 6.

NOTE: \* Tacrolimus may be tapered on days 60-90 if donor chimerism of CD3+ cells is \< 50% at day 60 or patient has progressive disease.

* Matched-unrelated donor: Patients receive antithymocyte globulin, tacrolimus, and methotrexate as in HLA-identical donor regimen. Patients also receive oral mycophenolate mofetil twice daily on days 0 to 60.

  * Allogeneic Stem Cell Transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation on days 0 and 1. Patients then receive filgrastim subcutaneously daily beginning on day 7 and continuing until blood counts recover.
  * Donor Lymphocyte Infusion (DLI): After day 180 (or day 210 for patients without an HLA-identical donor), patients with stable or progressive disease and no active GVHD may receive up to 3 DLIs every 8 weeks.

Blood samples are collected at baseline and then periodically during study therapy for pharmacokinetic studies.

After completion of study therapy, patients are followed up every 3 months for 2 years and then every 6 months for up to 5½ years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed hematologic malignancies:

  * Chronic lymphocytic leukemia (CLL) or prolymphocytic leukemia (PLL)

    * Absolute lymphocytosis of \> 5,000/μL
    * Lymphocytes must appear morphologically mature with \< 55% prolymphocytes (CLL)

      * Patients with \> 55% prolymphocytes are considered as having PLL
    * Lymphocyte phenotype with expression of CD20, CD19, and CD5 (CLL)
  * Non-Hodgkin lymphoma

    * Any WHO classification of histologic subtype
    * Core biopsies acceptable for primary diagnosis and immunophenotyping
    * Bone marrow biopsies as sole means of diagnosis not allowed for follicular lymphoma
  * Hodgkin lymphoma

    * Any WHO classification of histologic subtype
    * Core biopsies acceptable for primary diagnosis and immunophenotyping
    * Bone marrow biopsy is required
  * Multiple myeloma

    * Patients must have active disease requiring treatment (Durie-Salmon stage I-III)
  * Acute myeloid leukemia

    * Must have \< 10% bone marrow blasts and no circulating blasts
  * Myelodysplastic syndrome (MDS)

    * MDS as define by WHO criteria
    * Must have \< 10% marrow blasts
* Relapsed or progressive disease or myelodysplasia ≥ 6 months after prior high-dose chemotherapy with autologous hematopoietic cell support

  * Prior syngeneic transplantation allowed
* Healthy donor meeting one of the following criteria:

  * HLA-identical sibling (6/6)

    * Serologic typing for class I (A, B) and molecular typing for class II (DRB1) required
  * 8/8 matched-unrelated donor

    * Molecular identity at HLA A, B, C, and DRB1 by high-resolution typing required
  * No syngeneic donors

PATIENT CHARACTERISTICS:

* Creatinine clearance ≥ 40 mL/min
* Total bilirubin ≤ 2 mg/dL
* AST ≤ 3 times upper limit of normal
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* DLCO ≥ 40% with no symptomatic pulmonary disease
* LVEF ≥ 30% by MUGA or ECHO
* No uncontrolled diabetes mellitus or active serious infection
* No known hypersensitivity to E.coli-derived products
* No HIV infection

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* At least 4 weeks should elapse between prior standard cytotoxic chemotherapy, radiation therapy, or surgery and the planned start of the preparative regimen on day -7

Primary outcomes:
measure: Event-free Survival (EFS)
timeFrame: Duration of study (up to 5.5 years)
measure: Comparison of EFS Distribution to That of CALGB-100002
timeFrame: 2 years
Secondary outcomes:
measure: Complete Response Rate
timeFrame: Up to 5.5 years
measure: Overall Survival
timeFrame: Up to 5.5 years
measure: Rate of Opportunistic Infections
timeFrame: 1 year post transplant
Other outcomes:
Locations:
city: Lewes
country: United States
facility: Tunnell Cancer Center at Beebe Medical Center
state: Delaware
city: Newark
country: United States
facility: CCOP - Christiana Care Health Services
state: Delaware
city: Orlando
country: United States
facility: Florida Hospital Cancer Institute at Florida Hospital Orlando
state: Florida
city: Baltimore
country: United States
facility: Greenebaum Cancer Center at University of Maryland Medical Center
state: Maryland
city: Elkton MD
country: United States
facility: Union Hospital of Cecil County
state: Maryland
city: Saint Louis
country: United States
facility: Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
state: Missouri
city: Voorhees
country: United States
facility: Cancer Institute of New Jersey at Cooper - Voorhees
state: New Jersey
city: New York
country: United States
facility: New York Weill Cornell Cancer Center at Cornell University
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University Comprehensive Cancer Center
state: North Carolina
city: Columbus
country: United States
facility: Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
state: Ohio
Study officials:
affiliation: Blood and Marrow Transplant Group of Georgia
name: Asad Bashey, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: