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A Trial of Reduced Intensity Conditioning and Transplantation of Haplotype Mismatched and KIR Class I Epitope-Mismatched Highly Purified CD34 Cells


Phase 1/Phase 2
18 Years
60 Years
Not Enrolling
Both
Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms

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Trial Information

A Trial of Reduced Intensity Conditioning and Transplantation of Haplotype Mismatched and KIR Class I Epitope-Mismatched Highly Purified CD34 Cells


OBJECTIVES:

- Determine the ability of a reduced-intensity conditioning regimen comprising
alemtuzumab, fludarabine, and melphalan with or without cyclosporine, mycophenolate
mofetil, and low-dose total body radiotherapy followed by haplotype-mismatched, KIR
class I epitope-mismatched CD34-positive allogeneic peripheral blood stem cell
transplantation to facilitate engraftment by day 35 post-transplantation in at least
85% of patients with relapsed, refractory, or poor-risk hematological malignancies.

- Determine the risk of graft-versus-host-disease in patients treated with these
regimens.

- Determine, preliminarily, the efficacy of these regimens, in terms of progression-free
survival, in these patients.

- Correlate outcomes, engraftment, and progression-free survival with the number of
detectable alloreactive natural killer cell clones before transplantation and after
engraftment in patients treated with these regimens.

- Determine immune reconstitution in patients treated with these regimens.

OUTLINE: This is a multicenter, pilot study. Patients are initially treated with
conditioning regimen A. If adequate donor engraftment is not achieved, subsequent patients
are treated with conditioning regimen B.

- Conditioning regimen A: Patients receive alemtuzumab IV over 2 hours on days -14 to
-12; fludarabine IV over 30 minutes on days -7 to -3; and melphalan IV over 20-30
minutes on day -2.

- Conditioning regimen B: Patients receive oral or IV cyclosporine twice daily and oral
or IV mycophenolate mofetil twice daily on days -15 to 0. Patients also receive
alemtuzumab, fludarabine, and melphalan as in conditioning regimen A. Patients undergo
low-dose total body irradiation twice daily on days -2 and -1.

All patients undergo allogeneic, T-cell-depleted, CD34-positive peripheral blood stem cell
transplantation on day 0. Patients receive sargramostim (GM-CSF) subcutaneously beginning on
day 1 and continuing until blood counts recover.

Patients are followed every 3 months for 1 year and then every 6 months for 5 years.

PROJECTED ACCRUAL: A total of 14-56 patients (14-28 per regimen) will be accrued for this
study.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically confirmed hematological malignancy of 1 of the following types:

- Acute myeloid leukemia meeting at least 1 of the following criteria:

- Poor-risk cytogenetics, including -5, 5q-, -7, 7q-, 11q23, and Philadelphia
(Ph) chromosome-positive in first or subsequent complete remission (CR)

- Relapsed or primary refractory disease with ≤ 10% blasts in the peripheral
blood and ≤ 20% blasts in the bone marrow

- Standard-risk cytogenetics in second CR AND autologous transplantation is
not feasible

- Standard-risk cytogenetics in third or subsequent CR

- Acute lymphoblastic leukemia meeting 1 of the following criteria:

- Second or subsequent CR

- High-risk cytogenetics, including Ph chromosome-positive and t(4:11) in
first CR

- Relapsed or primarily refractory disease with ≤ 10% blasts in the
peripheral blood and ≤ 20% blasts in the bone marrow

- High-risk myelodysplasia

- International Prognostic Scoring System Score ≥ 2.5

- Chronic myeloid leukemia (CML)* with an inadequate response to imatinib meeting
1 of the following criteria:

- Second or subsequent chronic phase

- Accelerated phase NOTE: *Patients with CML in blast crisis (> 30%
promyelocytes and myeloblasts in the bone marrow) are not eligible

- Non-Hodgkin's lymphoma meeting 1 of the following criteria:

- Primarily refractory disease or in refractory relapse

- Relapsed disease after autologous stem cell transplantation

- Chemosensitive relapsed disease without CR to standard salvage therapy AND
no option for autologous stem cell transplantation due to blood or marrow
involvement or failure to harvest sufficient autologous stem cells

- Chronic lymphocytic leukemia meeting both of the following criteria:

- Stage III or IV disease

- Refractory to fludarabine

- Multiple myeloma meeting 1 of the following criteria:

- Primarily refractory disease or in refractory relapse

- Relapsed disease after autologous stem cell transplantation

- No relapsed disease < 6 months after autologous stem cell transplantation

- No available eligible HLA-matched (i.e., 5 of 6 or 6 of 6 antigen match for HLA-A,
-B, and -DR loci) family donor by serological or molecular typing

- Available suitable family donor meeting the following criteria:

- Parent, sibling, or child of the recipient

- ≥ 16 years of age

- Identical for only one HLA haplotype (i.e., haploidentical) AND incompatible at
the HLA-A, -B, -C, and -DR loci of the unshared haplotype by serological or
molecular typing

- Mismatched with respect to KIR class I epitopes graft-vs-host directional
activity

- Mismatching that predicts both graft-vs-host and host-vs-graft
bi-directional activity eligible

- No mismatching that predicts only host-vs-graft directional activity

PATIENT CHARACTERISTICS:

Age

- 18 to 60

Performance status

- ECOG 0-1

Life expectancy

- Not specified

Hematopoietic

- Not specified

Hepatic

- Bilirubin < 2 times upper limit of normal (ULN)

- AST and ALT < 2 times ULN

Renal

- Creatinine ≤ 2 mg/dL

Cardiovascular

- LVEF > 40% (corrected)

Pulmonary

- DLCO > 50% of predicted

Other

- No active infection requiring oral or IV antibiotics

- HIV negative

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

- See Disease Characteristics

Chemotherapy

- See Disease Characteristics

Endocrine therapy

- Concurrent corticosteroids allowed for adrenal failure, treatment of graft-vs-host
disease, or as premedication during study

- No concurrent corticosteroids for antiemesis

Radiotherapy

- Not specified

Surgery

- Not specified

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Outcome Measure:

Engraftment rate

Safety Issue:

No

Principal Investigator

Sherif S. Farag, MD, PhD

Investigator Role:

Study Chair

Investigator Affiliation:

Indiana University Melvin and Bren Simon Cancer Center

Authority:

United States: Federal Government

Study ID:

CDR0000370797

NCT ID:

NCT00085449

Start Date:

May 2006

Completion Date:

Related Keywords:

  • Leukemia
  • Lymphoma
  • Multiple Myeloma and Plasma Cell Neoplasm
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Neoplasms
  • recurrent adult acute myeloid leukemia
  • adult acute myeloid leukemia in remission
  • recurrent adult acute lymphoblastic leukemia
  • adult acute lymphoblastic leukemia in remission
  • myelodysplastic/myeloproliferative neoplasm, unclassifiable
  • previously treated myelodysplastic syndromes
  • atypical chronic myeloid leukemia, BCR-ABL1 negative
  • chronic myelomonocytic leukemia
  • recurrent adult Burkitt lymphoma
  • recurrent grade 1 follicular lymphoma
  • recurrent grade 2 follicular lymphoma
  • recurrent grade 3 follicular lymphoma
  • recurrent adult diffuse small cleaved cell lymphoma
  • recurrent adult immunoblastic large cell lymphoma
  • recurrent small lymphocytic lymphoma
  • recurrent marginal zone lymphoma
  • recurrent mantle cell lymphoma
  • recurrent adult lymphoblastic lymphoma
  • accelerated phase chronic myelogenous leukemia
  • chronic phase chronic myelogenous leukemia
  • recurrent adult diffuse mixed cell lymphoma
  • recurrent adult diffuse large cell lymphoma
  • refractory chronic lymphocytic leukemia
  • stage III chronic lymphocytic leukemia
  • stage IV chronic lymphocytic leukemia
  • refractory multiple myeloma
  • secondary myelodysplastic syndromes
  • de novo myelodysplastic syndromes
  • adult acute myeloid leukemia with t(8;21)(q22;q22)
  • adult acute myeloid leukemia with t(16;16)(p13;q22)
  • adult acute myeloid leukemia with inv(16)(p13;q22)
  • adult acute myeloid leukemia with 11q23 (MLL) abnormalities
  • adult acute myeloid leukemia with t(15;17)(q22;q12)
  • Neoplasms
  • Leukemia
  • Lymphoma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Plasmacytoma
  • Myelodysplastic Syndromes
  • Preleukemia
  • Myeloproliferative Disorders
  • Myelodysplastic-Myeloproliferative Diseases

Name

Location

Roswell Park Cancer InstituteBuffalo, New York  14263
Memorial Sloan-Kettering Cancer CenterNew York, New York  10021
University of Chicago Cancer Research CenterChicago, Illinois  60637
University of Minnesota Cancer CenterMinneapolis, Minnesota  55455
Duke Comprehensive Cancer CenterDurham, North Carolina  27710
CCOP - Christiana Care Health ServicesWilmington, Delaware  19899
Massachusetts General Hospital Cancer CenterBoston, Massachusetts  02114
Holden Comprehensive Cancer Center at University of IowaIowa City, Iowa  52242-1002
Siteman Cancer Center at Barnes-Jewish HospitalSaint Louis, Missouri  63110
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel HillChapel Hill, North Carolina  27599-7570
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State UniversityColumbus, Ohio  43210-1240
St. Joseph's Hospital and Medical CenterPaterson, New Jersey  07503
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer InstituteBoston, Massachusetts  02115
UCSF Comprehensive Cancer CenterSan Francisco, California  94115
Mount Sinai Medical CenterNew York, New York  10029
Wake Forest University Comprehensive Cancer CenterWinston-Salem, North Carolina  27157-1096
Hollings Cancer Center at Medical University of South CarolinaCharleston, South Carolina  29425
UNMC Eppley Cancer Center at the University of Nebraska Medical CenterOmaha, Nebraska  68198-7680
Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical CenterLos Angeles, California  90048-1865
Lombardi Comprehensive Cancer Center at Georgetown University Medical CenterWashington, District of Columbia  20007
Don Monti Comprehensive Cancer Center at North Shore University HospitalManhasset, New York  11030
Virginia Commonwealth University Massey Cancer CenterRichmond, Virginia  23298-0037
Moores UCSD Cancer CenterLa Jolla, California  92093-0658
Western Pennsylvania Cancer Institute at Western Pennsylvania HospitalPittsburgh, Pennsylvania  15224-1791