Reduced Intensity Donor Stem Cell Transplant in Treating Patients With High Risk Acute Lymphocytic Leukemia in Complete Remission

Phase 2

Completed

• Conditions: Adult Acute Lymphoblastic Leukemia in Remission; Childhood Acute Lymphoblastic Leukemia in Remission; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia
• Interventions: Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation; Biological: donor lymphocytes; Drug: cyclosporine; Radiation: total-body irradiation; Drug: fludarabine phosphate; Drug: mycophenolate mofetil; Other: laboratory biomarker analysis; Procedure: peripheral blood stem cell transplantation

• Registration Number: NCT00031655
• Lead Sponsor: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Brief Summary

The reason for doing this study is to determine whether a new method of blood stem cell transplant (also known as bone marrow transplant) is able to treat acute lymphocytic leukemia. Blood stem cells are the "seed cells" necessary to make all blood cells. This new method of transplant uses a combination of low dose radiation and chemotherapy that may be less toxic and cause less harm than a conventional transplant. This lower dose transplant is called a "nonmyeloablative transplant". Researchers want to see if using less radiation and less chemotherapy combined with new immune suppressing drugs after the transplant will help a stem cell transplant to work. Researchers hope that this treatment will cure acute lymphocytic leukemia with fewer side effects. Researchers are hoping to see a mixture of recipient and donor blood cells after transplant. This mixture of donor and recipient blood cells is called "mixed chimerism". Researchers hope that donor cells will attack and eliminate the leukemia. This is called the "graft-versus-leukemia" effect. In addition, after the transplant, white blood cells from the donor may be given to enhance or "boost" the graft-versus-leukemia effect, and hopefully remove all remaining cancer cells. This study is being done because at the present time blood stem cell transplantation (or bone marrow transplantation) is the only known curative therapy for acute lymphocytic leukemia. Because of age or underlying health status acute lymphocytic leukemia patients have a higher likelihood of experiencing severe harm from a conventional blood stem cell transplant. Researchers are doing this study to see if this new nonmyeloablative method of low dose radiation and low dose chemotherapy given before transplant and immune suppressive drugs after transplant will help make the transplant safer and also cure acute lymphocytic leukemia

Detailed Description

PRIMARY OBJECTIVES:

I. To determine if a one-year disease-free survival (DFS) of \> 25% can be achieved among adult patients with high risk acute lymphocytic leukemia (ALL) in complete remission (CR) who undergo nonmyeloablative allografting.

II. To determine if a one-year DFS of \>= 40% can be achieved among pediatric patients with high risk ALL in CR who undergo nonmyeloablative allografting.

SECONDARY OBJECTIVES:

I. To determine if a day +200 transplant-related mortality (TRM) of \< 25% can be achieved among patients with high risk ALL in CR who undergo nonmyeloablative allografting.

II. To evaluate the efficacy and toxicity of donor lymphocyte infusion (DLI) in the treatment of minimal residue disease (MRD) after nonmyeloablative allografting for patients with high risk ALL in CR.

OUTLINE:

NONMYELOALATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 and undergo total body irradiation (TBI) on day 0.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation (PBSCT) on day 0. Patients with minimal residual disease may receive donor lymphocyte infusion IV.

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) every 12 hours on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO very 8 hours on days 0 to 40 with taper to day 96.

After completion of study treatment, patients are followed up at days 28, 56, 84, 120, 180, and 360; at 18 months; and annually for up to 5 years.

Study Timeline

• Study Start: 2001-09
• Study First Submitted: 2002-03-08
• Study First Submitted QC: 2003-01-26
• Study First Posted: 2003-01-27
• Primary Completion: 2006-08
• Study Completion: 2012-11
• Status Verified: 2012-12
• Last Update Submitted: 2012-12-05
• Last Update Posted: 2012-12-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

• ADULT PATIENTS:

• Patients 50-75 years old with high risk ALL in first CR (CR1) or ALL in CR >= second CR (CR2)

• Patients >= 18 years old and < 50 years old with high risk ALL in CR1 who are not eligible for a conventional allogeneic transplantation based on general medical condition

• Patients >= 18 years old and < 50 years old with high risk ALL in CR1 who refuse a conventional allogeneic transplant

• Patients >= 18 years old and < 50 years old with ALL in CR >= CR2 who are not eligible for a conventional allogeneic transplantation based on general medical condition

• Patients >= 18 years old and < 50 years old with high risk ALL in CR >= CR2 who refuse a conventional allogeneic transplant

• CR is defined as < 5% blasts by morphology on a bone marrow aspirate and the absence of peripheral blasts

• High risk adult ALL in CR1 includes those patients with one or more of the following:

  • Age >=30 years
  • Non T-cell phenotype
  • Cytogenetic abnormalities including t(9;22), t(4;11), trisomy 8, or monosomy 7
  • Failure to achieve CR after 4 weeks of induction chemotherapy

• PEDIATRIC PATIENTS:

• Patients < 18 years old with ALL in high risk CR1 who are not candidates for conventional allogeneic transplantation based on general medical condition

• Patients < 18 years old with ALL in CR >= CR2 who are not candidates for conventional allogeneic transplantation based on general medical condition

• Patients < 12 years old require approval by the Fred Hutchinson Cancer Research Center (FHCRC) principal investigator prior to enrollment

• CR is defined as < 5% blasts by morphology on a bone marrow aspirate and absence of peripheral blasts

• High risk pediatric ALL in CR1 includes those patients with one or more of the following:

  • Cytogenetic abnormalities including:

    • t(9;22) with a white blood cell (WBC) >= 25,000 at diagnosis or
    • t(4;11) in patients < 1 year old and >= 10 years old or
    • Hypodiploidy (< 45 chromosomes)

  • Failure to achieve CR after 4 weeks of induction chemotherapy

  • Persistent peripheral blasts after one week of induction chemotherapy

• DONOR: FHCRC matching Grade 2.1: Unrelated donors who are prospectively:

  • Matched for human leukocyte antigen (HLA)-DRB1 and DQB1 alleles (must be defined by high resolution typing) and
  • Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing

• DONOR: A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion; donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment; this determination is based on the standard practice of the individual institution; the recommended procedure for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel reactive antibody (PRA) screens to class I and class II antigens for all patients before hematopoietic cell transplantation (HCT); if the PRA shows > 10% activity, then flow cytometric or B and T cell cytotoxic cross matches should be obtained; the donor should be excluded if any of the cytotoxic cross match assays are positive; for those patients with an HLA class I allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be obtained regardless of the PRA results

• DONOR: Patient and donor pairs homozygous at a mismatched allele are considered a two-allele mismatch, i.e., the patient is A*0101 and the donor is A*0102, and this type of mismatch is not allowed

• DONOR: Donor must consent to peripheral blood stem cell (PBSC) mobilization with filgrastim (G-CSF) arranged through the National Marrow Donor Program (NMDP) or other donor centers

Exclusion Criteria

• Active central nervous system (CNS) disease
• Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology
• Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
• Pregnancy or breastfeeding
• Human immunodeficiency virus (HIV) seropositivity
• ORGAN DYSFUNCTION, ADULT CRITERIA:
• Requiring supplementary continuous oxygen OR diffusing capacity of the lung for carbon monoxide (DLCO) < 40%
• Cardiac ejection fraction < 35%
• Patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bridging fibrosis, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease
• Karnofsky performance score < 50
• ORGAN DYSFUNCTION, PEDIATRIC CRITERIA:
• Lansky play-performance score < 40
• Patients with active non-hematologic malignancies (except non-melanoma skin cancers)
• Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (nonmyeloablative allogeneic PBSCT)	nonmyeloablative allogeneic hematopoietic stem cell transplantation	NONMYELOALATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Patients with minimal residual disease may receive donor lymphocyte infusion IV. IMMUNOSUPPRESSION: Patients receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO very 8 hours on days 0 to 40 with taper to day 96.
Treatment (nonmyeloablative allogeneic PBSCT)	donor lymphocytes	NONMYELOALATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Patients with minimal residual disease may receive donor lymphocyte infusion IV. IMMUNOSUPPRESSION: Patients receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO very 8 hours on days 0 to 40 with taper to day 96.
Treatment (nonmyeloablative allogeneic PBSCT)	cyclosporine	NONMYELOALATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Patients with minimal residual disease may receive donor lymphocyte infusion IV. IMMUNOSUPPRESSION: Patients receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO very 8 hours on days 0 to 40 with taper to day 96.
Treatment (nonmyeloablative allogeneic PBSCT)	total-body irradiation	NONMYELOALATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Patients with minimal residual disease may receive donor lymphocyte infusion IV. IMMUNOSUPPRESSION: Patients receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO very 8 hours on days 0 to 40 with taper to day 96.
Treatment (nonmyeloablative allogeneic PBSCT)	fludarabine phosphate	NONMYELOALATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Patients with minimal residual disease may receive donor lymphocyte infusion IV. IMMUNOSUPPRESSION: Patients receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO very 8 hours on days 0 to 40 with taper to day 96.
Treatment (nonmyeloablative allogeneic PBSCT)	laboratory biomarker analysis	NONMYELOALATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Patients with minimal residual disease may receive donor lymphocyte infusion IV. IMMUNOSUPPRESSION: Patients receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO very 8 hours on days 0 to 40 with taper to day 96.
Treatment (nonmyeloablative allogeneic PBSCT)	peripheral blood stem cell transplantation	NONMYELOALATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Patients with minimal residual disease may receive donor lymphocyte infusion IV. IMMUNOSUPPRESSION: Patients receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO very 8 hours on days 0 to 40 with taper to day 96.
Treatment (nonmyeloablative allogeneic PBSCT)	mycophenolate mofetil	NONMYELOALATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Patients with minimal residual disease may receive donor lymphocyte infusion IV. IMMUNOSUPPRESSION: Patients receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 177 and mycophenolate mofetil PO very 8 hours on days 0 to 40 with taper to day 96.

Primary Outcome Measures

Name	Time	Method
Leukemia-free survival	1 year	Incidence of survival without relapse. Kaplan-Meier estimates will be used to estimate one-year leukemia-free survival.

Secondary Outcome Measures

Name	Time	Method
Karnofsky performance score and Lansky performance score	1 year
Transplant-related mortality	1 year
Efficacy of DLI for the elimination of MRD	Up to day 120
Toxicity of DLT, graded using a modified version of the National Cancer Institute (NCI) Common Toxicity Criteria	Up to 5 years
Overall survival	1 year
Incidence of relapse	1 year
Incidence of rejection	1 year
Incidence of acute grade II-IV graft-versus-host disease (GVHD) and chronic GVHD, graded using a modified version of the National Cancer Institute (NCI) Common Toxicity Criteria	Up to 5 years

Trial Locations

Locations (3)

Veterans Affairs Puget Sound Healthcare System; 🇺🇸 Seattle, Washington, United States

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium; 🇺🇸 Seattle, Washington, United States

Oregon Health and Sciences University; 🇺🇸 Portland, Oregon, United States