Reduced Intensity Donor Peripheral Blood Stem Cell Transplant in Treating Patients With De Novo or Secondary Acute Myeloid Leukemia in Remission

• Sponsor: Fred Hutchinson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00045435
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 17
• Locations: 2
• Arm: 1
• Actual Duration (Months): 81.1
• Patients Per Site: 8.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase II trial studies how well reduced intensity donor peripheral blood stem cell (PBSC) transplant works in treating patients with de novo or secondary acute myeloid leukemia (AML) in remission. Giving low doses of chemotherapy, such as fludarabine phosphate, and total-body irradiation (TBI) before a donor PBSC transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); 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 Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Secondary Acute Myeloid Leukemia	Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation; Drug: fludarabine phosphate; Radiation: total-body irradiation; Drug: cyclosporine; Drug: mycophenolate mofetil; Procedure: peripheral blood stem cell transplantation	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine if a one-year disease free survival of >= 35% can be achieved among patients

= 55 years old with de novo and secondary AML in first complete remission (CR1) who undergo nonmyeloablative hematopoietic stem cell transplant (HSCT) from human leukocyte antigen (HLA) identical related donors.

1. To determine if a day +200 nonrelapse related mortality of < 15% can be achieved among patients >= 55 years old with de novo and secondary AML in CR1 who undergo nonmyeloablative HSCT from HLA identical related donors.

OUTLINE:

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

TRANSPLANT: Patients undergo allogeneic PBSC transplant on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine (CSP) orally (PO) twice daily (BID) on days -3 to 56 with taper to day 77. Patients also receive mycophenolate mofetil (MMF) PO BID on days 0-27.

After completion of study treatment, patients are followed up on days 28, 56, and 84; months 6, 12, 18, and 24; and then yearly for 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Nonmyeloablative Allogeneic Peripheral Blood Stem Cell Transplantation From HLA Matched Related Donors for Treatment of Older Patients With De Novo or Secondary Acute Myeloid Leukemia in First Complete Remission
• Actual Study Start Date: Apr 1, 2002
• Actual Primary Completion Date: Jan 1, 2009
• Actual Study Completion Date: Jan 1, 2009

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (nonmyeloablative donor PBSC transplant) CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANT: Patients undergo allogeneic PBSC transplant on day 0. IMMUNOSUPPRESSION: Patients receive CSP PO BID on days -3 to 56 with taper to day 77. Patients also receive MMF PO BID on days 0-27.

Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation; Undergo nonmyeloablative allogeneic PBSC transplant; Drug: fludarabine phosphate; Given IV; Other Names: 2-F-ara-AMP Beneflur Fludara ; Radiation: total-body irradiation; Undergo TBI; Other Names: TBI ; Drug: cyclosporine; Given PO; Other Names: ciclosporin cyclosporin cyclosporin A CYSP Sandimmune ; Drug: mycophenolate mofetil; Given PO; Other Names: Cellcept MMF ; Procedure: peripheral blood stem cell transplantation; Undergo nonmyeloablative allogeneic PBSC transplant; Other Names: PBPC transplantation PBSC transplantation peripheral blood progenitor cell transplantation transplantation, peripheral blood stem cell

Outcome Measures

Primary Outcome Measures

1. Disease-free Survival-incidence of Survival Without Relapse [By 1 year after transplant]

   Sufficient evidence will be taken to be an observed rate of DFS at one year after transplant that corresponds to a one-sided 95% confidence interval with an upper limit lower than 35%.

2. Nonrelapse Mortality (NRM)-Incidence of Nonrelapse Death [200 days after transplant]

   Defined as death without morphologic evidence of disease. Sufficient evidence will be taken to be an observed rate of NRM within 200 days of transplant that corresponds to a one-sided 80% confidence interval with a lower limit greater than 15%.

Secondary Outcome Measures

1. Overall Survival [By 1 year after transplant]

   Percent patients surviving.

2. Incidence of Relapse [By 1 year after transplant]

   Percent patients with relapsed disease post-transplant.

3. Incidence of Rejection [By 1 year after transplant]

   Percent patients who developed infections post-transplant.

4. Incidence of Acute and Chronic GVHD [aGVHD: 100 days after transplant; cGVHD: 1 Year after transplant.]

   Percent patients with acute/chronic GVHD

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with de novo AML (French-American-British [FAB] MO-M2, M4-M7) or secondary AML who achieve CR1 after induction chemotherapy and one or two cycles of consolidation chemotherapy

• Transplant conditioning must occur within 6 months of diagnosis

• Patient enrollment must be approved by the Fred Hutchinson Cancer Research Center (FHCRC) principal investigator (PI) or the PI's designee

• DONOR: Related donor who is genotypically or phenotypically identical

• DONOR: Age >= 12 years

• DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis

• DONOR: Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian)

Exclusion Criteria:

• AML FAB M3

• AML involvement of the central nervous system (CNS) as defined by a positive cytospin of cerebral spinal fluid at the time of enrollment

• Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology

• Human immunodeficiency virus (HIV) seropositivity

• Fungal infections with radiographic progression after receipt of amphotericin B or active triazole for greater than one month

• Diffusion capacity of carbon monoxide (DLCO) corrected < 40%

• Total lung capacity (TLC) < 40%

• Forced expiratory volume in one second (FEV1) < 40% or requiring supplementary oxygen

• The FHCRC principal investigator of the study must approve enrollment of all patients with pulmonary nodules

• Cardiac ejection fraction < 40%

• 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, bridging fibrosis, 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, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3mg/dL, or symptomatic biliary disease

• Karnofsky Performance Score < 70

• Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment

• Females who are pregnant or breastfeeding

• No intensive chemotherapy can be given within three weeks (or the interval in which a cycle of standard chemotherapy would be administered in a non-transplant setting) prior to initiating the nonmyeloablative transplant conditioning

• 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

• Patients with active bacterial or fungal infections unresponsive to medical therapy

• DONOR: Identical twin

• DONOR: Pregnancy

• DONOR: HIV seropositivity

• DONOR: Inability to achieve adequate venous access

• DONOR: Known allergy to G-CSF

• DONOR: Current serious systemic illness

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	OHSU Cancer Institute	Portland	Oregon	United States	97210
2	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Fred Hutchinson Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Brenda Sandmaier, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Brenda Sandmaier, Principal Investigator, Fred Hutchinson Cancer Center
• ClinicalTrials.gov Identifier: NCT00045435
• Other Study ID Numbers: 1654.00; NCI-2011-01307
• First Posted: Jan 27, 2003
• Last Update Posted: Jan 29, 2020
• Last Verified: Jan 1, 2020

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasm Metastasis; Leukemia, Monocytic, Acute; Leukemia, Myelomonocytic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Myelodysplastic Syndromes; Cyclosporine; Mycophenolic Acid; Fludarabine; Fludarabine phosphate; Cyclosporins

Study Results

Participant Flow

Arm/Group Title	Treatment (Nonmyeloablative Donor PBSC Transplant)
Arm/Group Description	Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI & allogeneic PBSC transplant on day 0. Patients also receive CSP PO BID on days -3 to 56 with taper to day 77, and MMF PO BID on days 0-27. Nonmyeloablative allogeneic hematopoietic stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant Fludarabine phosphate: Given IV Total-body irradiation: Undergo total-body irradiation Cyclosporine: Given PO Mycophenolate mofetil: Given PO Peripheral blood stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant
Period Title: Overall Study
STARTED	17
COMPLETED	17
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Nonmyeloablative Donor PBSC Transplant)
Arm/Group Description	Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI & allogeneic PBSC transplant on day 0. Patients also receive CSP PO BID on days -3 to 56 with taper to day 77, and MMF PO BID on days 0-27. Nonmyeloablative allogeneic hematopoietic stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant Fludarabine phosphate: Given IV Total-body irradiation: Undergo total-body irradiation Cyclosporine: Given PO Mycophenolate mofetil: Given PO Peripheral blood stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant
Overall Participants	17
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	10 58.8%
>=65 years	7 41.2%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64.8
Sex: Female, Male (Count of Participants)
Female	4 23.5%
Male	13 76.5%
Region of Enrollment (participants) [Number]
United States	17 100%

Outcome Measures

1. Primary Outcome

Title	Disease-free Survival-incidence of Survival Without Relapse
Description	Sufficient evidence will be taken to be an observed rate of DFS at one year after transplant that corresponds to a one-sided 95% confidence interval with an upper limit lower than 35%.
Time Frame	By 1 year after transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Nonmyeloablative Donor PBSC Transplant)
Arm/Group Description	Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI & allogeneic PBSC transplant on day 0. Patients also receive CSP PO BID on days -3 to 56 with taper to day 77, and MMF PO BID on days 0-27. Nonmyeloablative allogeneic hematopoietic stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant Fludarabine phosphate: Given IV Total-body irradiation: Undergo total-body irradiation Cyclosporine: Given PO Mycophenolate mofetil: Given PO Peripheral blood stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant
Measure Participants	17
Number [percentage of participants]	47 276.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment (Nonmyeloablative Donor PBSC Transplant)
	Comments	The study was to be stopped after 20 patients if the upper bound of a 1-sided 95% confidence interval for relapse-free survival was <35%.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percent
	Estimated Value	47
	Confidence Interval	(1-Sided) 95%; to 69
	Parameter Dispersion	Type: Value:
	Estimation Comments	The criterion for stopping was not met.

2. Primary Outcome

Title	Nonrelapse Mortality (NRM)-Incidence of Nonrelapse Death
Description	Defined as death without morphologic evidence of disease. Sufficient evidence will be taken to be an observed rate of NRM within 200 days of transplant that corresponds to a one-sided 80% confidence interval with a lower limit greater than 15%.
Time Frame	200 days after transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Nonmyeloablative Donor PBSC Transplant)
Arm/Group Description	Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI & allogeneic PBSC transplant on day 0. Patients also receive CSP PO BID on days -3 to 56 with taper to day 77, and MMF PO BID on days 0-27. Nonmyeloablative allogeneic hematopoietic stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant Fludarabine phosphate: Given IV Total-body irradiation: Undergo total-body irradiation Cyclosporine: Given PO Mycophenolate mofetil: Given PO Peripheral blood stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant
Measure Participants	17
Number [percentage of participants]	6 35.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment (Nonmyeloablative Donor PBSC Transplant)
	Comments	The study was to be stopped if the lower bound of a 1-sided 80% confidence interval for NRM was greater than 15%
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	percent
	Estimated Value	6
	Confidence Interval	(1-Sided) 80%; 1 to
	Parameter Dispersion	Type: Value:
	Estimation Comments	The stopping criterion was not met.

3. Secondary Outcome

Title	Overall Survival
Description	Percent patients surviving.
Time Frame	By 1 year after transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Nonmyeloablative Donor PBSC Transplant)
Arm/Group Description	Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI & allogeneic PBSC transplant on day 0. Patients also receive CSP PO BID on days -3 to 56 with taper to day 77, and MMF PO BID on days 0-27. Nonmyeloablative allogeneic hematopoietic stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant Fludarabine phosphate: Given IV Total-body irradiation: Undergo total-body irradiation Cyclosporine: Given PO Mycophenolate mofetil: Given PO Peripheral blood stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant
Measure Participants	17
Number [percentage of participants]	70.6 415.3%

4. Secondary Outcome

Title	Incidence of Relapse
Description	Percent patients with relapsed disease post-transplant.
Time Frame	By 1 year after transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Nonmyeloablative Donor PBSC Transplant)
Arm/Group Description	Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI & allogeneic PBSC transplant on day 0. Patients also receive CSP PO BID on days -3 to 56 with taper to day 77, and MMF PO BID on days 0-27. Nonmyeloablative allogeneic hematopoietic stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant Fludarabine phosphate: Given IV Total-body irradiation: Undergo total-body irradiation Cyclosporine: Given PO Mycophenolate mofetil: Given PO Peripheral blood stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant
Measure Participants	17
Number [percentage of participants]	41.2 242.4%

5. Secondary Outcome

Title	Incidence of Rejection
Description	Percent patients who developed infections post-transplant.
Time Frame	By 1 year after transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Nonmyeloablative Donor PBSC Transplant)
Arm/Group Description	Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI & allogeneic PBSC transplant on day 0. Patients also receive CSP PO BID on days -3 to 56 with taper to day 77, and MMF PO BID on days 0-27. Nonmyeloablative allogeneic hematopoietic stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant Fludarabine phosphate: Given IV Total-body irradiation: Undergo total-body irradiation Cyclosporine: Given PO Mycophenolate mofetil: Given PO Peripheral blood stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant
Measure Participants	17
Number [percentage of participants]	0 0%

6. Secondary Outcome

Title	Incidence of Acute and Chronic GVHD
Description	Percent patients with acute/chronic GVHD
Time Frame	aGVHD: 100 days after transplant; cGVHD: 1 Year after transplant.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Nonmyeloablative Donor PBSC Transplant)
Arm/Group Description	Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI & allogeneic PBSC transplant on day 0. Patients also receive CSP PO BID on days -3 to 56 with taper to day 77, and MMF PO BID on days 0-27. Nonmyeloablative allogeneic hematopoietic stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant Fludarabine phosphate: Given IV Total-body irradiation: Undergo total-body irradiation Cyclosporine: Given PO Mycophenolate mofetil: Given PO Peripheral blood stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant
Measure Participants	17
Grade II-IV aGVHD	35.3 207.6%
cGVHD	35.3 207.6%

Adverse Events

Time Frame	AEs: Conditioning through Day 100; SAEs: Conditioning through Day 200
Arm/Group Title	Treatment (Nonmyeloablative Donor PBSC Transplant)
Arm/Group Description	Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI & allogeneic PBSC transplant on day 0. Patients also receive CSP PO BID on days -3 to 56 with taper to day 77, and MMF PO BID on days 0-27. Nonmyeloablative allogeneic hematopoietic stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant Fludarabine phosphate: Given IV Total-body irradiation: Undergo total-body irradiation Cyclosporine: Given PO Mycophenolate mofetil: Given PO Peripheral blood stem cell transplantation: Undergo nonmyeloablative allogeneic peripheral blood stem cell transplant
All Cause Mortality
	Treatment (Nonmyeloablative Donor PBSC Transplant)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Nonmyeloablative Donor PBSC Transplant)
	Affected / at Risk (%)	# Events
Total	5/17 (29.4%)
Cardiac disorders
Ventricular arrhythmia	1/17 (5.9%)	1
Immune system disorders
GVHD	1/17 (5.9%)	1
Infections and infestations
Sepsis	2/17 (11.8%)	2
Musculoskeletal and connective tissue disorders
Flank pain	1/17 (5.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary malignancy	1/17 (5.9%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Nonmyeloablative Donor PBSC Transplant)
	Affected / at Risk (%)	# Events
Total	4/17 (23.5%)
Cardiac disorders
Heart failure	1/17 (5.9%)	1
Ventricular arrhythmia	1/17 (5.9%)	1
Investigations
Neutrophil count decreased	2/17 (11.8%)	2
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/17 (5.9%)	3
Vascular disorders
Thromboembolic event	1/17 (5.9%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.