Fludarabine, Cyclophosphamide, and Total-Body Irradiation in Treating Patients Who Are Undergoing a Donor Bone Marrow Transplant for Hematologic Cancer

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Completed
• CT.gov ID: NCT00134004
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 210
• Locations: 3
• Arm: 1
• Duration (Months): 123
• Patients Per Site: 70
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

RATIONALE: Giving low doses of chemotherapy, such as fludarabine and cyclophosphamide, and radiation therapy before a donor bone marrow transplant helps stop the growth of cancer cells. Giving chemotherapy or radiation therapy before or after transplant also stops the patient's immune system from rejecting the donor's bone marrow stem cells. The donated stem cells may replace the patient's immune system 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 tacrolimus and mycophenolate mofetil after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation 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: cyclophosphamide; Drug: fludarabine phosphate; Drug: mycophenolate mofetil; Drug: tacrolimus; Procedure: allogeneic bone marrow transplantation; Radiation: radiation therapy	Phase 2

Detailed Description

OBJECTIVES:

• Determine transplant-related mortality, risk of relapse, and progression-free survival of patients with standard- or high-risk hematologic malignancies undergoing nonmyeloablative conditioning comprising fludarabine, cyclophosphamide, and total-body irradiation followed by HLA-haploidentical allogeneic bone marrow transplantation.

• Determine donor hematopoietic chimerism in patients' peripheral blood at 30, 60, and 180 days after transplantation.

• Determine hematologic and nonhematologic toxic effects of this regimen in these patients.

• Determine, when feasible, surface expression of HLA molecules and death receptors, sensitivity to cytotoxic lymphocytes, and expression of anti-apoptotic genes (e.g., Bcl-2, Bcl-xL, X-IAP, and c-FLIP) in cancer cells from patients who relapse after treatment with this regimen.

OUTLINE: This is a multicenter study. Patients are stratified according to risk of relapse (standard [defined as ≤ 30% risk] vs high [defined as ≥ 70% risk]).

• Nonmyeloablative conditioning regimen: Patients receive fludarabine IV over 30 minutes on days -6 to -2 and cyclophosphamide IV over 1-2 hours on days -6 and -5. Patients undergo total body irradiation on day -1.

• Allogeneic bone marrow transplantation: Patients undergo donor bone marrow infusion on day 0.

• Post-transplantation therapy: Patients receive cyclophosphamide IV over 1-2 hours on days 3 and 4.

• Graft-vs-host disease prophylaxis: Beginning on day 5, patients receive oral mycophenolate mofetil 3 times daily until day 35 and tacrolimus IV (then changing to orally) twice daily until day 180.

Treatment continues in the absence of disease progression.

After completion of study transplantation, patients are followed on days 30, 60, 100, and 180; at 1 year; and then annually for 4 additional years.

PROJECTED ACCRUAL: A total of 75-100 patients will be accrued for this study within 3-4 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 210 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Non-Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched Bone Marrow for Patients With Hematologic Malignancies
• Study Start Date: Oct 1, 2004
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Jan 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Mini-haplo Transplant Non-myeloablative haploidentical bone marrow transplant with a fludarabine, cyclophosphamide (Cy), TBI (total body irradiation) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis.	Drug: cyclophosphamide; Drug: fludarabine phosphate; Drug: mycophenolate mofetil; Drug: tacrolimus; Procedure: allogeneic bone marrow transplantation; Radiation: radiation therapy

Outcome Measures

Primary Outcome Measures

1. Transplant-related Mortality [Cumulative incidence for the entire study, up to 11 years]

   Percentage of participants who die for any reason other than recurrence of disease.

2. Relapse Rate [Cumulative incidence for the entire study, up to 11 years]

   Percentage of participants who experience disease relapse.

3. Progression-free Survival [2 years]

   Percentage of participants who do not experience disease relapse, disease progression, or death.

Secondary Outcome Measures

1. Graft Failure Rate [Cumulative incidence for the entire study, up to 11 years]

   Percentage of participants who experienced failure to engraft (also called graft failure or graft rejection). Failure to engraft is defined as <5% donor chimerism and absence of relapse or any other reason for that chimerism value. All participants who met this criterion were included in this outcome measure.

2. Hematologic and Non-hematologic Toxicities as Measured by NCI Common Toxicity Criteria for Adverse Events, v 3.0 Weekly Until 1 Year After Transplantation [1 year]

   Percentage of study participants who experienced a serious adverse event (SAE) within 1 year of bone marrow transplant. Complete data is provided in the Adverse Event tables.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months to 74 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following hematologic malignancies:

• Acute leukemia

• In second or subsequent complete remission (CR), as defined by absence of abnormal blast population by flow cytometry

• In first CR with any of the following poor-risk cytogenetic features:

• Alteration of chromosome 5 or 7

• Multiple abnormalities

• Philadelphia chromosome positive

• Chronic phase chronic myelogenous leukemia (CML)

• In first chronic phase and refractory to interferon alfa or imatinib mesylate

• In second or subsequent chronic phase

• Chronic lymphocytic leukemia, meeting 1 of the following criteria:

• Received prior chemotherapy with a nucleoside analog and had remission lasting < 6 months

• Received 1 prior therapy and has any of the following high-risk features:

• Cytogenetic abnormalities of 17p, 11q

• Mutations of the Zap70 gene

• Somatically unmutated immunoglobulin heavy chain variable region genes

• Hodgkin's lymphoma

• Ineligible for autologous stem cell transplantation (SCT) due to any of the following exclusion factors:

• LVEF < 45%

• FEV_1 or FVC < 50% of predicted (75% of predicted in patients with prior thoracic or mantle radiotherapy)

• Total bilirubin > 2.0 mg/dL (unless documented Gilbert's disease)

• Creatinine > 2.0 mg/dL

• Non-Hodgkin's lymphoma (NHL)

• Low-grade NHL allowed provided patient had a remission duration of < 1 year after administration of any established, multi-agent chemotherapy regimen (e.g., CVP, CHOP, or rituximab in combination with CHOP)

• Intermediate- or high-grade NHL allowed provided patient is ineligible for autologous SCT according to the criteria listed above

• Multiple myeloma

• Myelodysplastic syndromes

• Paroxysmal nocturnal hemoglobinuria

• Chronic myeloproliferative disorders other than CML, including any of the following:

• Chronic myelomonocytic leukemia

• Agnogenic myeloid metaplasia (or myeloid metaplasia with myelofibrosis), with hemoglobin < 10 g/dL OR WBC < 4,000/mm^{3 or > 30,000/mm}3

• Polycythemia vera or essential thrombocythemia in "spent" phase, with a history of 2 of the following:

• Marrow fibrosis

• Splenomegaly

• Cytopenia (i.e., absolute neutrophil count < 1,500/mm^{3, platelet count < 100,000/mm}3, hemoglobin < 10 g/dL)

• Polycythemia vera or essential thrombocythemia with transformation to myelodysplastic syndromes or acute myeloid leukemia (requires treatment to achieve < 20% blasts in marrow)

• No smoldering myeloma

• Patients with acute myeloid leukemia or myelodysplastic syndromes must have had comprehensive cytogenetic evaluation of bone marrow specimen during active disease

• Ineligible for or refused bone marrow transplantation from an HLA-matched sibling or unrelated donor

• Ineligible for or refused autologous SCT

• Must have an HLA mismatched (i.e., 3/6, 4/6, or 5/6) related (first-degree relative)* donor available

• Donor ≥ 18 years of age NOTE: *Patients with an inherited recombinant HLA haplotype may receive marrow from the parent in whose gamete the recombination occurred

NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.

PATIENT CHARACTERISTICS:

Age

• 6 months to 74 years

Performance status

• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• See Disease Characteristics

Hepatic

• See Disease Characteristics

• Bilirubin < 3.1 mg/dL

Renal

• See Disease Characteristics

Cardiovascular

• See Disease Characteristics

• LVEF ≥ 35%

Pulmonary

• See Disease Characteristics

• FEV_1 or FVC ≥ 40% of predicted in patients without prior thoracic or mantle radiotherapy (60% of predicted in patients with prior thoracic or mantle radiotherapy)

Other

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• HIV negative

• Geographically accessible

• No debilitating medical or psychiatric illness that would preclude giving informed consent or receiving optimal treatment or follow-up

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics

• No prior transfusions from donor

Chemotherapy

• See Disease Characteristics

Endocrine therapy

• Not specified

Radiotherapy

• See Disease Characteristics

Surgery

• Not specified

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Blood and Marrow Transplant Program at Northside Hospital	Atlanta	Georgia	United States	30342
2	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231-2410
3	Hahnemann University Hospital	Philadelphia	Pennsylvania	United States	19102-1192

Sponsors and Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• National Cancer Institute (NCI)

Investigators

• Study Chair: Ephraim J. Fuchs, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT00134004
• Other Study ID Numbers: J0457 CDR0000440990; P01CA015396; P30CA006973; JHOC-J0457; JHOC-04072704
• First Posted: Aug 24, 2005
• Last Update Posted: Oct 6, 2015
• Last Verified: Sep 1, 2015

• Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: adult acute lymphoblastic leukemia in remission; adult acute myeloid leukemia in remission; childhood acute lymphoblastic leukemia in remission; childhood acute myeloid leukemia in remission; childhood chronic myelogenous leukemia; chronic phase chronic myelogenous leukemia; refractory chronic lymphocytic leukemia; extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue; 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); chronic idiopathic myelofibrosis; chronic myelomonocytic leukemia; de novo myelodysplastic syndromes; previously treated myelodysplastic syndromes; noncontiguous stage II adult Burkitt lymphoma; noncontiguous stage II adult diffuse large cell lymphoma; noncontiguous stage II adult diffuse mixed cell lymphoma; noncontiguous stage II adult diffuse small cleaved cell lymphoma; noncontiguous stage II adult immunoblastic large cell lymphoma; noncontiguous stage II adult lymphoblastic lymphoma; noncontiguous stage II grade 1 follicular lymphoma; noncontiguous stage II grade 2 follicular lymphoma; noncontiguous stage II grade 3 follicular lymphoma; noncontiguous stage II mantle cell lymphoma; noncontiguous stage II marginal zone lymphoma; noncontiguous stage II small lymphocytic 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 Hodgkin lymphoma; recurrent adult immunoblastic large cell lymphoma; recurrent adult lymphoblastic lymphoma; recurrent/refractory childhood Hodgkin lymphoma; recurrent childhood large cell lymphoma; recurrent childhood lymphoblastic lymphoma; recurrent childhood small noncleaved cell lymphoma; nodal marginal zone B-cell lymphoma; 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; refractory multiple myeloma; relapsing chronic myelogenous leukemia; secondary myelodysplastic syndromes; splenic marginal zone lymphoma; stage I multiple myeloma; stage II multiple myeloma; stage III multiple myeloma; stage III adult Burkitt lymphoma; stage III adult diffuse large cell lymphoma; stage III adult diffuse mixed cell lymphoma; stage III adult diffuse small cleaved cell lymphoma; stage III adult Hodgkin lymphoma; stage III adult immunoblastic large cell lymphoma; stage III adult lymphoblastic lymphoma; stage III grade 1 follicular lymphoma; stage III grade 2 follicular lymphoma; stage III grade 3 follicular lymphoma; stage III mantle cell lymphoma; stage III marginal zone lymphoma; polycythemia vera; essential thrombocythemia; stage III small lymphocytic lymphoma; stage IV mantle cell lymphoma; stage IV marginal zone lymphoma; stage IV grade 1 follicular lymphoma; stage IV grade 2 follicular lymphoma; stage IV grade 3 follicular lymphoma; stage IV adult Burkitt lymphoma; stage IV adult diffuse large cell lymphoma; stage IV adult diffuse mixed cell lymphoma; stage IV adult diffuse small cleaved cell lymphoma; stage IV adult immunoblastic large cell lymphoma; stage IV adult lymphoblastic lymphoma; stage IV small lymphocytic lymphoma; stage IV adult Hodgkin lymphoma; childhood myelodysplastic syndromes
• Additional relevant MeSH terms: Lymphoma; Leukemia; Multiple Myeloma; Neoplasms, Plasma Cell; Preleukemia; Plasmacytoma; Myelodysplastic Syndromes; Myeloproliferative Disorders; Syndrome; Mycophenolic Acid; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Tacrolimus

Study Results

Participant Flow

Arm/Group Title	Mini-haplo BMT
Arm/Group Description	Non-myeloablative haploidentical bone marrow transplant with a fludarabine, cyclophosphamide (Cy), TBI (total body irradiation) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis.
Period Title: Overall Study
STARTED	210
COMPLETED	210
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Mini-haplo BMT
Arm/Group Description	Non-myeloablative haploidentical bone marrow transplant with a fludarabine, cyclophosphamide (Cy), TBI (total body irradiation) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis.
Overall Participants	210
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	52
Sex: Female, Male (Count of Participants)
Female	61 29%
Male	149 71%
Region of Enrollment (participants) [Number]
United States	210 100%

Outcome Measures

1. Primary Outcome

Title	Transplant-related Mortality
Description	Percentage of participants who die for any reason other than recurrence of disease.
Time Frame	Cumulative incidence for the entire study, up to 11 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mini-haplo BMT
Arm/Group Description	Non-myeloablative haploidentical bone marrow transplant with a fludarabine, cyclophosphamide (Cy), TBI (total body irradiation) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis.
Measure Participants	210
Number [percentage of participants]	18 8.6%

2. Primary Outcome

Title	Relapse Rate
Description	Percentage of participants who experience disease relapse.
Time Frame	Cumulative incidence for the entire study, up to 11 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mini-haplo BMT
Arm/Group Description	Non-myeloablative haploidentical bone marrow transplant with a fludarabine, cyclophosphamide (Cy), TBI (total body irradiation) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis.
Measure Participants	210
Number [percentage of participants]	55 26.2%

3. Primary Outcome

Title	Progression-free Survival
Description	Percentage of participants who do not experience disease relapse, disease progression, or death.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mini-haplo BMT
Arm/Group Description	Non-myeloablative haploidentical bone marrow transplant with a fludarabine, cyclophosphamide (Cy), TBI (total body irradiation) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis.
Measure Participants	210
Number [percentage of participants]	34 16.2%

4. Secondary Outcome

Title	Graft Failure Rate
Description	Percentage of participants who experienced failure to engraft (also called graft failure or graft rejection). Failure to engraft is defined as <5% donor chimerism and absence of relapse or any other reason for that chimerism value. All participants who met this criterion were included in this outcome measure.
Time Frame	Cumulative incidence for the entire study, up to 11 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mini-haplo BMT
Arm/Group Description	Non-myeloablative haploidentical bone marrow transplant with a fludarabine, cyclophosphamide (Cy), TBI (total body irradiation) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis.
Measure Participants	210
Number [percentage of participants]	13 6.2%

5. Secondary Outcome

Title	Hematologic and Non-hematologic Toxicities as Measured by NCI Common Toxicity Criteria for Adverse Events, v 3.0 Weekly Until 1 Year After Transplantation
Description	Percentage of study participants who experienced a serious adverse event (SAE) within 1 year of bone marrow transplant. Complete data is provided in the Adverse Event tables.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mini-haplo BMT
Arm/Group Description	Non-myeloablative haploidentical bone marrow transplant with a fludarabine, cyclophosphamide (Cy), TBI (total body irradiation) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis.
Measure Participants	210
Number [percentage of participants]	9.5 4.5%

Adverse Events

Arm/Group Title	Mini-haplo BMT
Arm/Group Description	Non-myeloablative haploidentical bone marrow transplant with a fludarabine, cyclophosphamide (Cy), TBI (total body irradiation) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis.
All Cause Mortality
	Mini-haplo BMT
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Mini-haplo BMT
	Affected / at Risk (%)	# Events
Total	20/210 (9.5%)
Cardiac disorders
Atrial fibrillation	1/210 (0.5%)	1
Gastrointestinal disorders
Ascites	1/210 (0.5%)	1
Cholestasis	1/210 (0.5%)	1
GI bleed	2/210 (1%)	2
Infections and infestations
Fungemia	3/210 (1.4%)	3
Neutropenic fever	1/210 (0.5%)	1
Pneumonia	5/210 (2.4%)	5
Sepsis	6/210 (2.9%)	6
Investigations
Multi-organ failure	1/210 (0.5%)	1
Nervous system disorders
Altered mental status	1/210 (0.5%)	1
Posterior reversible encephalopathy syndrome	1/210 (0.5%)	1
Seizure	1/210 (0.5%)	1
Renal and urinary disorders
Acute kidney injury	2/210 (1%)	2
Renal failure	4/210 (1.9%)	4
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/210 (0.5%)	1
Dyspnea	1/210 (0.5%)	1
Idiopathic pneumonia syndrome	1/210 (0.5%)	1
Pulmonary Vascular Obstructive Disease	1/210 (0.5%)	1
Respiratory failure	8/210 (3.8%)	8
Vascular disorders
Subdural hematoma	3/210 (1.4%)	3
Other (Not Including Serious) Adverse Events
	Mini-haplo BMT
	Affected / at Risk (%)	# Events
Total	11/210 (5.2%)
Infections and infestations
Pneumonia	11/210 (5.2%)	11

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.