Chemotherapy and Donor Peripheral Stem Cell Transplant in Treating Patients With Hematologic Disease or Hematologic Cancer - Full Text View

Sponsored by:	National Heart, Lung, and Blood Institute (NHLBI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00003838

Purpose

RATIONALE: Giving low doses of chemotherapy, such as fludarabine and cyclophosphamide, before a donor stem cell transplant helps stop the growth of abnormal cells and cancer. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining abnormal or cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving antithymocyte globulin before transplant and cyclosporine after transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving chemotherapy followed by a donor peripheral stem cell transplant works in treating patients with hematologic disease or hematologic cancer.

Condition	Intervention	Phase
Chronic Myeloproliferative Disorders Graft Versus Host Disease Leukemia Lymphoma Multiple Myeloma and Plasma Cell Neoplasm Myelodysplastic Syndromes Myelodysplastic/Myeloproliferative Diseases	Biological: anti-thymocyte globulin Biological: therapeutic allogeneic lymphocytes Drug: cyclophosphamide Drug: cyclosporine Drug: fludarabine phosphate Procedure: peripheral blood stem cell transplantation	Phase II

Study Type:	Interventional
Study Design:	Treatment
Official Title:	Non-Myeloablative Allogeneic Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Hematologic Malignancies in High Risk Patients and in Patients With Debilitating Hematologic Diseases

Resource links provided by NLM:

Genetics Home Reference related topics: aceruloplasminemia hemophilia

MedlinePlus related topics: Anemia Cancer Leukemia, Adult Acute Leukemia, Adult Chronic Leukemia, Childhood Lymphoma Multiple Myeloma

Drug Information available for: Cyclophosphamide Fludarabine Cyclosporine Fludarabine monophosphate Cyclosporin

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Transplant-related mortality (200-day survival) [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Engraftment [ Designated as safety issue: No ]
Degree of donor-host chimerism [ Designated as safety issue: No ]
Incidence of acute and chronic graft-versus-host disease [ Designated as safety issue: Yes ]
Transplant-related morbidity [ Designated as safety issue: Yes ]
Disease-free survival [ Designated as safety issue: No ]

Estimated Enrollment:	90
Study Start Date:	February 1999
Estimated Primary Completion Date:	December 2009 (Final data collection date for primary outcome measure)

Detailed Description:

OBJECTIVES:

Determine the safety and toxicity of a low-intensity nonmyeloablative preparative regimen followed by an allogeneic peripheral blood stem cell transplantation in high-risk patients with hematologic cancer or disease.
Determine engraftment in patients treated with this regimen.
Determine the incidence and severity of acute and chronic graft-versus-host disease after the transplantation in these patients.
Determine the efficacy of controlling hematologic cancers by induction of a graft-versus-tumor effect in these patients.
Determine the rate of disease-free survival, relapse, transplant-related mortality, and death from all causes in patients treated with this regimen.

OUTLINE:

Nonmyeloablative intensive immunosuppressive conditioning regimen: Patients receive cyclophosphamide IV over

1 hour on days -7 and -6 and fludarabine IV over 30 minutes on days -5 to -1. High-risk patients also receive antithymocyte globulin IV on days -5 through -2.
Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo allogeneic PBSCT on day 0.

Patients receive T-cell replete, donor-derived, granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood stem cells to establish hematopoietic and lymphoid reconstitution.

Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine (CSA) IV or orally twice daily beginning on day -4 and continuing to 100 followed by a taper. Patients with < 100% donor T-cell chimerism on day 30 receive a 12-day CSA taper in the absence of acute GVHD > grade 2. Patients with 100% donor T-cell chimerism by day 30 and without evidence of acute GVHD > grade 2 receive a CSA taper from days 60 through 100.

Patients with evidence of disease progression and without acute GVHD > grade 2 also undergo a CSA taper, regardless of chimerism results. Patients also receive methotrexate IV on days 1, 3, and 6.

Patients are followed at 3 and 6 months, every 6 months for 2.5 years, and then annually for 5 years.

PROJECTED ACCRUAL: A total of 90 patients (45 per group) will be accrued for this study.

Eligibility

Ages Eligible for Study:	8 Years to 80 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Group A

Any of the following diseases:
- Chronic myelogenous leukemia in chronic phase
- Acute lymphoblastic leukemia in complete or partial remission
- Acute myelogenous leukemia (AML) in first complete or partial remission except for AML with good risk karyotypes: AML M3 t(15;17), AML M4Eo (inv. 16), AML t(8;21)
- AML in second or subsequent complete remission
- Myelodysplastic syndromes
  - Refractory anemia with excess blasts (RAEB)
  - RAEB in transformation
  - Chronic myelomonocytic leukemia
- Myeloproliferative diseases associated with either cytopenia or uncontrolled proliferation
- Chronic lymphocytic leukemia in complete or partial remission
- Prolymphocytic leukemia in complete or partial remission
- Mantle cell lymphoma
- Lymphoproliferative disorders
- Viral-associated hemophagocytic syndromes
- Relapsed Hodgkin's lymphoma
- Relapsed non-Hodgkin's lymphoma
- Therapy responsive or stable plateau phase multiple myeloma or extramedullary plasmacytomas AND
- Age 10 to 55 with high risk for transplant-related complications and mortality due to history of one of the following:
  - Dose-intensive chemotherapy or radiotherapy
  - History of allogeneic or autologous transplantation
  - History of multiple myeloma or extramedullary plasmacytoma
  - Chronic disease or comorbid medical condition, including significant pulmonary, hepatic, kidney, cardiac, or other organ system disease that would result in increased risk of death from a standard myeloablative transplantation

Group B:

Any of the following diseases:
- Paroxysmal nocturnal hemoglobinuria associated with life-threatening thrombosis, cytopenia, transfusion dependence, or recurrent debilitating hemolytic crisis (age 8 to 80)
- Aplastic anemia or pure red cell aplasia associated with transfusion dependence and/or neutropenia and failed immunosuppressive therapy (age 8 to 80)
- Refractory anemia (RA) or RA with ringed sideroblasts that has failed treatment with antithymocyte globulin or cyclosporine, with transfusion dependence and/or neutropenia (age 8 to 80) AND
- Curable by allogeneic bone marrow transplantation but high procedural mortality with conventional bone marrow transplantation may delay or prevent this treatment

PATIENT CHARACTERISTICS:

Age:

8 to 80

Performance status:

ECOG 0-2

Life expectancy:

Not specified

Hematopoietic:

See Disease Characteristics

Hepatic:

See Disease Characteristics
Bilirubin no greater than 4 mg/dL
SGOT/SGPT no greater than 5 times upper limit of normal

Renal:

Creatinine no greater than 2.5 mg/dL

Cardiovascular:

LVEF at least 30%

Pulmonary:

DLCO at least 40% predicted

Other:

Not pregnant or nursing
No psychiatric disorder or severe mental deficiency
No other major illness or organ failure
No other malignant disease liable to relapse or progress within 5 years

PRIOR CONCURRENT THERAPY:

Biologic therapy

See Disease Characteristics

Chemotherapy

See Disease Characteristics

Endocrine therapy

Not specified

Radiotherapy

See Disease Characteristics

Surgery

Not specified

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00003838

Locations

United States, Maryland
NIH - Warren Grant Magnuson Clinical Center	Recruiting
Bethesda, Maryland, United States, 20892-1182
Contact: Patient Recruitment 800-411-1222

Sponsors and Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

Study Chair:

Richard W. Childs, MD

National Heart, Lung, and Blood Institute (NHLBI)

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Publications:

Takahashi Y, McCoy JP Jr, Carvallo C, Rivera C, Igarashi T, Srinivasan R, Young NS, Childs RW. In vitro and in vivo evidence of PNH cell sensitivity to immune attack after nonmyeloablative allogeneic hematopoietic cell transplantation. Blood. 2004 Feb 15;103(4):1383-90. Epub 2003 Oct 2.

Chakrabarti S, Takahashi Y, Srinivasan R, et al.: Durable engraftment and long-term survival following fludarabine-based nonmyeloablative hematopoietic cell transplantation (HCT) in allo-immunized patients with ATG-refractory severe aplastic anemia (SAA) and paroxysmal nocturnal hemoglobinuria (PNH). [Abstract] Blood 102 (11): A-1711, 2003.

Espinoza-Delgado IJ, Shetty V, Geller N, et al.: Impact of age on transplant related mortality (TRM) following fludarabine and cyclophosphamide-based nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). [Abstract] Blood 102 (11): A-2656, 2003.

Gorak E, Geller N, Srinivasan R, et al.: Decreased survival in patients with pulmonary engraftment syndrome following nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). [Abstract] Blood 102 (11): A-1714, 2003.

Reese A, Stevens WT, Donohue T, et al.: Clinical and laboratory features of minor ABO incompatible reduced intensity blood hematopoietic cell transplantation using cyclosporin (CsA) vs. CsA/mycophenolate mofetil (CsA/MMF) for graft-vs-host disease (GVHD) prophylaxis. [Abstract] Blood 102 (11): A-2620, 2003.

Carvallo C, Geller N, Kurlander R, Srinivasan R, Mena O, Igarashi T, Griffith LM, Linehan WM, Childs RW. Prior chemotherapy and allograft CD34+ dose impact donor engraftment following nonmyeloablative allogeneic stem cell transplantation in patients with solid tumors. Blood. 2004 Feb 15;103(4):1560-3. Epub 2003 Oct 9.

Srinivasan R, Chakrabarti S, Walsh T, Igarashi T, Takahashi Y, Kleiner D, Donohue T, Shalabi R, Carvallo C, Barrett AJ, Geller N, Childs R. Improved survival in steroid-refractory acute graft versus host disease after non-myeloablative allogeneic transplantation using a daclizumab-based strategy with comprehensive infection prophylaxis. Br J Haematol. 2004 Mar;124(6):777-86.

Bolan CD, Carter CS, Wesley RA, Yau YY, Barrett AJ, Childs RW, Read EJ, Leitman SF. Prospective evaluation of cell kinetics, yields and donor experiences during a single large-volume apheresis versus two smaller volume consecutive day collections of allogeneic peripheral blood stem cells. Br J Haematol. 2003 Mar;120(5):801-7.

Chakrabarti S, Balow JE, Srinivasan R, et al.: High-incidence of nephrotic syndrome associated with significant morbidity following nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). [Abstract] Blood 102 (11): A-2687, 2003.

Daniels JT, Fusaro V, Rosenblatt K, et al.: Serologic methods to diagnose acute GVHD based on protein patterns using surface-enhanced-laser-desorption-ionization-time of flight (SELDI-TOF) mass spectrometry. [Abstract] Blood 102 (11): A-3536, 2003.

Stroncek DF, Njoroge JM, Procter JL, Childs RW, Miller J. A preliminary comparison of flow cytometry and tube agglutination assays in detecting red blood cell-associated C3d. Transfus Med. 2003 Feb;13(1):35-41.

Hematti P, Sloand EM, Carvallo CA, Albert MR, Yee CL, Fuehrer MM, Blancato JK, Kearns WG, Barrett JA, Childs RW, Vogel JC, Dunbar CE. Absence of donor-derived keratinocyte stem cells in skin tissues cultured from patients after mobilized peripheral blood hematopoietic stem cell transplantation. Exp Hematol. 2002 Aug;30(8):943-9.

Nakamura R, Cortez K, Solomon S, Battiwalla M, Gill VJ, Hensel N, Childs R, Barrett AJ. High-dose acyclovir and pre-emptive ganciclovir to prevent cytomegalovirus disease in myeloablative and non-myeloablative allogeneic stem cell transplantation. Bone Marrow Transplant. 2002 Aug;30(4):235-42.

Bolan CD, Childs RW, Procter JL, Barrett AJ, Leitman SF. Massive immune haemolysis after allogeneic peripheral blood stem cell transplantation with minor ABO incompatibility. Br J Haematol. 2001 Mar;112(3):787-95.

Bolan CD, Leitman SF, Griffith LM, Wesley RA, Procter JL, Stroncek DF, Barrett AJ, Childs RW. Delayed donor red cell chimerism and pure red cell aplasia following major ABO-incompatible nonmyeloablative hematopoietic stem cell transplantation. Blood. 2001 Sep 15;98(6):1687-94.

Cortez KJ, Erdman DD, Peret TC, Gill VJ, Childs R, Barrett AJ, Bennett JE. Outbreak of human parainfluenza virus 3 infections in a hematopoietic stem cell transplant population. J Infect Dis. 2001 Nov 1;184(9):1093-7. Epub 2001 Oct 12.

Graber C, de Almeider KN, Childs R, Barrett AJ, Gill VJ, Bennett JE. CMV reactivation in nonmyeloablative HSCT. Bone Marrow Transplant. 2001 Apr;27(7):775. No abstract available.

Barrett J, Childs R. Non-myeloablative stem cell transplants. Br J Haematol. 2000 Oct;111(1):6-17. Review. No abstract available.

Childs R, Clave E, Contentin N, Jayasekera D, Hensel N, Leitman S, Read EJ, Carter C, Bahceci E, Young NS, Barrett AJ. Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses. Blood. 1999 Nov 1;94(9):3234-41.

Childs R, Epperson D, Bahceci E, Clave E, Barrett J. Molecular remission of chronic myeloid leukaemia following a non-myeloablative allogeneic peripheral blood stem cell transplant: in vivo and in vitro evidence for a graft-versus-leukaemia effect. Br J Haematol. 1999 Nov;107(2):396-400.

Responsible Party:	National Heart, Lung, and Blood Institute ( Richard W. Childs )
Study ID Numbers:	CDR0000066996, NHLBI-99-H-0050
Study First Received:	November 1, 1999
Last Updated:	June 23, 2009
ClinicalTrials.gov Identifier:	NCT00003838 History of Changes
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

recurrent adult Hodgkin lymphoma
extramedullary plasmacytoma
Waldenstrom macroglobulinemia
stage I multiple myeloma
stage II multiple myeloma
stage III multiple myeloma
recurrent childhood lymphoblastic lymphoma
stage I chronic lymphocytic leukemia
stage II chronic lymphocytic leukemia
stage III chronic lymphocytic leukemia
chronic phase chronic myelogenous leukemia
adult acute myeloid leukemia in remission
adult acute lymphoblastic leukemia in remission
childhood acute myeloid leukemia in remission
childhood acute lymphoblastic leukemia in remission

polycythemia vera
chronic idiopathic myelofibrosis
essential thrombocythemia
recurrent/refractory childhood Hodgkin lymphoma
refractory anemia
refractory anemia with ringed sideroblasts
refractory anemia with excess blasts
refractory anemia with excess blasts in transformation
chronic myelomonocytic leukemia
T-cell large granular lymphocyte leukemia
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult diffuse mixed cell lymphoma

Study placed in the following topic categories:

Anti-Infective Agents
Cyclosporine
Mantle Cell Lymphoma
Cyclosporins
Refractory Anemia
Graft Versus Host Disease
Preleukemia
Leukemia, Prolymphocytic
Hemorrhagic Disorders
Neoplasm Metastasis
Thrombocythemia, Hemorrhagic
Myelodysplastic Myeloproliferative Disease
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Hematologic Diseases
Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative

Leukemia, Myelomonocytic, Chronic
Blood Coagulation Disorders
Leukemia, Myeloid
Waldenstrom Macroglobulinemia
Plasmacytoma
Chronic Myelogenous Leukemia
Fludarabine
Lymphoma, Non-Hodgkin
Immunologic Factors
Precancerous Conditions
Blood Protein Disorders
Lymphoma, Follicular
Lymphoblastic Lymphoma
Lymphoma, B-Cell
Leukemia

Additional relevant MeSH terms:

Anti-Infective Agents
Cyclosporine
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Cyclosporins
Preleukemia
Hemorrhagic Disorders
Pathologic Processes
Therapeutic Uses
Cardiovascular Diseases
Dermatologic Agents
Immunoproliferative Disorders
Immune System Diseases
Hematologic Diseases

Myeloproliferative Disorders
Multiple Myeloma
Neoplasms
Fludarabine
Antimetabolites
Precancerous Conditions
Immunologic Factors
Blood Protein Disorders
Antineoplastic Agents
Paraproteinemias
Cyclophosphamide
Hemostatic Disorders
Leukemia
Syndrome
Antifungal Agents

ClinicalTrials.gov processed this record on September 02, 2009