Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Chemotherapy and Donor Peripheral Stem Cell Transplant in Treating Patients With Hematologic Disease or Hematologic Cancer

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase II Treatment Active 8 to 80 NHLBI NHLBI-99-H-0050 NCT00003838

Special Category: NIH Clinical Center trial

Objectives

1. 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.
2. Determine engraftment in patients treated with this regimen.
3. Determine the incidence and severity of acute and chronic graft-versus-host disease after the transplantation in these patients.
4. Determine the efficacy of controlling hematologic cancers by induction of a graft-versus-tumor effect in these patients.
5. Determine the rate of disease-free survival, relapse, transplant-related mortality, and death from all causes in patients treated with this regimen.

Entry 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

Prior/Concurrent Therapy:

Biologic therapy

• See Disease Characteristics

Chemotherapy

• See Disease Characteristics

Endocrine therapy

• Not specified

Radiotherapy

• See Disease Characteristics

Surgery

• Not specified

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

Expected Enrollment

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

Outcomes

Transplant-related mortality (200-day survival)

Engraftment
Degree of donor-host chimerism
Incidence of acute and chronic graft-versus-host disease
Transplant-related morbidity
Disease-free survival

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.

Takahashi Y, McCoy JP Jr, Carvallo C, et al.: In vitro and in vivo evidence of PNH cell sensitivity to immune attack after nonmyeloablative allogeneic hematopoietic cell transplantation. Blood 103 (4): 1383-90, 2004.[PUBMED Abstract]

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, et al.: Prior chemotherapy and allograft CD34+ dose impact donor engraftment following nonmyeloablative allogeneic stem cell transplantation in patients with solid tumors. Blood 103 (4): 1560-3, 2004.[PUBMED Abstract]

Srinivasan R, Chakrabarti S, Walsh T, et al.: 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 124 (6): 777-86, 2004.[PUBMED Abstract]

Bolan CD, Carter CS, Wesley RA, et al.: 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 120 (5): 801-7, 2003.[PUBMED Abstract]

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, et al.: A preliminary comparison of flow cytometry and tube agglutination assays in detecting red blood cell-associated C3d. Transfus Med 13 (1): 35-41, 2003.[PUBMED Abstract]

Hematti P, Sloand EM, Carvallo CA, et al.: Absence of donor-derived keratinocyte stem cells in skin tissues cultured from patients after mobilized peripheral blood hematopoietic stem cell transplantation. Exp Hematol 30 (8): 943-9, 2002.[PUBMED Abstract]

Nakamura R, Cortez K, Solomon S, et al.: High-dose acyclovir and pre-emptive ganciclovir to prevent cytomegalovirus disease in myeloablative and non-myeloablative allogeneic stem cell transplantation. Bone Marrow Transplant 30 (4): 235-42, 2002.[PUBMED Abstract]

Bolan CD, Childs RW, Procter JL, et al.: Massive immune haemolysis after allogeneic peripheral blood stem cell transplantation with minor ABO incompatibility. Br J Haematol 112 (3): 787-95, 2001.[PUBMED Abstract]

Bolan CD, Leitman SF, Griffith LM, et al.: Delayed donor red cell chimerism and pure red cell aplasia following major ABO-incompatible nonmyeloablative hematopoietic stem cell transplantation. Blood 98 (6): 1687-94, 2001.[PUBMED Abstract]

Cortez KJ, Erdman DD, Peret TC, et al.: Outbreak of human parainfluenza virus 3 infections in a hematopoietic stem cell transplant population. J Infect Dis 184 (9): 1093-7, 2001.[PUBMED Abstract]

Graber C, de Almeider KN, Childs R, et al.: CMV reactivation in nonmyeloablative HSCT. Bone Marrow Transplant 27 (7): 775, 2001.[PUBMED Abstract]

Barrett J, Childs R: Non-myeloablative stem cell transplants. Br J Haematol 111 (1): 6-17, 2000.[PUBMED Abstract]

Childs R, Clave E, Contentin N, et al.: Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses. Blood 94 (9): 3234-41, 1999.[PUBMED Abstract]

Childs R, Epperson D, Bahceci E, et al.: 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 107 (2): 396-400, 1999.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

National Heart, Lung, and Blood Institute

Richard Childs, MD, Protocol chair		Ph: 301-594-8008 Email: childsr@nih.gov

U.S.A.
Maryland
	Bethesda
	NIH - Warren Grant Magnuson Clinical Center
		Patient Recruitment	Ph:  800-411-1222

Registry Information
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
Trial Start Date		1999-02-19
Trial Completion Date		2009-12-30 (estimated)
Registered in ClinicalTrials.gov		NCT00003838
Date Submitted to PDQ		1999-03-30
Information Last Verified		2008-11-30