• 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 ]

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.

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.

• 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

• 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.
• 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.
• 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.

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