NMA Allogeneic Hematopoietic Cell Transplant in Hematologic Cancer/Disorders

• ClinicalTrials.gov Identifier: NCT00053989
• Recruitment Status: Completed
• First Posted: February 6, 2003
• Results First Posted: February 10, 2020
• Last Update Posted: February 10, 2020
• Sponsor: Roswell Park Cancer Institute
• Information provided by (Responsible Party): Roswell Park Cancer Institute

Study Description

Brief Summary:

RATIONALE: Giving low doses of chemotherapy before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. 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 cancer cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving immunosuppressive therapy before or after the transplant may stop this from happening.

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

Condition or disease	Intervention/treatment	Phase
Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases; Fanconi Anemia; Aplastic Anemia	Biological: anti-thymocyte globulin; Biological: graft-versus-tumor induction therapy; Biological: sargramostim; Biological: therapeutic allogeneic lymphocytes; Drug: cyclophosphamide; Drug: fludarabine phosphate; Drug: methylprednisolone; Drug: mycophenolate mofetil; Drug: tacrolimus; Procedure: allogeneic bone marrow transplantation; Procedure: peripheral blood stem cell transplantation; Procedure: umbilical cord blood transplantation	Phase 2

Detailed Description:

OBJECTIVES:

• Determine the safety and toxic effects of nonmyeloablative allogeneic peripheral blood stem cell transplantation in patients with a hematologic malignancy or aplastic anemia.
• Determine clinical response and overall outcome of patients treated with this regimen.
• Determine the incidence of graft-vs-tumor effect, graft-vs-host disease, and chimerism in patients treated with this regimen.

OUTLINE:

• Preparative regimen:

  • Matched related and unrelated donor transplantation:

    • Patients receive cyclophosphamide IV over 2 hours on days -5 and -4 and fludarabine IV over 30 minutes on days -5 to -1.

  • Cord blood transplantation:

    • Patients receive the same regimen as above plus anti-thymocyte globulin IV over 4 hours on days -3 to -1.

• Graft-vs-host disease (GVHD) prophylaxis:

  • Matched related and unrelated donor transplantation:

    • Patients receive oral tacrolimus (or IV) once daily and oral mycophenolate mofetil (MMF) (or IV) twice daily on days -1 to 60 followed by tapering* of this regimen. Patients then receive methotrexate IV on days 1, 3, and 6.

  • Cord blood transplantation:

    • Patients receive tacrolimus and MMF in the same regimen as above plus methylprednisolone twice daily on days 1-19 or until blood counts recover.
• Allogeneic stem cell reinfusion: Patients undergo allogeneic bone marrow or peripheral blood stem cell transplantation on day 0. Patients then receive sargramostim (GM-CSF) subcutaneously daily beginning on day 7 and continuing until blood counts recover.
• Donor lymphocyte infusion (DLI): Patients not converting to 100% donor T-cell chimerism by day 120 and showing signs of progresson of disease after tacrolimus and MMF withdrawal may receive DLI every 8 weeks for up to 3 infusions. Cord blood recipients do not receive DLI.

Patients are followed at day 100-120, every 3 months for 2 years, and then every 6 months for 5 years.

PROJECTED ACCRUAL: A total of 30-60 patients will be accrued for this study within 6-7 years.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 41 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Non-Myeloablative Allogeneic Hematopoietic Peripheral Blood Stem Cell Transplantation for Hematologic Malignancies and Disorders
• Actual Study Start Date: January 29, 2002
• Actual Primary Completion Date: July 19, 2018
• Actual Study Completion Date: July 19, 2018

Arms and Interventions

Arm

Intervention/treatment

Experimental: All patients; All patients enrolled on study

Biological: anti-thymocyte globulin; iv; Biological: graft-versus-tumor induction therapy; iv; Biological: sargramostim; iv; Biological: therapeutic allogeneic lymphocytes; iv; Drug: cyclophosphamide; injection; Drug: fludarabine phosphate; iv; Other Name: FLUDARA; Drug: methylprednisolone; oral; Drug: mycophenolate mofetil; oral; Drug: tacrolimus; oral; Procedure: allogeneic bone marrow transplantation; iv; Procedure: peripheral blood stem cell transplantation; iv; Procedure: umbilical cord blood transplantation; iv

Outcome Measures

Primary Outcome Measures :

1. Day 100 TRM [ Time Frame: from start or conditioning (day -6 or -5) through day +100 after HSC infusion ]
   treatment related mortality within 100 days from hematopoietic stem cell (HSC) infusion on day 0
2. Day 100 Best Response [ Time Frame: from start of conditioning on day -6 or -5 through day +100 after HSC infusion ]
   Best disease response measured within 100 days from hematopoietic stem cell (HSC) infusion on day 0 using disease specific response criteria defined in the protocol

Secondary Outcome Measures :

1. PFS [ Time Frame: 1 year ]
   Progression free survival defined as time from HSC infusion (day 0) until progression of disease or death due to any cause. Patients are censored if alive without disease progression through 1 year after HSC infusion
2. OS [ Time Frame: 1 year ]
   Overall survival with events defined as death due to any cause and censored patients are alive as of 1 year post HSC infusion
3. Acute GvHD [ Time Frame: Day +100 ]
   overall grade II-IV acute GvHD

Eligibility Criteria

• Ages Eligible for Study: 4 Years to 75 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of aplastic anemia

  • Severe disease
  • Failed at least 1 course of standard immunosuppressive regimen with cyclosporine and anti-thymocyte globulin OR

• Histologically confirmed hematologic malignancy including the following:

  • Acute leukemia

    • Any of the following types:

      • Acute myeloid leukemia (AML) with antecedent myelodysplastic syndromes
      • Secondary AML
      • AML with high-risk cytogenetic abnormalities
      • Acute lymphoblastic leukemia with high-risk cytogenetic abnormalities
    • Resistant or recurrent disease after combination chemotherapy with at least 1 standard regimen OR
    • In first remission at high risk of relapse

  • Chronic myelogenous leukemia

    • Chronic phase meeting at least 1 of the following criteria:

      • Failed imatinib mesylate
      • Failed interferon after at least 6 months of treatment with minimum of 21 million units of interferon per week
      • Unable to tolerate interferon
    • Accelerated phase (blasts less than 20%)

  • Myeloproliferative and myelodysplastic syndromes

    • Myelofibrosis (after splenectomy)
    • Refractory anemia
    • Refractory anemia with excess blasts
    • Chronic myelomonocytic leukemia

  • Lymphoproliferative disease

    • Chronic lymphocytic leukemia

      • Symptomatic disease after first-line chemotherapy

    • Low-grade non-Hodgkin's lymphoma (recurrent or persistent)

      • Symptomatic disease after first-line chemotherapy

    • Multiple myeloma

      • Progressive disease after autologous stem cell transplantation

    • Waldenstrom's macroglobulinemia

      • Failed 1 standard regimen

  • Non-Hodgkin's lymphoma meeting the following criteria:

    • Intermediate or high grade
    • Controlled and chemosensitive disease
    • First remission lymphoblastic or small non-cleaved cell lymphoma at high risk of relapse

  • Hodgkin's lymphoma

    • Relapsed and chemosensitive disease
• Not eligible for standard myeloablative allogeneic stem cell transplantation

• Availability of any of the following donor types:

  • Related donor matched at 5 or 6 HLA antigens (A, B, DR)

  • Unrelated donor fully matched by molecular analysis at A, B, DRB1, and DQB1 loci

    • Single antigen mismatch at C allowed
  • Cord blood that is 4, 5, or 6 match with recipient HLA antigens (A, B, DR) NOTE: No syngeneic donors permitted
• No uncontrolled CNS disease (for hematologic malignancies) 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

• 4 to 75 (if related or unrelated donor peripheral blood or marrow transplantation)
• 4 to 60 (if unrelated cord blood transplantation)

Performance status

• Karnofsky > 50%

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Bilirubin less than 3 times normal
• Alkaline phosphatase less than 3 times normal
• AST/ALT less than 3 times normal
• No Child's class B or C liver failure

Renal

• Creatinine clearance greater than 40 mL/min

Cardiovascular

• Cardiac ventricular ejection fraction at least 35% by MUGA
• No cardiovascular disease

Pulmonary

• DLCO at least 40% of predicted, corrected for hemoglobin and/or alveolar ventilation

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV antibody negative
• No uncontrolled diabetes mellitus
• No active serious infection
• No other disease that would preclude study therapy
• No other concurrent malignancy except non-melanoma skin cancer
• No concurrent serious psychiatric illness

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics
• patients may have received a prior autologous blood or marrow transplantation (BMT)
• At least 6 months since prior allogeneic BMT

Chemotherapy

• See Disease Characteristics
• At least 2 weeks since prior chemotherapy, radiation or surgery

Endocrine therapy

• Not specified

Radiotherapy

• At least 2 weeks since prior radiotherapy

Surgery

• At least 2 weeks since prior surgery

Contacts and Locations

Locations

United States, New York

Roswell Park Cancer Institute

Buffalo, New York, United States, 14263-0001

Sponsors and Collaborators

Roswell Park Cancer Institute

Investigators

• Principal Investigator: Philip L. McCarthy, MD; Roswell Park Cancer Institute

  Study Documents (Full-Text)

Documents provided by Roswell Park Cancer Institute:

Study Protocol and Statistical Analysis Plan  [PDF] October 19, 2018

More Information

• Responsible Party: Roswell Park Cancer Institute
• ClinicalTrials.gov Identifier: NCT00053989
• Other Study ID Numbers: CDR0000269673; RP01-05
• First Posted: February 6, 2003
• Results First Posted: February 10, 2020
• Last Update Posted: February 10, 2020
• Last Verified: December 2019

Keywords provided by Roswell Park Cancer Institute:

accelerated phase chronic myelogenous leukemia; chronic myelomonocytic leukemia; primary myelofibrosis; de novo myelodysplastic syndromes; chronic phase chronic myelogenous leukemia; relapsing chronic myelogenous leukemia; refractory anemia with excess blasts; stage I multiple myeloma; stage II multiple myeloma; stage III multiple myeloma; Waldenstrom macroglobulinemia; stage III adult lymphoblastic lymphoma; stage IV adult lymphoblastic lymphoma; noncontiguous stage II adult Burkitt lymphoma; stage III adult Burkitt lymphoma; stage IV adult Burkitt lymphoma; recurrent adult Hodgkin lymphoma; adult acute myeloid leukemia in remission; secondary acute myeloid leukemia; recurrent childhood acute lymphoblastic leukemia; recurrent adult acute myeloid leukemia; childhood acute lymphoblastic leukemia in remission; adult acute lymphoblastic leukemia in remission; noncontiguous stage II adult lymphoblastic lymphoma; refractory multiple myeloma; refractory anemia; refractory chronic lymphocytic leukemia; previously treated myelodysplastic syndromes; secondary myelodysplastic syndromes; grade 1 follicular lymphoma

Additional relevant MeSH terms:

Lymphoma; Leukemia; Multiple Myeloma; Neoplasms, Plasma Cell; Preleukemia; Plasmacytoma; Anemia; Myelodysplastic Syndromes; Anemia, Aplastic; Myeloproliferative Disorders; Fanconi Anemia; Myelodysplastic-Myeloproliferative Diseases; Syndrome; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease; Pathologic Processes; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Bone Marrow Diseases; Precancerous Conditions