NMA Allogeneic Hematopoietic Cell Transplant in Hematologic Cancer/Disorders

Non-Myeloablative Allogeneic Hematopoietic Peripheral Blood Stem Cell Transplantation for Hematologic Malignancies and Disorders

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.

Study Overview

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

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 Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: All patients; All patients enrolled on study

Drug: tacrolimus; oral; Drug: mycophenolate mofetil; oral; 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 Names: FLUDARA; Drug: methylprednisolone; oral; Procedure: allogeneic bone marrow transplantation; iv; Procedure: peripheral blood stem cell transplantation; iv; Procedure: umbilical cord blood transplantation; iv

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Day 100 TRM	treatment related mortality within 100 days from hematopoietic stem cell (HSC) infusion on day 0	from start or conditioning (day -6 or -5) through day +100 after HSC infusion
Day 100 Best Response	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	from start of conditioning on day -6 or -5 through day +100 after HSC infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS	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	1 year
OS	Overall survival with events defined as death due to any cause and censored patients are alive as of 1 year post HSC infusion	1 year
Acute GvHD	overall grade II-IV acute GvHD	Day +100

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2002
• Primary Completion (Actual): July 19, 2018
• Study Completion (Actual): July 19, 2018

Study Registration Dates

• First Submitted: February 5, 2003
• First Submitted That Met QC Criteria: February 5, 2003
• First Posted (Estimate): February 6, 2003

Study Record Updates

• Last Update Posted (Actual): February 10, 2020
• Last Update Submitted That Met QC Criteria: January 29, 2020
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: primary myelofibrosis; stage III adult Burkitt lymphoma; stage IV adult Burkitt lymphoma; refractory anemia; refractory anemia with excess blasts; chronic myelomonocytic leukemia; de novo myelodysplastic syndromes; previously treated myelodysplastic syndromes; secondary myelodysplastic syndromes; 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); secondary acute myeloid leukemia; childhood acute lymphoblastic leukemia in remission; childhood acute myeloid leukemia in remission; chronic phase chronic myelogenous leukemia; childhood chronic myelogenous leukemia; childhood myelodysplastic syndromes; recurrent adult acute myeloid leukemia; atypical chronic myeloid leukemia; myelodysplastic/myeloproliferative disease, unclassifiable; adult acute myeloid leukemia in remission; recurrent adult Hodgkin lymphoma; recurrent/refractory childhood Hodgkin lymphoma; relapsing chronic myelogenous leukemia; Waldenstrom macroglobulinemia; stage II multiple myeloma; stage III multiple myeloma; recurrent marginal zone lymphoma; recurrent small lymphocytic lymphoma; extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue; nodal marginal zone B-cell lymphoma; splenic marginal zone lymphoma; stage I multiple myeloma; refractory chronic lymphocytic leukemia; stage III adult lymphoblastic lymphoma; stage IV adult lymphoblastic lymphoma; refractory multiple myeloma; recurrent adult acute lymphoblastic leukemia; recurrent childhood acute lymphoblastic leukemia; noncontiguous stage II adult lymphoblastic lymphoma; accelerated phase chronic myelogenous leukemia; adult acute lymphoblastic leukemia in remission; recurrent childhood acute myeloid leukemia; noncontiguous stage II adult Burkitt lymphoma; grade 1 follicular lymphoma; grade 2 follicular lymphoma
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Genetic Diseases, Inborn; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; DNA Repair-Deficiency Disorders; Precancerous Conditions; Anemia, Hypoplastic, Congenital; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Lymphoma; Syndrome; Myelodysplastic Syndromes; Multiple Myeloma; Neoplasms, Plasma Cell; Leukemia; Preleukemia; Anemia; Fanconi Anemia; Plasmacytoma; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Anemia, Aplastic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuroprotective Agents; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Methylprednisolone; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Tacrolimus; Mycophenolic Acid; Sargramostim; Antilymphocyte Serum
• Other Study ID Numbers: CDR0000269673; RP01-05