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Investigator(s):
Michael Bishop, M.D. Principal Investigator Phone: 301-435-2764 mbishop@mail.nih.gov	Steven Pavletic, M.D., M.S. Protocol Chair Phone: 301-402-4899 pavletis@mail.nih.gov
Referral Contact(s):
Mike Krumlauf, R.N., B.S.N., O.C.N. Research Nurse Phone: 301-594-2056 Fax: 301-435-6830 krumlaum@mail.nih.gov

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Primary Eligibility:

• Patient must have one of the following diagnoses:
• B-cell chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma, meeting one of the following criteria:
• Relapse or progression after fludarabine and ≥ 1 other salvage regimen
• Relapse or progression after autologous hematopoietic stem cell transplantation (HSCT)
• T-cell CLL
  • Patients ineligible for a specified therapy (e.g., due to refractory cytopenias) may be eligible for this study
• Prolymphocytic leukemia (PLL) meeting one of the following criteria:
• T-cell PLL: Treatment failure after alemtuzumab and ≥ 1 other regimen
• B-cell PLL: Treatment failure after fludarabine and ≥ 1 other regimen
• Hodgkin lymphoma meeting one of the following criteria:
• Primary treatment failure and ineligible for autologous HSCT
• Relapse or progression after autologous HSCT
• Follicular lymphoma or marginal zone lymphoma (splenic, nodal, or extranodal/MALT-type), meeting one of the following criteria:
• Chemotherapy refractory disease
• Relapse after ≥ 2 prior regimens
• Relapse or progression after autologous HSCT
• Burkitt lymphoma or acute lymphoblastic lymphoma, meeting one of the following criteria:
• High-risk disease in remission
• Primary refractory disease
• Recurrent disease
• Relapse or progression after autologous HSCT
• Diffuse large B-cell lymphoma, follicular large cell lymphoma, peripheral T-cell lymphoma, mantle cell lymphoma, or anaplastic large cell lymphoma, meeting one of the following criteria:
• Primary refractory disease
• Relapse or progression after autologous HSCT
• Stable disease or better response to last therapy
• Cutaneous T-cell lymphoma (e.g., mycosis fungoides, Sezary syndrome), meeting one of the following criteria:
• Stage III or IV disease
• Disease progressed or failed to respond to ≥ 2 prior regimens, including ≥ 1 systemic therapy
• Multiple myeloma, meeting one of the following criteria:
• Relapse or progression after autologous HSCT
• Plasma cell leukemia
• Adverse cytogenetics [del(13q) or 11q translocation]
• Myelodysplastic syndromes (MDS), meeting one of the following criteria:
• Refractory anemia with excess blasts (RAEB) I or II
• High-risk disease by IPSS
• Secondary MDS
• Myeloproliferative disorders (MPD), meeting one of the following criteria:
• Agnogenic myeloid metaplasia with at least two of the following adverse-risk features:
• Hemoglobin < 10 g/dL OR > 10 g/dL with transfusion dependence
• WBC < 4,000/mm³ OR > 30,000/mm³ OR requires cytoreductive therapy to maintain WBC < 30,000/mm³
• Abnormal cytogenetics, including +8, 12p-
• Polycythemia vera or essential thrombocythemia in transformation to secondary acute myeloid leukemia (AML)
• Idiopathic myelofibrosis
• Chronic myelomonocytic leukemia
• AML meeting one of the following criteria:
• In first complete remission (CR) with high-risk cytogenetics, meeting both of the following criteria:
• Residual disease detectable by flow cytometry, cytogenetic analysis, FISH, or PCR
• Adverse cytogenetics defined as complex karyotype (≥ 3 abnormalities); inv(3) or t(3;3); t(6;9); t(6;11); monosomy 7; trisomy 8, alone or with an abnormality other than t(8;21), t(9;11), inv(16) or t(16;16); or t(11;19)(q23;p13.1)
• Primary induction failure, defined as failure to achieve a CR with primary induction chemotherapy
• In second or greater CR
• Secondary AML, defined as AML related to antecedent MDS, MPD, or cytotoxic chemotherapy
• Acute lymphocytic leukemia, meeting one of the following criteria:
• First CR with high-risk disease meeting both of the following criteria:
• Residual disease detectable by flow cytometry, cytogenetic analysis, FISH, or PCR
• Adverse cytogenetics defined as translocations involving t(4;11), t(1;19), t(8;14), 11q23, t(9;22), or bcr-abl rearrangement or complex cytogenetic abnormalities
• Primary induction failure, defined as failure to achieve a CR with primary induction chemotherapy
• Second or greater CR
• Chronic myelogenous leukemia (CML) not eligible for myeloablative allogeneic HSCT and meeting one of the following criteria:
• Chronic phase CML
• Never responded to or progressed after receiving a tyrosine kinase inhibitor (e.g., imatinib mesylate)
• Accelerated phase CML
• Patients with primary or secondary acute leukemia, RAEB, CML, or other eligible diagnosis in transformation to acute leukemia must have 5% blasts in bone marrow and no circulating blasts in peripheral blood
• Patients who do not meet these criteria may be re-evaluated for study eligibility after receiving standard induction therapy for acute leukemia and determined to be in remission
• Patients with non-Hodgkin lymphoma must have at least stable disease after the last therapy
• Has a 10/10 allele-matched unrelated donor available
• Unrelated donor matched at HLA-A, B, C, DRB1, and DQ loci by high-resolution typing (10/10 allele match)
• No active CNS involvement by malignancy (i.e., known positive CSF cytology or parenchymal lesions visible by CT scan or MRI)
• No progressive disease within 8 weeks after prior therapy or within 12 weeks after prior autologous HSCT
• ECOG performance status (PS) 0–2 OR Karnofsky PS 60–100%
• Absolute neutrophil count 1,000 cells/μl (without transfusion)
• Platelet count ≥ 20,000/mm³ (without transfusion)
• Serum total bilirubin < 2.5 mg/dL (up to 10 mg/dL if thought to be due to liver involvement by malignancy)
• Serum ALT and AST ≤ 2.5 times upper limit of normal (ULN) (up to 10 times ULN if thought to be due to liver involvement by malignancy)
• Creatinine ≤ 1.5 mg/dL and creatinine clearance ≥ 50 mL/min/1.73 m²
• LVEF > 45% by MUGA or 2D-echo
• DLCO > 50% of the expected value when corrected for hemoglobin
• No other disease that would preclude study participation
• No active infections

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Treatment Plan:

Induction Chemotherapy:
Patients receive 1 of 2 induction chemotherapy regimens (EPOCH-F/R vs FLAG) based on diagnosis.

• EPOCH-F/R (for patients with Hodgkin lymphoma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, prolymphocytic leukemia, or multiple myeloma):
  • Patients receive fludarabine phosphate IV over 30 minutes once daily, etoposide IV continuously, doxorubicin hydrochloride IV continuously, and vincristine IV continuously on Days 1–4
  • Patients receive cyclophosphamide IV over 30 minutes on Day 5; and oral prednisone on Days 1–5
  • Patients with CD20+ disease also receive rituximab IV on Day 1
  • All patients receive filgrastim (G-CSF) subcutaneously (SC) beginning on Day 6 and continuing until blood counts recover
  • Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity

• FLAG (for patients with acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndromes, chronic myelogenous leukemia, myeloproliferative disorders, or chronic myelomonocytic leukemia):
  • Patients receive fludarabine phosphate IV over 30 minutes and cytarabine IV over 4 hours on Days 1–5
  • Patients also receive G-CSF SC beginning on Day 0 and continuing until blood counts recover
  • Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity

• Patients with responsive or stable disease after receiving EPOCH-F/R and patients who achieve remission after FLAG proceed to allogeneic hematopoietic stem cell transplantation

Preparative regimen and allogeneic hematopoietic stem cell transplantation (HSCT):

• Patients receive fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 2 hours on Days -6 to -3
• Patients undergo G-CSF-mobilized allogeneic HSCT on Day 0
• Patients also receive G-CSF SC beginning on Day 0 and continuing until blood counts recover

Graft-versus-host disease (GVHD) prophylaxis:
Patients are randomized at study enrollment to receive 1 of 2 GVHD prophylaxis regimens.

Arm I (TMS)

• Patients receive tacrolimus IV continuously or orally and oral sirolimus on Days -3 to 63, followed by a taper if GVHD does not develop
• Patients also receive methotrexate IV over 15 minutes on Days 1, 3, 6, and 11

Arm II (CA)

• Patients receive alemtuzumab IV over 8 hours on Days -8 to -4
• Patients also receive cyclosporine IV over 2 hours or orally every 12 hours on Days -1 to 100, followed by a taper if GVHD does not develop

• Patients with persistent or progressive malignancy post-HSCT or mixed chimerism that does not improve after tapering or discontinuing immune suppression may receive donor lymphocyte infusions (DLIs)
• DLI may be administered alone or after chemotherapy every 4 weeks provided GVHD is not present
• Blood samples are obtained at baseline and then periodically before and after HSCT
• Punch biopsies of skin and buccal mucosa and whole saliva samples are collected at Day 63 and at 6 months (or at the development of GVHD) post-transplant and examined by immunofluorescence, confocal microscopy, gene expression profiles, and protein-based assays
• After completion of study therapy, patients are followed periodically for 2 years

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Additional Information:

• This trial will be conducted at the NIH Clinical Center in Bethesda, MD. It is open to patients who meet the eligibility requirements, regardless of where they live in the United States.
• There is no charge for medical care received at NIH Clinical Center.
• FAQs about this study - provides information for patients about the trial such as frequency and duration of visits, costs, how to enroll, treatment plan.
• PDQ (Physicians Data Query) - provides additional details about this study for health care providers.

Reviewed: 7/7/08
Updated: 7/15/08