Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Chemotherapy, Donor Stem Cell Transplant, and Graft-Versus-Host Disease Prevention in Treating Patients With Advanced Hematologic Cancer or Other Disease

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase II, Phase I Biomarker/Laboratory analysis, Treatment Active 18 to 69 NCI NCI-07-C-0195 07-C-0195, NCT00520130

Special Category: NIH Clinical Center trial

Objectives

Primary

1. Assess the effects of two biologically distinct graft-vs-host disease (GVHD) prophylaxis regimens (tacrolimus/methotrexate/sirolimus [TMS] and alemtuzumab/cyclosporine [AC]) on immune reconstitution in patients with high-risk advanced hematologic malignancies or other disorders receiving targeted immune-depleting chemotherapy and reduced-intensity allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-matched unrelated donors.
2. Assess the overall safety of this therapy, as determined by engraftment, severe (grade III-IV) acute GVHD, early and late treatment-related mortality, and overall survival, in these patients.

Secondary

1. Assess the effects of two different GVHD prophylaxis regimens (TMS and AC) on CD4+ T-cell receptor Vβ repertoire by CDR3 spectratyping at 1, 6, and 12 months post-transplantation.
2. Assess the effects of these regimens on CD8+ T-cell receptor Vβ repertoire by CDR3 spectratyping at 1, 3, 6, and 12 months post-transplantation.
3. Assess the effects of these regimens on the kinetics of CD4+ and CD8+ T cells and NK-cell depletion and recovery.
4. Correlate serum interleukin (IL)-7 and IL-15 levels during early immune reconstitution after administration of these regimens.
5. Characterize the pattern of post-transplant CD14+ monocyte production of inflammatory cytokines IL-1-α and TNF-α.
6. Assess the impact of these regimens on donor/recipient chimerism.
7. Determine the incidence and severity of acute GVHD following sequential targeted immune-depleting chemotherapy and reduced-intensity allogeneic HSCT from HLA-matched unrelated donors.
8. Determine and monitor incidence, organ severity, and overall severity of chronic GVHD prospectively using the newly developed NIH Consensus Conference diagnosis and staging criteria and preliminarily validate these tools for use in clinical practice and trials.
9. Evaluate the feasibility of isolating and expanding clinically relevant numbers of tumor-derived lymphocytes from patients' bone marrow or lymph nodes.
10. Detect post-transplant antibodies that selectively recognize tumor cell surface antigens.
11. Prospectively evaluate the pathogenesis of chronic GVHD by examining the immune cell reconstitution in the target tissues and cellular and molecular events preceding and coinciding with the clinical onset of chronic GVHD.
12. Prospectively assess long and short term cardiac toxicities of etoposide, doxorubicin hydrochloride, vincristine, cyclophosphamide, and fludarabine (EPOCH-F) regimen in patients who have received greater than 450 mg/m² of anthracyclines prior to study enrollment.

Entry Criteria

Disease Characteristics:

• Patient must have one of the following diagnoses:
  • B-cell chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma, meeting 1 of the following criteria:
    • Relapse or progression after fludarabine and ≥ 1 other salvage regimen
    • Relapse or progression after autologous hematopoietic stem cell transplantation (HSCT)
    • Patients ineligible for a specified therapy (e.g., due to refractory cytopenias) may be eligible for this study
  
  
  
  • 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 1 of the following criteria:
    • T-cell PLL: Treatment failure after alemtuzumab and ≥ 1 other regimen
      • Treatment failure is defined as relapse within 6 months or failure to achieve remission
    • B-cell PLL: Treatment failure after fludarabine and ≥ 1 other regimen
      • Treatment failure is defined as relapse within 6 months or failure to achieve remission
    • Patients ineligible for a specified therapy (e.g., due to refractory cytopenias) may be eligible for this study
  
  
  
  • Hodgkin lymphoma, meeting 1 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 1 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 1 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 1 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 1 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 1 of the following criteria:
    • Relapse or progression after autologous HSCT
    • Plasma cell leukemia
    • Adverse cytogenetics [del(13q) or 11q translocation]
  
  
  
  • Myelodysplastic syndromes (MDS), meeting 1 of the following criteria:
    • Refractory anemia with excess blasts (RAEB) I or II
    • High-risk disease by IPSS
    • Secondary MDS
  
  
  
  • Myeloproliferative disorders (MPD), meeting 1 of the following criteria:
    • Agnogenic myeloid metaplasia with at least 2 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 1 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
    • In first complete remission with hyperleukocytosis (i.e., WBC ≥ 100,000) at diagnosis
  
  
  
  • Acute lymphocytic leukemia, meeting 1 of the following criteria:
    • First 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 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 1 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
    • Blastic phase CML

     [Note: *Patients with chronic or accelerated phase CML must have < 10% blasts in the peripheral smear or bone marrow after induction therapy.]

  
  
  



• Patients with primary or secondary acute leukemia, RAEB, CML, or other eligible diagnosis in transformation to acute leukemia must have ≤ 10% 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

Prior/Concurrent Therapy:

• See Disease Characteristics
• Recovered from prior therapy (nonhematologic toxicity ≤ grade 2)
• At least 2 weeks since prior cytotoxic chemotherapy

Patient Characteristics:

• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
• Life expectancy ≥ 3 months
• Absolute neutrophil count ≥ 1,000/μL* (without transfusion)
• Platelet count ≥ 20,000/mm³* (without transfusion)
• Serum total bilirubin < 2.5 mg/dL (≤ 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) (≤ 10 times ULN if thought to be due to liver involvement by malignancy)
• Creatinine ≤ 1.5 mg/dL
• Creatinine clearance ≥ 50 mL/min
• LVEF > 45% by MUGA or 2D-echo
  • Patients who have received a prior cumulative anthracycline dose > 450 mg/m² will have a cardiology consult to determine if further anthracycline administration is an absolute contradindication in patients who may require induction chemotherapy with EPOCH-F
• DLCO > 50% of the expected value when corrected for hemoglobin
• No chronic active hepatitis B
  • Hepatitis B core antibody positivity allowed provided patient is hepatitis B surface antigen negative with no evidence of active infection
• No hepatitis C infection with evidence of cirrhosis
• No HIV infection
• No active infection that is not responding to antimicrobial therapy
• No active or recent second malignancy unless it has been treated with potentially curative therapy and meets ≥ 1 of the following criteria:
  • Patient has had no evidence of that disease for ≥ 5 years
  • Deemed to be at low risk for recurrence (≤ 20% at 5 years)
• No history of psychiatric disorder that may compromise compliance with transplant protocol or that does not allow for appropriate informed consent
• Not pregnant or lactating
• Fertile patients must use an effective method of contraception

 [Note: * Values below these levels may be accepted at the discretion of the principal investigator or study chairperson, if thought to be due to bone marrow involvement by malignancy]

Expected Enrollment

Outcomes

Change in the CD4+ T-cell repertoire diversity determined by spectratype complexity index within a Vβ family at 3 months post-transplant
Overall safety
Graft rejection based on CD3+ chimerism
Acute graft-vs-host disease
Treatment-related mortality (early and at 1 year)
Overall survival at 1 year

Immune reconstitution parameters

Outline

• 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; 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 28 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. To determine T-cell receptor Vβ repertoire, samples are examined by reverse transcriptase-PCR and Vβ spectratype analysis. Peripheral blood monocytes are analyzed by flow cytometry for expression of markers of T cell proliferation, cytokine production and gene expression, cytotoxic T lymphocyte generation, and antigen-presenting cell function. To correlate monocyte cytokine expression patterns with GVHD, cytokine capture flow cytometry is used to evaluate markers of T1 (interleukin [IL]-2 and interferon-γ) and T2 (IL-4 and IL-10) cytokine excretion.

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.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Michael Bishop, MD, Protocol chair		Ph: 301-435-2764 Email: mbishop@mail.nih.gov
Steven Pavletic, MD, Protocol co-chair		Ph: 301-402-4899

U.S.A.
Maryland
	Bethesda
	Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
		Clinical Trials Office - Warren Grant Magnusen Clinical Center - NCI Clinical Trials Referral Office	Ph:  888-NCI-1937

Registry Information
Official Title		Pilot Trial of Targeted Immune-Depleting Chemotherapy and Reduced-Intensity Allogeneic hematopoietic Stem Cell Transplantation Using HLA-Matched Unrelated Donors and Utilizing Two Graft-Versus-Host Disease Prophylaxis Regimens for the Treatment of Leukemias, Lymphomas, and Pre-Malignant Blood Disorders
Trial Start Date		2007-07-23
Registered in ClinicalTrials.gov		NCT00520130
Date Submitted to PDQ		2007-07-23
Information Last Verified		2008-07-28