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Allogeneic HSCT Without Preparative Chemotherapy or With Low-Intensity Preparative Chemotherapy Using Sirolimus and Sirolimus-Generated Donor Th2 Cells for Therapy of Refractory Leukemia, Lymphoma, Myeloma, or Myelodysplastic Syndrome


Phase 2
15 Years
75 Years
Open (Enrolling)
Both
Hematologic Neoplasms, Neural Tube Defects, Myeloproliferative Disorders

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Trial Information

Allogeneic HSCT Without Preparative Chemotherapy or With Low-Intensity Preparative Chemotherapy Using Sirolimus and Sirolimus-Generated Donor Th2 Cells for Therapy of Refractory Leukemia, Lymphoma, Myeloma, or Myelodysplastic Syndrome


Background:

Patients with cancers of the blood and immune system often benefit from transplants of stem
cells from a genetically well-matched sibling. However, severe problems may follow these
transplants because of the high-dose chemotherapy and radiation that accompany the
procedure. Also, donated immune cells sometimes attack healthy tissues in a reaction called
graft-versus-host disease (GVHD), damaging organs such as the liver, intestines and skin. To
reduce toxicity of high-dose preparative chemotherapy, this study performs allogeneic
transplant after low doses of chemotherapy. In an attempt to improve anti-tumor effects
without increasing GVHD, this study uses donor immune cells (Th2 cells) grown in the
laboratory; some patients will receive standard donor immune cells (not grown in
laboratory). All patients will receive immune modulating drugs sirolimus and cyclosporine to
prevent GVHD.

Objective:

To determine the safety, treatment effects and rate of GVHD in patients receiving
transplants that use low-intensity chemotherapy, sirolimus plus cyclosporine, and transplant
booster with either Th2 cells or standard immune cells.

Eligibility:

Patients 18 to 75 years of age with acute or chronic leukemia, non-Hodgkin's lymphoma,
Hodgkin's disease, multiple myeloma, or myelodysplastic syndrome.

Patients must have a suitable genetically matched sibling donor and adequate kidney, heart
and lung function.

Design: The protocol has three treatment groups: cohort 1, Th2 booster at two weeks
post-transplant; cohort 2, standard T cell booster at two weeks post-transplant; cohort 3,
multiple infusion of Th2 cells.

Condition Hematologic Neoplasms, Myeloproliferative Disorders

Intervention Biological; therapeutic allogeneic lymphocytes

Drug: Sirolimus

Study Type: Interventional

Study Design: Primary Purpose: Treatment

Phase: Phase II

Inclusion Criteria


- INCLUSION CRITERIA: PATIENT RECIPIENT

1. Patients with hematologic malignancies, myelodysplasia, or myeloproliferative
disorders, as summarized in the following table. The diagnosis must be
histologically confirmed by the Laboratory of Pathology of NCI or Hackensack
(There will be no central pathology review).

2. Chronic Lymphocytic Leukemia - Disease Status: a) Relapse post-fludarabine, b)
Non-CR after salvage regimen.

Hodgkin's and Non-Hodgkin's Lymphoma (all types, including Mantle Cell Lymphoma)
- Disease Status: a) Primary treatment failure, b) Relapse after autologous SCT,
c) Non-CR after salvage regimen

Special Cases of High-Risk Lymphoma, including but not limited to : (1) plasma
dendritic cell type, 2) Hepato-splenic T cell type, 3) gamma delta pinniculitic
T cell type, 4) Muco-cutaneous NK cell type and 5) stage III-IV nasal NK cell
type- Disease Status: a) Primary treatment failure, b) Relapse after autologous,
c) Non-CR after salvage regimen, d) In forist CR or any later CR

Chronic EBV-associated lymphoproliferative disease a) At any point after
diagnosis, including up-front therapy

Multiple Myeloma - Disease Status: a) Primary treatment failure, b) Relapse
after autologous SCT, c) Non-CR after salvage regimen.

Acute Myelogenous Leukemia - Disease Status: a) CR number 1 and high-risk
[excludes t(8;21), t(15;17), or inv(16)], b) CR number 2 or greater).

Acute Lymphocytic Leukemia - Disease Status: a) CR number 1 plus high-risk
[t(9;22) or bcr-abl(+); t(4;11), 1(1;19), t(8;14)], b) In CR number2 or greater.

Myelodysplastic Syndrome - Disease Status: a) RAEB, b) RAEB-T (requires marrow
and blood blasts less than 10% after induction chemotherapy).

Myeloproliferative disorders - Disease Status: a) Idiopathic myelofibrosis, b)
Polycythemia vera, c) Essential thrombocytosis, d) Chronic myelomonocytic
leukemia.

Chronic Myelogenous Leukemia - Disease Status: a) Chronic phase CML, refractory
to imatinib treatment b) Accelerated phase CML. b) Accelerated phase CML

Patients with myeloproliferative disorders must be end-stage, which is primarily
defined as disease severity refractory to splenectomy.

3. Patient age of 18 to 75 years.

4. Consenting first degree relative matched at 6/6 HLA antigens (A, B, and DR).

5. Patient or legal guardian must be able to give informed consent.

6. All previous therapy must be completed at least 2 weeks prior to study entry,
with recovery to less than or equal to non-hematologic grade 2 toxicity of
previous therapy.

7. ECOG performance status equal to 0 or 1.

8. Life expectancy of at least 3 months.

9. Acute leukemia must be in hematologic remission (less than 10% blood or marrow
blasts).

10. Left ventricular ejection fraction greater than or equal to 45%, preferably by
2-D echo, or by MUGA. However, patients with LVEF of between 35% and 44% may
also be eligible provided that such patients are cleared by a Cardiology
Consultation that must include a cardiac stress test.

11. Corrected DLCO greater than 50% of expected value.

12. Creatinine less than or equal to1.5 mg/dl and creatinine clearance greater than
or equal to 50 ml/min.

13. Serum total bilirubin less than 2.5 mg/dl; serum ALT and AST equal 2.5 times
upper limit of normal. Values above these levels may be accepted, at the
discretion of the PI or study chairman, if such elevations are thought to be due
to liver involvement by malignancy.

14. Adequate central venous access potential.

15. Potential patients referred for the study may not be eligible for the
experimental protocol therapy due to reasons such as uncertainty about donor HLA
typing or need to control malignant disease, infection, or metabolic abnormality
such as hypercalcemia on a emergent basis. Should a referred patient present to
us in such a scenario, the patient will be referred back to their primary
hematologist-oncologist for treatment. However, if referral back to the
referring physician is not in the best interest of the patient according to the
clinical judgement of the PI, then the patient may receive standard treatment
for the malignant disease or complicating conditions (infection, metabolic
problems under the durrent study. If it becomes apparent that the patient will
not be able to proceed to experimental therapy, then he/she must come off study.
Recipient-Subjects receiving a standard therapy, and availability of receiving
the same treatment elsewhere, outside of a research protocol. Because such
standard care therapy is not experimental, it is not necessary to complete the
eligibility criteria prior to receiving such standard care; however, prior to
initiation of the experimental therapy, the patient must meet each of the
eligibility crieteria detailed above. Attempts will be made to standardize such
pretransplant

chemotherapy (by administration of EPOCH-FR chemotherapy, which is detailed later in this
protocol); however, other regimens using approved agents will be allowed if such regimens
are thought to be in the best interest of the patient.

INCLUSION CRITERIA: DONOR

1. First-degree relative with genotypic identity at 6/6 HLA loci (HLA- A, B, and DR).

2. Age 15 to 90 years and able to give consent or assent. For donors < 18 years old,
the legal guardian must be able to provide informed consent.

3. Adequate venous access for peripheral apheresis, or consent to use a temporary
central venous catheter for apheresis.

4. Donors must be HIV negative.

5. Donors with a history of hepatitis B or hepatitis C infection may be eligible.
However, eligibility determination of such patients will require a hepatology
consultation. The risk/benefit of the transplant and the possibility of transmitting
hepatitis will be discussed with the patient and eligibility will then be determined
by the principal investigator and LAI.

6. Lactating donors must substitute formula feeding for her infant during period of
filgrastim administration (to prevent any filgrastim effect on infant).

EXCLUSION CRITERIA: PATIENT

1. Active infection that is not responding to antimicrobial therapy.

2. Active CNS involvement by malignancy.

3. HIV infection (treatment may result in progression of HIV and other viral
infections).

4. Chronic active hepatitis B. Patient may be hepatitis B core antibody positive. For
patients with concomitant positive hepatitis B surface antigen, patient will require
a hepatology consultation. The risk/benefit profile of transplant and hepatitis B
will be discussed with the patient and eligibility determined by the principal
investigator and Lead Associate Investigator.

5. Hepatitis C infection. Patient may have hepatitis C infection. However, each patient
will require a hepatology consultation. The risk/benefit profile of transplant and
hepatitis C will be discussed with the patient and eligibility determined by the
principal investigator and Lead Associate Investigator.

6. Pregnant or lactating. Patients of childbearing potential must use an effective
method of contraception. The effects of the chemotherapy, the subsequent transplant
and the medications used after the transplant are highly likely to be harmful to a
fetus. The effects upon breast milk are also unknown and may be harmful to the
infant.

7. History of psychiatric disorder which may compromise compliance with transplant
protocol, or which does not allow for appropriate informed consent.

EXCLUSION CRITERIA: DONOR

1. History of psychiatric disorder which may compromise compliance with transplant
protocol, or which does not allow for appropriate informed consent.

2. History of hypertension that is not controlled by medication, stroke, autoimmune
disease, or severe heart disease (donors with symptomatic angina will be excluded).
Donors with a history of coronary artery bypass grafting or angioplasty who are
symptom free will receive a cardiology evaluation and be considered on a case-by-case
basis.

3. History of prior malignancy. However, cancer survivors who have undergone potentially
curative therapy may be considered for stem cell donation on a case-by-case basis. In
addition, donors with localized cancer such as prostate cancer that are on a
watch-and-wait management due to the low-risk of disease progression may also be
considered for stem cell donation on a case-by-case basis. The risk/benefit of the
transplant and the possibility of transmitting viable tumor cells at the time of
transplantation will be discussed with the patient.

4. Donors must not be pregnant (unknown effect of filgrastim on fetus). Donors of
childbearing potential must use an effective method of contraception.

5. Anemia (Hb less than 11 gm/dl) or thrombocytopenia (platelets less than 100,000 per
microliter). However, potential donors with Hb levels less than 11 gm/dl that is due
to iron deficiency will be eligible as long as the donor is initiated on iron
replacement therapy and the case is individually approved by NIH or Hackensack Blood
Bank.

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Outcome Measure:

Safety and feasibility

Safety Issue:

Yes

Principal Investigator

Daniel H Fowler, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

040055

NCT ID:

NCT00074490

Start Date:

December 2003

Completion Date:

June 2015

Related Keywords:

  • Hematologic Neoplasms
  • Neural Tube Defects
  • Myeloproliferative Disorders
  • Leukemia
  • Lymphoma
  • Multiple Myeloma
  • Bone Marrow Transplantation
  • Immune Therapy
  • Neoplasms
  • Myelodysplastic Syndromes
  • Myeloproliferative Disorders
  • Neural Tube Defects
  • Spinal Dysraphism
  • Hematologic Neoplasms

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892
Hackensack University Medical CenterHackensack, New Jersey  07601