Donor Stem Cell Transplant With No or Low-Intensity Chemotherapy Using Sirolimus and Treated Immune Cells to Treat Blood and Lymph Cancers

Background

In protocol 99-C-0143, we evaluated a new approach to allogeneic hematopoietic stem cell
transplant (HSCT) that involved intensive host T cell ablation and graft augmentation with in
vitro generated donor T helper 2 (Th2) cells. Rapid full donor engraftment occurred with this
regimen; however, grade II to IV acute graft versus host disease (GVHD) was not significantly
reduced in Th2 cell recipients. In an attempt to improve clinical results using Th2 cell
graft engineering, this second-generation Th2 cell clinical trial was developed that
incorporates the following interventions: (1) In an attempt to reduce transplant-related
toxicity, this protocol now uses a very low-intensity host preparative chemotherapy; (2) In
an attempt to reduce GVHD, this study will utilize Th2 cells expanded in the presence of the
immune modulation agent, rapamycin (sirolimus), as murine Th2 cells grown in rapamycin reduce
GVHD more effectively than control Th2 cells; (3) To further reduce GVHD, subjects will
receive a short-course of sirolimus therapy in addition to standard cyclosporine GVHD
prophylaxis; and (4) Using this novel low-intensity transplant platform, compare in a
preliminary manner the post-transplant outcome of patients receiving pre-emptive donor
lymphocyte infusion (DLI) using either Th2 cells or unmanipulated donor T cells.

Objectives

In the setting of human leukocyte antigen (HLA)-matched sibling allogeneic HSCT using GVHD
prophylaxis of cyclosporine and short-course sirolimus, compare in a preliminary manner the
safety, feasibility, alloengraftment, clinical anti-tumor effects, and GVHD rate of
low-intensity Preparative Chemotherapy with pre-emptive DLI using either Th2 cells or
unmanipulated T cells at day 14 post-HSCT.

Eligibility

Subjects that are 16 to 75 years of age that have a suitable 6/6 HLA-matched sibling donor
are potentially eligible. Subjects with a diagnosis of acute or chronic leukemia,
non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, or myelodysplastic syndrome are
potentially eligible. Adequate kidney, cardiac, and pulmonary function are required.

Design

- Patients age 18 or older with lymphoma (all types) or chronic lymphocytic leukemia will
be randomized just prior to the transplant regimen to receive DLI with either donor Th2
cells (cohort 1) or unmanipulated T cells (cohort 2); n=10 patients will be accrued to
each arm provided that stopping rules pertaining to excessive GVHD or graft rejection
are not met. For these randomized patients, the preparative regimen will consist of
low-intensity fludarabine (120 mg/m(2)) plus cyclophosphamide (1200 mg/m(2)) and GVHD
prophylaxis will consist of short-course, high-dose sirolimus followed by maintenance
cyclosporine. Cohorts 1 and 2 will be compared in a preliminary manner with respect to
their post-transplant outcome, in particular: (a) conversion of mixed chimerism to
predominant donor chimerism; (b) rate and severity of classical acute and late acute
GVHD at the day 100 and day 180 post-transplant time points; and (c) time to induction
of leukemia/lymphoma remission (if entering transplant with disease) or time to relapse
(if entering transplant in remission).

- Patients with non-lymphoma diagnoses, patients with lymphoma that are under the age of
18 and lymphoma patients that are projected to be unable to complete the
protocol-defined therapy through day 180 post-transplant will not be randomized but will
be treated on cohort 3 (n=40), which will evaluate transplantation without the Flu/Cy
preparative regimen and with pre-emptive Th2 cell DLI. The primary objective of cohort 3
is to evaluate whether transplantation without a preparative regimen will reduce the
rate of acute GVHD associated with Th2 cell DLI from 41% (the rate observed with the
fludarabine/cyclophosphamide (Flu/Cy) preparative regimen) to a rate of 15% (6 cases out
of 40).

- 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 National Cancer
Institute (NCI) or Hackensack (There will be no central pathology review).

2. Chronic Lymphocytic Leukemia - Disease Status: a) Relapse post-fludarabine, b)
Non-Complete Response (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 stem
cell transplant (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 natural killer (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 first CR or any later CR

Chronic Epstein Barr Virus (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 stem cell transplant (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) Refractory Anemia with Excess
Blasts (RAEB), b) Refractory Anemia with Excess Blasts in Transformation (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 (CML) - 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 16 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 intravenous therapy administered outside of the National Institutes
of Health (NIH) Clinical Center 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. Eastern Cooperative Oncology Group (ECOG) performance status equal to 0 or 1.

8. Life expectancy of at least 3 months.

9. Patients with acute leukemia must have chemotherapy sensitive disease, as defined
by at least a 50% reduction in circulating absolute blast count due to the most
proximal regimen.

10. Left ventricular ejection fraction greater than or equal to 45%, preferably by
2-dimension (2-D) echo, or by multi-gated acquisition scan (MUGA). However,
patients with left ventricular ejection fraction (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 diffusing capacity or transfer of the lung for carbon monoxide (DLCO)
greater than 50% of expected value.

12. Creatinine less than or equal to 1.5 mg/dl or creatinine clearance greater than
or equal to 50 ml/min.

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

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
human leukocyte antigen (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 principal investigator (PI),
then the patient may receive standard treatment for the malignant disease or
complicating conditions (infection, metabolic problems under the current study.
In other cases, a patient may have reasonable control of malignancy but does not
meet the cluster of differentiation 4 (CD4) cell cut-off of 50 cells per
microliter required for cohort 3 therapy; in such cases, standard care
chemotherapy regimens may be administered for the specific goal of reducing the
CD4 count (that is, immune depleting regimens such as the pentostatin plus
cyclophosphamide combination, administered similar to the manner that we have
developed on protocol 08-C- 0088). 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 criteria detailed above. Attempts will be made to standardize such
pretransplant chemotherapy (by administration of etoposide, prednisolone,
oncovin, cyclophosphamide, hydroxydaunorubicin, fludarabine, rituximab (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 11 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 human immunodeficiency virus (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 lead associate investigator (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 central nervous system (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 (Hemoglobin (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 National Institutes
of Health (NIH) or Hackensack Blood Bank.