Trial Information

Phase II Trial of Targeted Immune-Depleting Chemotherapy and Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation Using 8/8 and 7/8 HLA-matched Unrelated Donors and Utilizing Two Graft-versus-Host Disease Prophylaxis Regimens for the Treatment of Leukemias, Lymphomas, and Pre-malignant Blood Disorders

Background:

- The major limitations to the broader applicability of allogeneic hematopoietic stem
cell transplantation (HSCT) for the treatment of malignancies are lack of suitable
donors and therapy-related toxicities which include delayed and incomplete immune
reconstitution and graft-versus-host disease (GVHD). Based on the theory that the rapid
establishment of donor chimerism was essential for an optimal graft-versus-tumor
effect, we have employed a strategy of targeted immunedepleting chemotherapy prior to
reduced-intensity allogeneic HSCT. It is our intent to investigate this approach in the
setting of HLA-matched unrelated donors in a pilot manner.

- A clearly superior GVHD prophylaxis regimen has not been established in the unrelated
donor transplant setting. The best results that have been reported are with the
combination of alemtuzumab plus cyclosporine [AC] and the combination of tacrolimus,
methotrexate, and sirolimus [TMS]. These two regimens work by mechanisms which are
biologically distinct and potentially have markedly different effects upon immune
reconstitution that have not been well studied. In addition neither of these regimens
has been assessed for their affects on chronic GVHD using the NIH Consensus Conference
Criteria. It is our intent to study the effects that these two regimens have on immune
reconstitution and chronic GVHD in the setting sequential targeted immune-depleting
chemotherapy and reduced-intensity allogeneic HSCT from HLA-matched unrelated donors.

Objectives:

- Primary objectives:

1. to assess the effects of two biologically distinct GVHD prophylaxis regimens, TMS
and AC, on immune reconstitution in patients receiving targeted-immune depletion
and reduced-intensity allogeneic HSCT from HLA-matched unrelated donors. As part
of a comprehensive assessment of immune reconstitution, the primary immunologic
endpoint will be the determination of CD4+ T cell receptor V BETA repertoire by
CDR3 spectratyping at 3 months post-transplant.

2. to assess overall safety of these two regimens in this setting, as determined by
engraftment, acute GVHD, early and late treatment-related mortality, and overall
survival.

3. to 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 those tools for use in clinical
practice and trials (Pavletic, Imanguli, and Cowen).

- Secondary objectives include further assessment of immune reconstitution, study of
engraftment kinetics, and assessment of those patients who receive higher doses of
anthracyclines for long and short term toxicities

Eligibility:

- Adults (18 - 74 years) with advanced or high risk hematologic malignancies including
AML, ALL, MDS, CLL, NHL, HL,CML, multiple myeloma, and MPD who lack a suitable HLA
matched sibling.

- An unrelated donor matched at a minimum of 7 of 8 alleles (HLA-A,-B,-C, and DRB1) by
high resolution typing, identified through the National Marrow Donor Program.

- Life expectancy of at least 3 months, ECOG less than or equal to 2 and relatively
normal major organ functions.

Design:

- Patients will receive disease-specific induction chemotherapy (EPOCH-F/R or FLAG) prior
to transplant for disease control and immune depletion. If disease is controlled
(greater than PR) and immune depletion objectives have been met, patients may forgo
induction chemotherapy and move forward to the transplant conditioning regimen.

- All patients will receive an identical conditioning regimen consisting of
cyclophosphamide 1200 mg/m(2)/day IV for 4 days and fludarabine 30 mg/m(2)/day for 4
days.

- Patients will be stratified according to degree of HLA-match and randomized at the time
of enrollment to one of two GHVD prophylaxis regimens:

- Arm A (TMS): Tacrolimus, starting day -3 before transplant, given initially at
0.02 mg/kg/day CIV and then an equivalent oral dose for six months, methotrexate 5
mg/m(2) IV on days +1, +3, +6, and +11 post-transplant, and sirolimus given as an
initial loading dose of 12 mg p.o. on day -3 pre-transplant and subsequently 4 mg
daily through day +63 post transplant.

- Arm B (AC): Alemtuzumab at 20 mg/day IV over 8 h on days -8 to -4 pre-transplant
and cyclosporine, starting day -1 before transplant, given initially at 2mg/kg IV
every 12 hours and then an equivalent oral dose for six months and.

- A maximum of 105 patients will be enrolled and randomly assigned to the two arms in
order to yield 44 patients per arm (88 total patients) who are able to be evaluated for
development of severe chronic GVHD. This represents an increase of 20 patients over the
number permitted prior to this amendment: 25 patients (50 total) randomly assigned to
each arm within the 8/8 match group and 13/arm (26 total) within the 7/8 match group
(maximum study enrollment = 76 transplanted patients from among up to 85 patients
registered).