Antithymocyte Globulin, Clofarabine, and Rituximab in Treating Patients After an Unsuccessful Stem Cell Transplant

OBJECTIVES:

Primary

- To determine the rate of sustained donor engraftment at 42 days and survival at 100 days
post transplantation in patients treated with anti-thymocyte globulin, clofarabine, and
rituximab.

Secondary

- To determine incidence of treatment-related mortality at day 100 post transplantation.

- To determine incidence of neutrophil recovery by day 42 post transplantation.

- To determine survival at day 100 and 1 year post transplantation.

- To determine the proportion of patients with chimerism at day 28 post transplantation.

- To determine incidence and severity of grades II-IV acute graft-vs-host disease by day
100 post transplantation.

OUTLINE:

- Conditioning regimen: Patients receive rituximab intravenously (IV) on day -7,
anti-thymocyte globulin IV over 4-6 hours on days -6 to -4, and clofarabine IV over 1
hour on days -4 to -2.

- Hematopoietic stem cell transplantation (HSCT): Patients undergo HSCT on day 0. Patients
may receive umbilical cord blood, peripheral blood stem cells, or bone marrow from
unrelated or related donors.

- Graft-vs-host disease (GVHD) prophylaxis: Patients receive oral cyclosporine twice daily
or cyclosporine IV every 8 hours beginning on day -3 and continuing for 100 or 180 days
post transplantation followed by a taper; mycophenolate mofetil IV every 8 hours
beginning on day -3 and continuing for 30 days (or 7 days after engraftment with no
evidence of GVHD); and filgrastim (G-CSF) IV once daily beginning on day 1 and
continuing until blood counts recover.

After completion of study therapy, patients are followed on days 100, 180, and 360.

Patient Inclusion Criteria:

- Timing of relevant evaluations: Taking in account the need for rapid intervention, if
white blood count is less than 200 on day +20, bone marrow aspirate should be
performed on day +21. Unless there is an increase in absolute neutrophil count (ANC)
to > 500 in the following 7 days, bone marrow aspirate should be repeated on day +28.
If the white blood count is still less than 200 and bone marrow is acellular, bone
marrow (BM) or peripheral blood stem cell (PBSC) donor should be reactivated and
availability of cord blood (CB) units assessed. If the BM or PBSC donor is not
confirmed within 14 days of the request for the donation (typically second donation
from the same donor), CB unit should be used instead.

Primary or secondary graft failure after hematopoietic stem cell transplantation defined as
a > 50% loss of donor chimerism from previous maximum or less than 25% donor beyond day +42
with pancytopenia and no evidence of relapse. Patients with any diagnosis, type of donor,
hematopoietic cell graft or conditioning regimen should be considered for this study.

- primary graft failure is defined as:

- ANC < 500

- BM < 10% on two occasions (Day +21 and Day +28)

- Donor chimerism need not to be considered, provided there is no evidence of
malignancy

- secondary graft failure is defined as < 5% cellularity and ANC < 500 for more than 7
days any time after primary engraftment).

- Women of childbearing potential must agree to use adequate contraception
(diaphragm, birth control pills, injections, intrauterine device [IUD], surgical
sterilization, subcutaneous implants, or abstinence, etc.) for the duration of
treatment.

- Patients or their guardian are able and willing to provide written informed
consent.

Patient Exclusion Criteria:

The presence of any of the following excludes a patient from study enrollment:

- Uncontrolled active infection defined as more than one week with no response to
appropriately chosen antibiotics

- Evidence of recurrence of primary malignancy.

- Pregnant or lactating. The agents used in this study may be teratogenic to a fetus and
there is no information on the excretion of agents into breast milk. All females of
childbearing potential must have a blood test or urine study within 2 weeks prior to
registration to rule out pregnancy. Women of childbearing age must use appropriate
methods as described.

- Allergy to rituximab.

- Evidence of HIV infection or positive HIV serology.

- Autologous recovery defined as defined as greater than 90% recipient PCR product in
the competitive VNTR PCR performed on gradually increasing white blood cell count.

Donor Inclusion Criteria:

- Related donors must be 2-75 years of age and in good health.

- Meets match criteria

- Able and willing to undergo cell collection procedures (bone marrow cell collection or
leukapheresis)

- Not pregnant or lactating.

- HIV-1, HIV-2 negative; HTLV-1, HTLV-2 negative, Hepatitis B and C negative.

- Patients or their guardian are able and willing to provide informed consent