Sirolimus, Tacrolimus, Anti-Thymocyte Globulin, and Rituximab in Preventing Graft-versus-Host Disease in Patients Undergoing Donor Stem Cell Transplant

PRIMARY OBJECTIVES:

I. Incidence and severity of acute GVHD (aGVHD). II. To determine time to engraftment
absolute neutrophil count (ANC) (> 0.5 x 10^9/L for 3 consecutive days), and platelet (> 20
X 10^9/L for 3 consecutive days).

III. Safety defined by serious adverse events (SAE) and adverse events (AE) related to this
immunosuppressive regimen in the first six months post transplant.

SECONDARY OBJECTIVES:

I. Incidence of chronic GVHD (cVHD) measured within two years after transplant. II. Overall
and disease-free survival at two years post hematopoietic cell transplantation (HCT).

III. Incidence of opportunistic infections, defined as infection that occurs in people with
weakened immune systems and caused by an organism that does not normally cause disease.
These include: fungal infections, pneumocystis carinii pneumonia (PCP), and viral infections
(cytomegalovirus [CMV], varicella zoster virus [VZV], herpes simplex virus [HSV], BK virus
[BK], Epstein-Barr virus [EBV] including post-transplant lymphoproliferative disorder
[PTLD]).

IV. Incidence of thrombotic microangiopathy within 100 days of HCT. V. Immunocorrelative
studies: T-cell, B cell, natural-killer (NK) cell, regulatory cell, and allo-reactive T cell
quantitation studies, using flow cytometry at 30, 60, 90, and 180 days post transplant.

OUTLINE:

Patients receive rituximab intravenously (IV) over 90 minutes on day -7 and 3, tacrolimus IV
continuously or orally (PO) once daily (QD), sirolimus PO QD beginning on day -3 with taper,
and anti-thymocyte globulin IV over 6 hours on days -3 to -1.

After completion of study treatment, patients are followed up on days 30, 60, 90, 180 and
then 1 and 2 years thereafter.

Inclusion Criteria:

- Lack of suitable related human leukocyte antigen (HLA) matched or unrelated HLA
matched donor within a reasonable amount of time; in case of a need for an urgent
transplant (within 6-8 weeks from the referral time), and a related or unrelated
matched donor cannot be found soon enough, this patient will be a candidate for
haploidentical or mismatched transplant

- Availability of either a suitable haploidentical or partial matched unrelated donor
as determined by the treating physician; high resolution molecular HLA typing is
mandatory for HLA Class I and II

- No more than 4/8 HLA allele or antigen mismatch will be allowed for a
haploidentical related (1st degree family member) donor

- Only 6/8 or 5/8 HLA allele or antigen match will be allowed for unrelated donor

- Diagnosis of hematological malignancy:

- Non-Hodgkin lymphoma: any complete remission (CR)/partial remission (PR)/stable
disease (SD)

- Hodgkin disease: any CR/PR/SD

- Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL): any CR; for
non-CR AML or ALL: bone marrow blast < 20% within 4 weeks of transplant

- Myelodysplastic syndrome (MDS): treated or untreated

- Chronic myelogenous leukemia (CML): in chronic phase or accelerated phase

- Chronic myelomonocytic leukemia (CMML)

- Multiple Myeloma: any CR/PR/SD

- Chronic lymphocytic leukemia (CLL): any CR/PR/SD

- Myelofibrosis and other myeloproliferative disorders: bone marrow blasts less
then 20 percent within four weeks of transplant

- Conditioning regimen will be picked from one of Karmanos Cancer Institute (KCI)
standard regimens by the treating physician

- Agrees to participate, and informed consent signed

- Karnofsky performance status (KPS) >= 70, Eastern Cooperative Oncology Group (ECOG)
performance status =< 2

- Creatinine clearance > 60 mL/min

- Ejection fraction > 50% patient with coronary heart disease (recent myocardial
infarctions, angina, cardiac stent, or bypass surgery in the last 6 months) need to
be cleared with a stress echo or nuclear myocardial perfusion stress test, and
cardiology consult; all other cardiac history will be at the discretion of the
principal investigator

- Serum bilirubin less than 3 X upper limit of normal

- Alanine aminotransferase (ALT), aspartate aminotransferase (AST) less than 3 X upper
limit of normal

- Forced vital capacity (FVC), forced expiratory volume in one second (FEV1) or carbon
monoxide (CO) diffusing capacity (DLCO) > 50% predicted

Exclusion Criteria:

- Bone marrow or ex vivo engineered or processed graft (cluster of differentiation
[CD34]+ enrichment, T-cell depletion, etc)

- Patients with documented uncontrolled central nervous system (CNS) disease

- Any patient with ascites

- Patients on home oxygen

- Active donor or recipient serology positive for human immunodeficiency virus (HIV)

- Known contraindication to administration of sirolimus, tacrolimus, anti-thymocyte
globulin, or rituximab

- Active Hepatitis B