Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplant (HSCT) For Lymphoma

This research study is a Pilot Study, which is the first time investigators are examining
this study intervention (allogeneic stem cell transplantation) for this population (patients
with CNS lymphoma), which is a type of stem cell transplantation.

Historically, patients with central nervous system (CNS) involvement by non-Hodgkin lymphoma
(NHL) have had high rates of disease relapse after initial therapy. Given these poor
outcomes with conventional chemotherapy, more intense treatment with high-dose chemotherapy
and autologous stem cell transplantation (ASCT) has been explored, yet relapse remains an
issue. For older patients, ASCT may not be feasible given the inability to tolerate
high-doses of chemotherapy.

In patients with systemic NHL who relapse after ASCT or cannot tolerate ASCT, yet are
responsive to chemotherapy, allogeneic stem cell transplant is often considered. Allogeneic
transplantation is thought to work by giving the recipient an entirely new blood system from
a donor. This new blood system includes a new immune system which can hopefully attack any
lymphoma much like it would attack a bacterial or viral infection. Currently, this is one
established standard of care for patients with lymphoma of the body who relapse after
initial chemotherapy treatment. The investigators are testing if this treatment can be
extended to patients with lymphoma of the central nervous system.

The following chemotherapy drugs included in this study which will be administered:
Fludarabine, Thiotepa, and Methotrexate. The FDA (the U.S. Food and Drug Administration) has
approved these chemotherapy agents individually as a treatment option for your disease. The
combination has not been approved by the FDA. Thiotepa and Methotrexate have been shown to
pass through the blood-brain barrier, a highly selective barrier that restricts many
chemicals from entering the brain and spinal cord. Fludarabine is the backbone chemotherapy
in all reduced intensity conditioning regimens.

Inclusion Criteria:

- Participants must have histologically or cytologically confirmed non-Hodgkin lymphoma
involving the central nervous system (CNS) as defined by:

- Biopsy of CNS mass in the brain, parenchyma, leptomeninges, or spinal cord
demonstrating NHL.

- Ocular biopsy from retina, subretinal pigment epithelial space, or optic nerve,
or vitrectomy specimen, demonstrating NHL.

- Biopsy of mass lesion outside of the CNS, or blood or body fluid specimen,
documenting NHL, in conjunction with brain or spinal CT, PET/CT (positron
emission tomography / computed tomography), or MRI showing radiographic
abnormalities characteristic of CNS involvement with lymphoma.

- CSF cytology demonstrating a malignant clonal NHL population, consistent with
lymphomatous leptomeningitis, with or without a radiographically or
pathologically identifiable CNS or systemic mass lesion. Patients with CSF
(cerebral spinal fluid) studies negative for NHL by cytology but positive for a
monoclonal population by flow cytometry and/or molecular PCR (polymerase chain
reaction) studies may be eligible if they have radiographic evidence of a CNS
lymphoma or if they have symptoms clinically consistent with CNS lymphomatous
involvement; for such cases, please contact the protocol chair, Dr. Yi Bin Chen,
to discuss eligibility prior to enrollment.

- Patients must have experienced relapsed disease after high-dose chemotherapy with
autologous stem cell transplantation (ASCT) OR have experienced relapse / progression
on first-line high-dose methotrexate-based therapy and are not candidates for ASCT in
the judgment of the treating physician. Discussion with the PI is encouraged for the
latter scenario.

- All participants must demonstrate a partial or complete response (PR or CR) of their
CNS and systemic disease to pre-enrollment therapy and must be in PR or CR at the
time of enrollment. Acceptable therapies include systemic or intrathecal
chemo/immunotherapy and/or radiotherapy as well as corticosteroids.

- Age ≥ 18 years as this study will be open at sites which treat adults.

- ECOG (Eastern Cooperative Oncology Group) performance status ≤ 2 (Karnofsky score ≥
60%, see Appendix A).

- Participants must have adequate organ function as defined below:

- Total serum bilirubin within normal institutional limits (unless patient has
Gilbert's syndrome, where then direct serum bilirubin should be within normal
institutional limits).

- AST (SGOT) / ALT(SGPT) ≤ 3× institutional upper limit of normal.

- Serum creatinine within normal institutional limits

--- OR

- Creatinine clearance ≥ 50 mL/min/1.73 m2 for participants with creatinine level
above institutional normal.

- Left ventricular ejection fraction ≥ 40% measured either by echocardiogram or
nuclear cardiac scan.

- FEV1 (forced expiratory volume in 1 second), FVC (forced vital capacity) and
DLCO all ≥ 50% of predicted (DLCO corrected for hemoglobin).

- Participants must have a well-matched adult donor willing to donate peripheral blood
stem cells with well-matched defined as: 8/8 matched related or unrelated donor
(HLA-A, B, C, DRB1 by allele level).

- Because chemotherapy agents as well as other therapeutic agents used in this trial
are known to be teratogenic, women of child-bearing potential and men must agree to
use adequate contraception (hormonal or barrier method of birth control; abstinence)
prior to study entry and for the duration of study participation. Should a woman
become pregnant or suspect she is pregnant while she or her partner is participating
in this study, she should inform her treating physician immediately. Men treated or
enrolled on this protocol must also agree to use adequate contraception prior to the
study, for the duration of study participation, and for 12 months after the date of
stem cell transplantation.

- Ability to understand and the willingness to sign a written informed consent
document.

- Eligibility Criteria for Donors

- Donors must be medically fit to donate peripheral blood stem cells through
standard G-CSF mobilization as assessed by institutional or unrelated marrow
registry standards.

- Donors will not have to sign a study specific informed consent to participate
given that donors will be undergoing standard G-CSF mobilization and
leukapheresis.

- Exclusion Criteria:

- Participants who have had chemotherapy or radiotherapy within 4 weeks prior to the
1st day of conditioning chemotherapy.

- Participants who are receiving any other investigational agents.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to fludarabine, thiotepa or other agents used in study.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant or lactating women are excluded from this study because they are routinely
ineligible to be treated with allogeneic stem cell transplantation.

- HIV-positive participants on combination antiretroviral therapy are ineligible
because of the potential for increased risk of lethal infections when treated with
marrow-suppressive therapy.