Autologous Transplant in HIV Patients (BMT CTN 0803)

BACKGROUND:

Non-Hodgkin lymphoma (NHL) is an AIDS-defining diagnosis for patients infected with the Human
Immunodeficiency Virus (HIV). While the incidence of NHL has decreased amongst HIV-infected
patients since the advent of highly-active anti-retroviral therapy (HAART), lymphoma remains
a significant cause of death for this patient population. The prognosis for patients with
AIDS-related lymphoma is dramatically different in the era of HAART therapy. In a comparison
of treatment outcomes for patients treated before and after the advent of HAART, there is a
statistically significant improvement in the overall survival of patients treated with HAART.
Unfortunately, despite considerable advances in the treatment of AIDS-related NHL,
induction-failure and disease relapse remain key challenges. The prognosis for patients with
refractory and relapsed NHL is poor with overall survival rates of less than 20 percent for
patients treated with non-transplant salvage therapies. Based upon a randomized trial and
numerous phase II trials, high-dose therapy with autologous hematopoietic cell
transplantation (HCT) has been established as the standard of care for patients with
chemotherapy-sensitive relapsed non-Hodgkin lymphoma.

DESIGN NARRATIVE:

All patients must have chemosensitive disease as demonstrated by response to induction or
salvage chemotherapy. Patients must also have less than or equal to 10percent bone marrow
involvement after their most recent salvage therapy. Patients cannot have had prior
autologous or allogeneic HCT. Patients must initiate conditioning therapy within 3 months of
mobilization or bone marrow harvest.

Mobilization therapy may be employed per institutional guidelines. Patients must have an
adequate autograft to be eligible for the protocol. Patients may not have HIV refractory to
pharmacologic therapy. Patients must not have opportunistic infection that is not responding
to therapy. Patients will receive Carmustine (BCNU) 300 mg/m^2 Day -6, Etoposide 100 mg/m^2
twice a day (BID) on Days -5 to -2, Cytarabine 100 mg/m2 BID on Days -5 to -2, and Melphalan
140 mg/m2 Day -1 followed by autologous HCT.

Patients will be followed for 2 years post-transplant. Survival data, time to progression
data, progression-free survival data, time to progression after Complete Remission (CR) data,
lymphoma disease-free survival data, time to hematopoietic recovery data, hematologic
function data, toxicity data, incidence of infections, treatment-related mortality data,
immunologic reconstitution data, data assessing the impact of therapy on the HIV reservoir
and microbial gut translocation will be recorded and reported periodically to the BMT CTN
Data and Coordinating Center (DCC).

Inclusion Criteria:

- Diagnosis of persistent or recurrent World Health Organization (WHO) classification
diffuse large B-cell lymphoma, composite lymphoma with > 50% diffuse large B-cell
lymphoma, mediastinal B-cell lymphoma, immunoblastic, plasmablastic, Burkitt's or
Burkitt-like or classical Hodgkin's lymphoma. Patients transformed from follicular
lymphoma are eligible for the study, pending fulfillment of other criteria.

- 15 years old or older

- Three or fewer prior regimens of chemotherapy over the entire course of their disease
treatment (including one induction chemotherapy and no more than 2 salvage
chemotherapies). Monoclonal antibody therapy and involved field radiation therapy will
not be counted as prior therapies.

- All patients must have chemosensitive disease as demonstrated by at least a partial
response to induction or salvage therapy.

- Less than or equal to 10% bone marrow involvement.

- Patients with adequate organ function as measured by: a)Cardiac: American Heart
Association Class I: Patients with cardiac disease but without resulting limitation of
physical activity. Ordinary physical activity does not cause undue fatigue,
palpitation, dyspnea, or anginal pain. Additionally, all patients must have a left
ventricular ejection fraction at rest greater than or equal to 40% demonstrated by
Multi Gated Acquisition Scan (MUGA) or echocardiogram; b)Hepatic: (i) Bilirubin less
than 2.0 mg/dL (except for isolated hyperbilirubinemia attributed to Gilbert syndrome
or antiretroviral therapy) and alanine transaminase (ALT) and aspartate transaminase
(AST) greater than 3x the upper limit of normal; (ii) Concomitant Hepatitis: Patients
with chronic hepatitis B or C may be enrolled on the trial providing the above
criteria are met. In addition, no active viral replication - undetectable (viral load
less than 500 copies/ml) hepatitis B DNA level by PCR and no clinical or pathologic
evidence of irreversible chronic liver disease; c)Renal: Creatinine clearance
(calculated creatinine clearance is permitted) greater than 40 mL/min; d)Pulmonary:
Carbon Monoxide Diffusing Capacity (DLCO), forced expiratory volume in 1 second
(FEV1), forced vital capacity (FVC) greater than or equal to 45% of predicted
(corrected for hemoglobin).

- Autologous peripheral stem cell graft with a minimum of greater than or less than 1.5
x 10^6 CD 34+ cells/kg (target greater than or less than 2.0 x 10^6 CD 34+ cells/kg)
or if peripheral blood stem cell (PBSC) mobilization fails, cells can be obtained by
bone marrow harvest per institutional practices (in cases where bone marrow will be
used for transplantation, the required CD34+ dose does not apply and institutional
requirements for total nucleated cell dose should apply).

- Initiate conditioning therapy within 3 months of mobilization or bone marrow harvest.

- Signed informed consent.

- Patients on antiretroviral therapies (ARVs) can either have: a) Undetectable HIV viral
load (VL less than 50 copies); b) If VL detectable at less than 2000 copies/mL must
have review of previous antiretroviral regimens or previous genotypic or phenotypic
testing which indicate the ability to fully suppress virus by addition of sensitive
drugs. This review will be carried out by the Infectious Disease (ID) specialist
caring for the patient; c)If VL detectable at greater than 2000 copies/mL, a current
HIV genotype and/or phenotype must be obtained. If a HAART regimen to which the
patient's virus is sensitive can be determined based on genotype and previous
antiretroviral experience, then the patient will be considered eligible in this
regard. This review will be carried out by the ID specialist caring for the patient.

Exclusion Criteria:

- Karnofsky performance score less than 70%.

- Uncontrolled bacterial, viral or fungal infection (currently taking medication and
with progression or no clinical improvement).

- Prior malignancy in the 5 years prior to enrollment except resected basal cell
carcinoma, treated cervical carcinoma in situ or Kaposi's sarcoma: a)Symptomatic
Kaposi's sarcoma currently requiring therapy is excluded (patients receiving topical
therapy for minimal disease are not included in this definition); b)Prior treatment
with topical agents, local radiation, or up to 6 cycles of cytotoxic chemotherapy at
least six months prior is permitted; c) Other cancers treated with curative intent
less than 5 years previously will not be allowed unless approved by the Medical
Monitor or Protocol Chair; d)Cancer treated with curative intent more than 5 years
previously will be allowed.

- Pregnant (positive β-HCG) or breastfeeding.

- Fertile men or women unwilling to use contraceptive techniques from the time of
initiation of mobilization until six-months post-transplant.

- Prior autologous or allogeneic HCT.

- Patients with evidence of Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML)
or abnormal cytogenetic analysis indicative of MDS on the pre-transplant bone marrow
examination. Pathology report documentation need not be submitted.