1 AMC 048: Modified CODOX-M/IVAC-Rituximab is safe and effective for HIV

33 Pages·2015·0.29 MB·English

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Blood First Edition Paper, prepublished online May 8, 2015; DOI 10.1182/blood-2015-01-623900
AMC 048: Modified CODOX-M/IVAC-Rituximab is safe and effective for HIV-
Associated Burkitt Lymphoma

Ariela Noy , Jeannette Y Lee , Ethel Cesarman , Richard Ambinder , Robert
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Baiocchi , Erin Reid , Lee Ratner , Nina Wagner-Johnston and Lawrence Kaplan
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for the AIDS Malignancy Consortium.

Ariela Noy is corresponding author:
Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill-
1
Cornell Medical Center, New York New York
[email protected]
212-639-7423

University of Arkansas Medical Center, 4301 West Markham Street, Little Rock, AR
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72205

Department of Pathology and Laboratory Medicine, Weill Cornell Medical College,
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1300 York Avenue, New York, NY 10065
Department of Oncology, Johns Hopkins School of Medicine, 733 North Broadway,
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Baltimore, MD 21205

Division of Hematology, Ohio State Medical Center, 410 West 10th Avenue,
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Columbus, OH 43210
University of California, San Diego Moores Cancer Center, 3855 Health Sciences
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Drive, La Jolla, CA 92093
Division of Oncology, Washington University School of Medicine, 660 South Euclid
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Avenue, St. Louis, MO 63110
Department of Medicine, University of California, 3333 California Street
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San Francisco, CA 94118

Running Title: Modified CODOX-M/IVAC-Rituximab for HIV-Burkitt

This trial was supported by the NCI under for the AIDS Malignancy
U01CA121947
Consortium.

A complete list of members of the AIDS Malignancy Consortium can be found in the
supplemental Appendix.

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Copyright © 2015 American Society of Hematology
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Key Points:
We report the first dedicated prospective study in HIV-Burkitt, demonstrating safety
and efficacy in a multi-institutional setting.
Modifiying an existing regimen, making it much less toxic, we offer a new
therapeutic option.

Abstract

Toxicity of dose-intensive regimens used for Burkitt lymphoma (BL) prompted
modification of the CODOX-M/IVAC regimen for HIV+ patients. We added
rituximab, reduced /rescheduled cyclophosphamide and methotrexate, capped
vincristine, and used combination intrathecal chemotherapy. Antibiotic prophylaxis
and growth factor support were required; HAART therapy, discretionary.
Thirteen AMC centers entered 34 patients from 2007- 2010. Median age (range)
42(19 – 55); High Risk, 32/34, stage III/IV 74%; CD4 count (cells/uL) 195 (0 –
721), CD4 <100 (cells/uL), 5 (15%). Twenty-six were on HAART; viral load <100
copies/mL in 12. Twenty-seven patients had grade 3-5 toxicity including 20
hematologic; 14 infectious and 6 metabolic. None had grade 3/4 mucositis. Five
patients did not complete treatments due to adverse events. Eleven patients died:
1treatment-related and 8 disease-related. The 1 year progression free and overall
survival were 69.3% (50.5%, 82.2.%) and 72.2% (95% CI 53.2%, 84.5%),
respectively and 2 year OS 69.0% (95% CI: 50.1%, 82.0%) . Modifications of the
CODOX-M/IVAC regimen resulted in a grade 3/4 toxicity rate of 79%, lower than
parent regimen (100%), without grade 3/4 mucositis. Despite a 68% protocol
completion rate, the 1-year entire cohort survival rate of 72%, compares favorably
with 2 reported studies excluding HIV + pts. [1, 2] This study is registered at
http://clinicaltrials.gov as NCT00392834.
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Introduction

Burkitt lymphoma (BL) is an aggressive non-Hodgkin’s lymphoma (NHL)
characterized by obligate myc gene expression driving a nearly 100% growth phase
fraction. More common in children or adolescents, BL accounts for 1-2% of adult
NHL. Most patients present with advanced disease involving multiple extra nodal
sites. Although historically BL was one of the first cancers to respond to
chemotherapy[3] early relapses occurred, often in the central nervous system
(CNS), with rapid disease progression[4]. Cure rates of 50-60% were achieved in
early stage patients with high dose cyclophosphamide, anti-metabolites, and
prophylactic intrathecal (IT) chemotherapy. However, only 20% of patients with
bone marrow (BM) or CNS involvement achieved durable responses.[5] [6, 7]In

1996, Magrath and colleagues reported a 92% 2-year event-free survival (EFS) rate
in HIV-negative adult and pediatric patients following intensive chemotherapy with
cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide,
high dose cytarabine (CODOX-M/ IVAC). Results were particularly impressive in
patients with BM and/ or CNS involvement, with an 80% two-year disease-free
survival.[1] Although inferior to the Magrath report, an international multicenter

phase II study demonstrated a 2-year EFS of 65% and 2-year overall cure rate of
72.8%, with excellent results even in high risk patients stratified by the
International Prognostic Index.[1, 2] Other regimens that incorporate high dose
cytarabine and methotrexate and intensive IT prophylaxis have also been similarly
successful.[8, 9]

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In contrast to the general population, BL comprises 25-40% of HIV associated NHL
prior to HAART.[10-12] and more recently estimated at 10%, though this recent study
included 31% NHL unspecified . [13] HIV-BL closely resembles the general

population in terms of stage, marrow (33-35%), CNS (17-19%) involvement and
[14]
histology.[15] Prior to highly active anti-retroviral therapy (HAART), combination
chemotherapy was less successful for patients with HIV-associated NHL than for
HIV-negative patients with similar NHL histopathology. Early deaths were often due
to opportunistic infection.[16]. However, improved immune function in the HAART
era has led to a reevaluation of full-dose chemotherapy. Moreover, HIV+ patients
with BL and preserved immune function may benefit from more aggressive
chemotherapeutic approaches with acceptable toxicities. [5]. Finally, retrospective
analyses suggest HAART era HIV+ BL patients do poorly with CHOP-like regimens,
[17]but may do well with intensive regimens.[18]Nonetheless, because of the

perceived risk of increased hematologic and infectious complications, many patients
with HIV-associated BL continue to be treated with cyclophosphamide, doxorubicin,
vincristine, and prednisone (CHOP) and other moderate dose chemotherapy
despite inferiority in HIV-negative BL patients.

AMC 048, the first ever dedicated phase II clinic therapeutic study in HIV associated
BL sought to determine if intensive therapy was feasible and appropriate in the
HAART era. We prospectively studied a further modification of the CODOX-M/ IVAC
regimen previously reported in 14 HIV-negative patients, [19] recognizing that the

various Burkitt regimens have not been prospectively compared.
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Methods:
Eligibility: This research protocol was approved by each site’s institutional review
boards and all participants gave written informed consent
Patients with documented HIV infection and newly-diagnosed untreated BL or atypical
BL as per WHO criteria [20] were eligible. As of 2009, the new WHO criteria replaced
atypical Burkitt with “B cell lymphoma unclassifiable, with features intermediate
between DLBCL and Burkitt lymphoma.”

Adequate cardiac (ejection fraction ≥ 50%), renal (serum creatinine of ≤ 1.5 mg/dL. or
creatinine clearance ≤ 60 mL/minute ) and hepatic function (AST (SGOT) and ALT
(SGPT) ≤ 3 x the upper limit of normal and a direct bilirubin level of ≤ 2.0 mg/dL) were
required unless secondary to antiretroviral therapy, in which the total bilirubin cut-off
was ≤ 3.5 mg/dL provided that the direct bilirubin was normal. An ANC ≥ 1000/µL and
Platelets ≥ 50,000/µL were necessary unless disease-related. A Karnofsky
performance status > 30% was required given the aggressiveness of this disease and
the often severely debilitated nature of the patients at initial presentation. Prior
malignancies were excluded unless disease free > 5 years other than curatively treated
cutaneous basal cell or squamous cell carcinoma, carcinoma in situ of the cervix, or
cutaneous Kaposi’s sarcoma (KS). Non-measurable disease (eg. Isolated bone marrow
involvement) was allowed.

Patients could enter after a pre-phase treatment of steroids for up to 7 days alone or
in combination with a non-CHOP regimen necessary for patient stabilization (e.g.,
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cyclophosphamide for normalization of disease-related hyperbilirubinemia). In
addition, patients could be entered after 1 cycle of CHOP or fractionated CHOP (e.g.
CODOX) with or without rituximab. This allowed patients to enter in cases of either
newly diagnosed HIV infection after chemotherapy initiation or minimal therapy
for disease stabilization elsewhere and transfer to a tertiary care center.

Evaluation of occult leptomeningeal disease: CSF was obtained prior to systemic
chemotherapy unless thrombocytopenia or leukemic disease precluded safe lumbar
puncture. Three cc of CSF were evaluated for CD19, CD10 and CD45 by routine flow
cytometry methods at each institution. If there were sufficient cells, kappa and
lambda light chain assays were also run. For subsequent lumbar punctures, only
cell count and cytology were required.

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Treatment Plan:

AMC 048 (Table 1) was based on the original NCI Magrath regimen[1] and
subsequent modifications made by Lacasce et al.[19] The goals of additional
changes pursued in AMC 048 and their brief rationales are included in the Online
Supplement A. Pretreatment evaluations included standard blood work, total body
CT or MRI, bone marrow biopsy, cerebrospinal fluid (CSF) analysis to include
routine studies, cytology. PET scan was recommended, but not required.

The protocol required baseline CSF flow cytometry, but it was only completed in 15
patients. The flow cytometry was performed at the individual site referencing an
appendix that specified immediate processing and cell count dependent antibody
staining. Specifically, a cell count of zero, engendered a 3 color flow of CD19, kappa
and lambda in a single tube. A cell count of one required two tubes for evaluation
separatinig out the kappa and lambda, while duplicating the other antibodies.
Additional evaluations were at the discretion of the laboratory.

Treatment Administration:
As per the original CODOX-M/IVAC regimen, we defined
Low risk disease: 1. Stage I, with a single focus of disease < 10 cm AND normal LDH
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OR 2. Intra-abdominal disease ONLY AND total resection AND normal LDH
post surgery.
Patients with low risk disease received three cycles of R-CODOX-M.

All other patients were considered high risk and received R-CODOX-M/ IVAC in an R-
CODOX-M/ IVAC / R-CODOX-M/ IVAC sequence for a total of 4 cycles.

As anasarca, pleural effusions, or ascites, can cause methotrexate pooling and delayed
clearance, treatment could be given in a reverse sequence: IVAC/R-CODOX-M/ IVAC . R-
CODOX-M/ Cycles were to remain 21-28 days in length.

Patients with CNS disease were to be treated with intensification of the prophylaxis
regimen. If the patient had CNS disease, treatment of the leptomeninges with liposomal
cytarabine and methotrexate was matched to the appropriate cycle. Specifically,
liposomal cytarabine (Depocyt) administered on day 1 or 3 of the CODOX-M cycle and
was not administered in any of the IVAC cycles. Methotrexate IT was administered in
the IVAC cycles. Details are found in online Supplement B. Of note, no patients were
enrolled with parenchymal CNS disease at diagnosis.

Prophylactic antibiotics: Details of prophylaxis for pneumocystis, mycobacterium
avium complex and neutropenic fever are outlined in online Supplement C.

Correlative studies:
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Immunohistochemistry studies were performed using standard techniques for p53,
Interferon regulatory factor 4 (IRF4),/multiple myeloma ongongene-1
(IRF4/MUM-1) and Ebstein Barr Virus RNA (EBER) by in situ hybridization.

Statistics:

The primary endpoint was one-year overall survival (OS) as treatment failures tend
to be either immediate of within the first few months after treatment completion.
Relapse after one year of follow up post treatment for BL is exceedingly rare.
A sample size of 31 patients was needed to test the null hypothesis that the one-year
OS rate was 0.65 against the alternative that it was 0.85 at the one-sided 0.10
significance level with power of 0.90 using a nonparametric survival model.[21] To
allow for a 10% dropout rate, 34 patients were enrolled. An early stopping rule
was to be invoked for treatment-related mortality, including infection-related death,
and was derived by determining the number of infection-related deaths. This would
occur <10% of the time if the true infection-related mortality rate was <4%. This
stopping rule was designed to detect a two-fold or greater increased risk of
treatment related death compared to AMC 010.[22] The stopping rule had a power
of 0.90. The remainder of the statistical methods can be found in Online Supplement
E.

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Results:

Patient characteristics

From 2007-2010, 13 AMC centers entered 34 patients (Table 2), all but 2 of whom
were high risk. Four had evidence of leptomeningeal disease. None had
parenchymal CNS disease. 88% were male. 65% were White, 15% were African-
American and 24% were Hispanic. The median age was 42 years (range: 19-55).
Only 9% were intravenous drug users. Median HIV viral load was 1819 copies/uL
with only 12 patients having a viral load <100 copies/uL and only 1 < 20 copies/uL.
Most patients, 26/31, were on HAART at study entry. Three were on their second
or greater HAART regimens. The median CD4 count was 195 cells/uL (range: 0 –
721). CD4 were less than 100 cells/uL in 5 ( 15%). HIV replication was measured
at initiation and completion of chemotherapy and every 4 months for 2 years. Of 10
patients with undetectable HIV viral load at baseline, 2 had detectable HIV viral
loads during the study. Of 8 patients who were not on antiretroviral therapy at
baseline, 2 went on antiretroviral therapy during the study.

Central pathology review

Pathology reported by the referring institution was Burkitt lymphoma in all but one
case of atypical Burkitt. Central pathology review occurred in 25 of 34 cases.
Others did not have available immunohistochemistry slides or tissue blocks. The
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