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Regular Article

CLINICAL TRIALS AND OBSERVATIONS

AMC 048: modified CODOX-M/IVAC-rituximab is safe and effective for

HIV-associated Burkitt lymphoma
Ariela Noy,1 Jeannette Y. Lee,2 Ethel Cesarman,3 Richard Ambinder,4 Robert Baiocchi,5 Erin Reid,6 Lee Ratner,7
Nina Wagner-Johnston,7 and Lawrence Kaplan,8 for the AIDS Malignancy Consortium
1
Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical Center, New York, NY; 2University of Arkansas Medical
Center, Little Rock, AR; 3Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY; 4Department of Oncology, Johns
Hopkins School of Medicine, Baltimore, MD; 5Division of Hematology, Ohio State Medical Center, Columbus, OH; 6University of California San Diego,
Moores Cancer Center, La Jolla, CA; 7Division of Oncology, Washington University School of Medicine, St. Louis, MO; and 8Department of Medicine,
University of California San Francisco, San Francisco, CA

The toxicity of dose-intensive regimens used for Burkitt lymphoma prompted modifica-
Key Points
tion of cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide,
• We report the first dedicated etoposide, and high-dose cytarabine (CODOX-M/IVAC) for HIV-positive patients. We
prospective study in HIV-Burkitt added rituximab, reduced and/or rescheduled cyclophosphamide and methotrexate,
lymphoma demonstrating capped vincristine, and used combination intrathecal chemotherapy. Antibiotic prophy-
safety and efficacy in a multi- laxis and growth factor support were required; highly active antiretroviral therapy
(HAART) was discretionary. Thirteen AIDS Malignancy Consortium centers enrolled 34
institutional setting.
patients from 2007 to 2010. Median age was 42 years (range, 19-55 years), 32 of 34 patients
• We offer a new therapeutic
were high risk, 74% had stage III to IV BL and CD4 count of 195 cells per mL (range, 0-721
option by modifying an cells per mL), and 5 patients (15%) had CD4 <100 cells per mL. Twenty-six patients were
existing regimen and making receiving HAART; viral load was <100 copies per mL in 12 patients. Twenty-seven patients
it much less toxic. had at least one grade 3 to 5 toxicity, including 20 hematologic, 14 infectious, and 6
metabolic. None had grade 3 to 4 mucositis. Five patients did not complete treatments
because of adverse events. Eleven patients died, including 1 treatment-related and 8 disease-related deaths. The 1-year progression-
free survival was 69% (95% confidence interval [CI], 51%-82%) and overall survival was 72% (95% CI, 53%-84%); 2-year overall survival
was 69% (95% CI, 50%-82%). Modifications of the CODOX-M/IVAC regimen resulted in a grade 3 to 4 toxicity rate of 79%, which was
lower than that in the parent regimen (100%), without grade 3 to 4 mucositis. Despite a 68% protocol completion rate, the 1-year
survival rate compares favorably with 2 studies that excluded HIV-positive patients. This trial was registered at http://
clinicaltrials.gov as #NCT00392834. (Blood. 2015;126(2):160-166)

Introduction
Burkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma
(NHL) characterized by obligate MYC gene expression driving a nearly
100% growth phase fraction. BL accounts for 1% to 2% of adult NHL
but is more common in children and adolescents. Most patients present
with advanced disease involving multiple extranodal sites. Historically,
BL was one of the first cancers to respond to chemotherapy,1 but early
relapses occurred, often in the central nervous system (CNS) with rapid
disease progression.2 Cure rates of 50% to 60% were achieved in early-
stage patients with high-dose cyclophosphamide, antimetabolites, and
prophylactic intrathecal (IT) chemotherapy. However, only 20% of
patients with bone marrow or CNS involvement achieved durable
responses.3-5 In 1996, Magrath et al6 reported a 92% 2-year event-free
survival (EFS) rate in HIV-negative adult and pediatric patients after
intensive chemotherapy with cyclophosphamide, vincristine, doxoru-
bicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose
cytarabine (CODOX-M/IVAC). Results were particularly impressive
in patients with bone marrow and/or CNS involvement, with an 80%
2-year disease-free survival rate. Although inferior to the Magrath
report, an international multicenter phase 2 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.6,7 Other regimens that incorporate high-dose cytarabine and
methotrexate and intensive IT prophylaxis have also been similarly
successful.8,9
In contrast to BL in the general population, BL comprised 25% to
40% of HIV-associated NHL before the era of highly active anti-
retroviral therapy (HAART).10-12 BL was more recently estimated at
10%, although this study included 31% NHL unspecified.13 Patients
with HIV-BL closely resemble the general BL population in terms of
stage, marrow involvement (33% to 35%), CNS involvement (17%
to 19%),14 and histology.15 Prior to HAART, combination chemo-
therapy was less successful for patients with HIV-associated NHL
than for HIV-negative patients with similar NHL histopathology. Early
deaths were often the result of opportunistic infection.16 However,

Submitted January 23, 2015; accepted May 4, 2015. Prepublished online as
Blood First Edition paper, May 8, 2015; DOI 10.1182/blood-2015-01-623900.
The online version of this article contains a data supplement.
There is an Inside Blood Commentary on this article in this issue.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked “advertisement” in accordance with 18 USC section 1734.
© 2015 by The American Society of Hematology

160 BLOOD, 9 JULY 2015 x VOLUME 126, NUMBER 2

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BLOOD, 9 JULY 2015 x VOLUME 126, NUMBER 2
improved immune function in the HAART era has led to a reeval-
uation of full-dose chemotherapy. Moreover, HIV-positive patients
with BL and preserved immune function may benefit from more
aggressive chemotherapeutic approaches with acceptable toxicities.3
Finally, retrospective analyses suggest that HAART era HIV-positive
BL patients do poorly with cyclophosphamide, doxorubicin, vincris-
tine, and prednisone (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 CHOP and other
moderate-dose chemotherapy despite inferiority in HIV-negative
BL patients.
The AIDS Malignancy Consortium 048 (AMC 048; Rituximab
and Combination Chemotherapy in Treating Patients With Newly
Diagnosed, HIV-Associated Burkitt’s Lymphoma) trial, which to
the best of our knowledge was the first dedicated phase 2 clinical
therapeutic study in HIV-associated BL, sought to determine whether
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
after noting that the various BL regimens had not been prospec-
tively compared.
Patients and 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 per World Health Organization criteria20 were eligible. As of 2009, the
new World Health Organization criteria replaced “atypical BL” 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
(aspartate aminotransferase and alanine aminotransferase #3 3 the upper limit
of normal and a direct bilirubin level of #2.0 mg/dL) was required unless it was
secondary to antiretroviral therapy, in which the total bilirubin cutoff was
#3.5 mg/dL, provided that the direct bilirubin was normal. An absolute
neutrophil count $1000/mL and platelets $50 000/mL were necessary unless
they were 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 the
patient had been disease free .5 years other than having curatively treated
cutaneous basal cell or squamous cell carcinoma, carcinoma in situ of the cervix,
or cutaneous Kaposi’s sarcoma. Nonmeasurable disease (eg, isolated bone
marrow involvement) was allowed.
Patients could enroll onto the study after a prephase treatment of steroids
for up to 7 days alone or in combination with a non-CHOP regimen necessary
for patient stabilization (eg, cyclophosphamide for normalization of disease-
related hyperbilirubinemia). In addition, patients could be enrolled after
1 cycle of CHOP or fractionated CHOP (eg, CODOX) with or without
rituximab. This allowed patients to enroll if they had either newly diagnosed
HIV infection after chemotherapy initiation or minimal therapy for disease
stabilization elsewhere and were transferred to a tertiary care center.
For evaluation of occult leptomeningeal disease, cerebrospinal fluid (CSF)
was obtained prior to systemic chemotherapy unless thrombocytopenia or
leukemic disease precluded safe lumbar puncture. Three cubic centimeters of
CSF was evaluated for CD19, CD10, and CD45 by routine flow cytometry
methods at each institution. If there were sufficient cells, k and l light chain
assays were also performed. For subsequent lumbar punctures, only cell count
and cytology were required.
MODIFIED CODOX-M/IVAC-RITUXIMAB FOR HIV-BURKITT 161
Treatment plan
Treatment in AMC 048 (Table 1) was based on the original National
Cancer Institute Magrath regimen6 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 supplemental Data available at the
Blood Web site. Pretreatment evaluations included standard blood work,
total body computed tomography scan or magnetic resonance imaging
scan, bone marrow biopsy, and CSF analysis, including routine studies, cy-
tology, and flow cytometry. Positron emission tomography scan was recom-
mended but not required.
The protocol required baseline CSF flow cytometry, but it was completed
in only 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 engen-
dered a 3-color flow of CD19 k and l in a single tube. A cell count of one
required 2 tubes for evaluation separating out the k and l while duplicating
the other antibodies. Additional evaluations were at the discretion of the
laboratory.
Treatment administration
Per the original CODOX-M/IVAC regimen, we defined low-risk disease
as stage I, with a single focus of disease ,10 cm and normal lactate
dehydrogenase or intra-abdominal disease only and total resection and
normal lactate dehydrogenase after surgery. Patients with low-risk disease
received 3 cycles of rituximab and CODOX-M (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.
Because 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 to 28
days long.
Patients with CNS disease were to be treated with an intensified
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 was administered
on day 1 or 3 of the CODOX-M cycle and was not administered in any of
the IVAC cycles. IT methotrexate was administered in the IVAC cycles.
Details are provided in supplemental Data. Of note, no patients with paren-
chymal CNS disease at diagnosis were enrolled. Details of prophylaxis for
Pneumocystis, Mycobacterium avium complex, and neutropenic fever are
outlined in supplemental Data.
Correlative studies
Immunohistochemistry studies were performed by using standard techniques
for p53, interferon regulatory factor 4/multiple myeloma oncogene 1 (IRF4/
MUM1), and Epstein-Barr virus (EBV) –encoded small RNAs (EBERs) in
situ hybridization.
Statistics
The primary end point was 1-year overall survival (OS) because treatment
failures tend to be either immediate or within the first few months after
treatment completion. Relapse after 1 year of follow-up after treatment of BL
is exceedingly rare.
A sample size of 31 patients was needed to test the null hypothesis that the
1-year OS rate was 0.65 against the alternative that it was 0.85 at the 1-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 twofold or greater increased
risk of treatment-related death compared with AMC 010.22 The stopping rule
had a power of 0.90. The remainder of the statistical methods can be found in
supplemental Data.
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162 NOY et al BLOOD, 9 JULY 2015 x VOLUME 126, NUMBER 2

Table 1. AMC 048 treatment plan

Day
Treatment 1 2 3 4 5 6 7 8 9 10 11 12 13 14-28
Regimen A: R-CODOX-M*
Rituximab 375 mg/m2 IVPB X†
Cyclophosphamide 800 mg/m2 IVPB X X
Vincristine 1.4 mg/m2 IVP‡ X X
Doxorubicin 50 mg/m2 IVP X
Pegfilgrastim 6 mg§ X
Methotrexate 3000 mg/m2 IVPB|| X (day 15)
Leucovorin IVPB X{
Cytarabine 50 mg IT X# X**
Methotrexate 12 mg IT X#
G-CSF†† X†† (approximately day 18)
Regimen B: IVAC*
Rituximab 375 mg/m2 IVPB X
Ifosfamide 1500 mg/m2 IVCI X X X X X
Mensa 1500 mg/m2 IVCI X X X X X
Etoposide 60 mg/m2 IVCI X X X X X
Cytarabine 2000 mg/m2 IVPB (no cap) X X
every 12 h 3 4 doses
Methotrexate 12 mg IT X
Pegfilgrastim 6 mg§ X

G-CSF, granulocyte colony-stimulating factor; IVCI, intravenous continuous infusion; IVP, intravenous push; IVPB, intravenous piggyback.
*Patients with low-risk disease received 3 cycles of regimen A. Patients with high-risk disease received 4 alternating cycles of regimens A and B.
†Rituximab was given once each cycle. Acute presentation of high-grade lymphoma and scheduling constraints may make it difficult to administer rituximab on the first
day of each cycle. Rituximab was given up to 3 days before a chemotherapy cycle and any time within the cycle such that a total of 4 doses were given with this regimen for
patients with high-risk disease. A missed dose was made up within 28 days of the last dose of IVAC.
‡Vincristine maximum 2-mg dose. Delays by a few days were allowed to accommodate scheduling or treatment of constipation.
||Methotrexate levels were drawn 24, 48, and 72 hours after treatment, with anticipated decrement in levels of 10-fold every 24 hours.
{Leucovorin was administered 24 hours after methotrexate and was initiated with a dose of 200 mg/m2 intravenously (IV) followed by 25 mg/m2 IV every 6 hours until the
methotrexate level reached ,50 nmol/L. Leucovorin was titrated for delayed methotrexate clearance or increases in creatinine.
#Methotrexate (12 mg intrathecally [IT]) mixed with cytarabine (50 mg IT) given on day 1. Hydrocortisone 50 mg was given to reduce arachnoiditis.
††G-CSF: Restarted after methotrexate levels had dropped below 50 nmol/L and continued until absolute neutrophil count (ANC) reached .1000 cells per mL.
§If pegfilgrastim was not available, G-CSF was given once per day until ANC .1000 cells per mL was substituted.
**Patients with high-risk disease received additional IT cytarabine 50 mg on day 3.

large B-cell lymphoma (DLBCL) (2), DLBCL (3), and high-grade

Results
Patient characteristics
From 2007 to 2010, 13 AMCs enrolled 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 years). Only 9% were IV drug users. Median
HIV viral load was 1819 copies per mL with only 12 patients having
a viral load ,100 copies per mL and only 1 patient having ,20 copies
per mL. Most patients (26 of 31) were given HAART at study entry, and
3 patients were receiving their second or greater HAART regimens. The
median CD4 count was 195 cells per mL (range, 0-721 cells per mL).
CD4 was less than 100 cells per mL in 5 patients (15%). HIV replication
was measured at initiation, at 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 receiving antiretroviral therapy at baseline, 2
began receiving antiretroviral therapy during the study.
Central pathology review
Pathology reported by the referring institution was BL in all but 1
patient who had atypical BL. Central pathology review was performed
for 25 of 34 patients. Other patients did not have available immuno-
histochemistry slides or tissue blocks. The diagnosis was BL (19), high-
grade lymphoma with features intermediate between BL and diffuse
NHL, not otherwise specified (1). All evaluable patients were CD201
CD101 and had a Ki-67 of 90% (4) or .95% (21). Fluorescence in
situ hybridization for MYC using a break-apart probe was performed
for patients in whom the immunophenotype and morphology were
not obvious for a diagnosis of BL. Two of the patients with ques-
tionable immunophenotype and morphology had myc rearrange-
ments and high proliferation rate, but both had large cells, which are
morphologically consistent with DLBCL, not BL. One of these pa-
tients was BCL2-positive and BCL6-negative, which ruled out BL,
and the second patient was BCL6-postive and was considered to
have MYC-positive germinal center-DLBCL. A third patient was
classified as having DLBCL because of clear morphologic features,
but no material was available for fluorescence in situ hybridization
analysis. Because of interobserver variability, all patients were in-
cluded in the analysis.
Treatment outcomes
Details of toxicities are provided in Table 3. Grade 3 to 4 toxicity
occurred at least once in 27 patients. In 20 patients, toxicity was he-
matologic: 17 patients had anemia, 16 had neutropenia despite pro-
phylactic hematopoietic growth factors, and 21 had thrombocytopenia.
Grade 4 transfusion level anemia occurred in 6 patients (18%) and
thrombocytopenia occurred in 20 (59%); 26 patients had nonhema-
tologic grade 3 to 4 toxicities, with electrolyte and neurologic distur-
bances being the most common. Neutropenic fever occurred in 8
(24%) of 34 patients.
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BLOOD, 9 JULY 2015 x VOLUME 126, NUMBER 2 MODIFIED CODOX-M/IVAC-RITUXIMAB FOR HIV-BURKITT 163

Table 2. Demographic and baseline characteristics 69% (95% CI, 51%-82%), the 1-year OS (the primary end point) was
Characteristic No. % 72% (95% CI, 53%-85%), and 2-year OS was 69% (95% CI, 50%-82%)
Gender (Figure 1). When restricted to 19 patients with confirmed BL by central
Male 30 88 pathology review, the 1-year PFS was 72.2% (95% CI, 45.6%-87.4%)
Female 4 12 and OS was 78% (95% CI, 51%-91.0%). Not surprisingly, the 1-year
Race OS was superior for those who completed all 4 cycles of treatment
White 22 65 (86% [95% CI, 62%-95%]) compared with those who did not
African American 5 15 (48% [95% CI, 18%-73%]; P , .001, log-rank test). Of note, little
Hawaiian/Pacific Islander 1 3
drop-off was seen after the first year, with only 1 patient progressing
Asian 2 6
between years 1 and 2.
Unknown 4 12
Ethnicity
Overall, 11 patients died. One patient died of treatment-related tox-
Hispanic 8 24
icity characterized by encephalopathy, with hepatic failure, hepatitis B,
Non-Hispanic 26 76 and pneumonia being contributing causes. This patient entered the
Age, years study with cirrhosis but met eligibility criteria. Eight died of systemic
Median 42.0 disease progression, including 1 patient who died as a result of CNS
Range 19-55 disease who did not have CNS disease at baseline. During the follow-up
CDC risk group period, 1 patient died in remission of fungal infection and 1 died of
Homosexual/bisexual contact 14 41 nonmalignant complications of HIV.
Heterosexual contact 10 29
At study entry, 26 of 31 patients were receiving HAART. The com-
IVDU 3 9
plete response and 1-year OS did not show a statistically significant
Heterosexual contact and IVDU 1 3
difference based on receipt of HAART at study entry, possibly because
Homosexual/bisexual and heterosexual 3 9
contact
of small numbers of patients, as it was higher for those receiving
Other (needle sticks, congenital HIV, 3 9 HAART (86% vs 50%), possibly because of small numbers of patients.
unknown) Similarly, low baseline CD4 (,100) or high baseline CD4 ($100) did
Receiving HAART at diagnosis 26 76 not predict a different outcome with respect to these measures.
Absolute CD4 count (n 5 33)
Median 195.0 Correlative studies
SD 174.6
Min-max 0-721 The immunohistochemistry panel was performed as feasible, depend-
HIV load (n 5 33) ing on the availability of material. Non-BL–defining proteins did not
Median 1819 correlate with OS: EBER positive (8 of 16) or negative and p53 positive
Min-max Undetectable-1 187 968
(10 of 10) or negative. Notably, however, staining for p53 fell into 3
Ann Arbor stage
groups: 9 had ,10%, 3 had 30% to 60%, and 8 had 80% to more than
I 4 12
II 2 6
IIE 1 3 Table 3. AEs at the patient level (most severe grade)
III 2 6
Grade
IV 25 74
Karnofsky performance status AE 1/2 3/4 5
40%-60% 7 23 Total 27 4
.70% 26 77 Fatigue 1 0 0
Local pathology diagnosis (n 5 35) Fever 2 0 0
BL 33 97 Weight loss 2 0 0
Burkitt-like lymphoma 1 3 Anemia 0 17 0
Central pathology diagnosis (n 5 25) Thrombocytopenia 1 21 0
BL 17 71 Neutropenia 1 16 0
High-grade, unclassifiable B-cell 3 21 Febrile neutropenia 0 8 0
lymphoma with features intermediate Allergic reaction 1 0 0
between DLBCL and atypical BL Pulmonary/thoracic 3 4 0
Indeterminate between DLBCL and BL 1 7 Cardiac 4 0 0
DLBCL 3 6 Opthalmologic 0 1 0
High-grade NHL, not otherwise specified 1 7 GI 10 6 1
Pain 2 1 0
CDC, Centers for Disease Control and Prevention; IVDU, intravenous drug user;
Infection 3 13 1
SD, standard deviation.
Metabolic (excluding tumor lysis) 6 34 0
Tumor lysis syndrome 0 1 0
Table 4 outlines treatment completion status; 68% of patients Musculoskeletal 0 1 0
completed the treatment. Early termination of therapy was a result Neurologic 6 7 1
of disease progression in 9%, adverse events in 12%, and patient Myelodysplasia 0 1 0
withdrawal in 3%. Adverse events leading to early termination were Renal 0 1 0
hematologic (3), neurologic (2), or hepatic/infectious (1). Psychiatric 1 3 0
The last patient completed treatment in 2011, and the protocol Dermatologic 6 0 0
Vascular 1 4 0
required 2-year follow-up after the last treatment in 2013. The analysis
Nonmalignancy complications of HIV N/A N/A 1
was completed in 2014. The median follow-up was 26 months. Despite
early terminations, the 1-year progression-free survival (PFS) was N/A, not applicable.
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164 NOY et al BLOOD, 9 JULY 2015 x VOLUME 126, NUMBER 2

Table 4. Treatment status universal toxicity of the unmodified parent regimen. Of particular note,
Low risk High risk Total we eliminated grade 3 and 4 mucositis. Nonhematologic toxicities were
(n 5 2) (n 5 32) (n 5 34) also manageable except in 1 patient with pretreatment cirrhosis who
Status No. % No. % No. % died of liver failure.
Treatment completed per protocol 2 100 21 66 23 68 In this study, despite early terminations, 1-year PFS was 69% (95%
Disease progression 0 3 9 3 9 CI, 51%-82%), 1-year OS (the primary end point) was 72% (95% CI,
Early termination 53%-85%), and 2-year OS was 69% (95% CI, 50%-82%). A study of
Adverse event 0 5 16 5 15 30 patients with HIV-associated BL treated with CODOX-M/IVAC
Patient withdrawal 0 1 3 1 3 resulted in a 3-year OS of 52% and EFS of 75%.23 Similarly, an
Counts did not recover within 0 1 3 1 3
international study of CODOX-M/IVAC in BL patients not infected
time frame to begin cycle 4
with HIV reported a 2-year EFS of 65% and 2-year overall cure rate of
Other complicating disease 1 3 1 3
72.8%.7 Nonetheless, our results were inferior to the previous Magrath
Patient #6 terminated treatment because of low platelet count (grade 4) and report of 92% 2-year EFS,6,7 which included 39 adults and 33 children
infection (grade 3) possibly related to doxorubicin and cyclophosphamide. Patient
and no patients with HIV infection.
#3 terminated treatment because of left hemiparesis (grade 3), possibly related to
cytarabine and vincristine. Patient #1 terminated treatment because of confusion Although we cannot say which individual modification contributed
(grade 3) unrelated to treatment. Patient #27 terminated treatment because of grade to the success of the program, rituximab may have had a positive im-
3 encephalopathy and grade 3 pneumonitis/pulmonary infiltrates. The encephalop- pact. One study in HIV-negative patients treated with a hyperfraction-
athy was reported as possibly related to treatment. (This patient with pretreatment
cirrhosis died 35 days later because of hepatic failure with contributing causes listed
ated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/
as hepatitis B, cirrhosis, pneumonia, and HIV, and death as a result of treatment toxicity cytarabine/methotrexate regimen strongly suggested that rituximab
was reported.) Patient #30 terminated treatment because of grade 4 neutropenia and improved relapse-free survival and OS compared with a historical
grade 3 white blood cell count, which were probably/possibly related to treatment.
cohort.24 In another retrospective study of 80 BL patients who received
CODOX-M/IVAC, 50% were treated with rituximab. Rituximab was
95%. IRF4/MUM1 staining was not significantly associated with OS. associated with a trend in improvement of 3-year OS of 77% vs 66%,
There were 6 MUM1-positive patients, 2 of whom died and 14 MUM1- and HIV-positive patients did as well as HIV-negative patients.
negative patients, 3 of whom died. The hazard ratio for MUM1-positive Regardless, it seems likely that with current supportive care, rituximab
vs MUM1-negative for OS was 1.42 (95% CI, 0.24-8.53; P 5 .70). does not contribute adversely to toxicity in our modified CODOX-M/
Within the subset of patients with confirmed BL, MUM1-positivity also IVAC regimen, which was of concern in the AMC 010 study of CHOP
did not predict survival (hazard ratio, 1.70; 95% CI, 0.24-12.05). None with or without rituximab in HIV-related NHL, particularly in the
of the patient tissues stained for the multidrug-resistant protein. subpopulation of patients with CD4 ,50 cells/uL.25
Additionally, limiting the dose of high-dose methotrexate, as
Occult leptomeningeal disease
previously done by Lacasce,19 and moving it to day 15 outside the
CODOX day 10 nadir likely lowered both the incidence of severe
We sought to investigate the use of flow cytometry to identify cyto- mucositis and the rate of neutropenic fever. The incidence of hema-
logically occult leptomeningeal disease at baseline in BL and determine tologic toxicity, which occurred in 24% of patients, was lower than the
its prognostic significance. CSF by cell count and cytology in 15 nearly 100% toxicity in the unmodified parent regimen. Although we
evaluable patients was negative in 12, positive in 2, and atypical in 1. hypothesized that the improved tolerability led to on-time drug ad-
Flow cytometry did not identify disease in the 12 cytology-negative ministration and overall improved outcomes, this would need to be
patients. Flow cytometry was positive in 3 patients: one with atypical cy- confirmed in a randomized trial. Similar to the procedures in Lacase,19
tology, one with positive cytology, and one with unavailable cytology. we capped vincristine at 2 mg and had no grade 3 to 4 peripheral
neuropathy. Although it was unusual, we cannot exclude that vincris-
EBV in tumor tine may have played a role in the patient who experienced hemiparesis
(a central neurotoxicity). Similarly, we do not attribute toxicity to
EBV-driven lymphomas may develop via a unique pathway that may vincristine in the case of hepatic encephalopathy, which occurred in the
be more resistant to chemotherapy. Alternatively, nuclear factor kappa
B activation in these tumors may create a new therapeutic target. As
noted above, EBER staining (positive or negative) was variable in our
sample (8 of 16) but did not predict for OS.

Discussion
AMC 048 modified the CODOX-M/IVAC regimen to reduce toxicity
while maintaining or improving the survival rate of patients with HIV-
associated BL. The study was initiated at a time when treating HIV-
related lymphoma intensively was controversial because of excess
chemotherapy-related toxicity in the pre-HAART era. Retrospective
studies, including one of CODOX-M/IVAC in the HAART era,18
suggested that high-risk patients with HIV-related BL could do well
with intensive chemotherapy. In AMC 048, the 1-year OS was 72%
(95% CI, 53%-85%), reasonably within reach of our 85% goal. We
also reduced morbidity, which compared favorably to the nearly Figure 1. Cumulative survival for all enrolled patients.
 From www.bloodjournal.org by guest on September 25, 2019. For personal use only.
BLOOD, 9 JULY 2015 x VOLUME 126, NUMBER 2
patient who died of exacerbation of preexisting cirrhosis (by eligible
baseline liver function tests) 35 days after therapy initiation.
Recently, Dunleavy et al26 reported a phase 2 trial in BL using short-
course infusional etoposide, prednisone, vincristine, cyclophosphamide,
and hydroxydaunorubicin plus rituximab (SC-EPOCH-R) for 3 cycles
in 11 HIV-positive patients and full-course dose-adjusted EPOCH-R in
an additional 19 non-HIV patients. Their 95% EFS and 100% OS ex-
ceed our study results. However, the small sample size leads to overlap-
ping 95% CIs for both EFS (72% to 100%) and OS (60% to 98%) with
our AMC 048 study. Moreover, none of the 11 HIV-positive patients
treated with SC-EPOCH with dose-dense rituximab (SC-EPOCH-RR)
had CNS disease, whereas 4 of our patients entered the study with
leptomeningeal disease. We suspect the EPOCH backbone is ill suited
to treatment of CNS disease because none of the agents included in
EPOCH have significant CNS penetration. We postulate that this would
be particularly problematic in the setting of baseline CNS parenchymal
disease. Although such patients were eligible for our study, none had
this baseline characteristic. It is also possible that the CODOX-M/
IVAC backbone is more effective for those at high risk of CNS meta-
stases or leptomeningeal disease at presentation.
With regard to toxicity, 88% of the SC-EPOCH-RR/EPOCH-R
cycles were administered to outpatients, whereas the AMC 048 regi-
men required hospitalization for both the high-dose methotrexate and
IVAC. Neutropenic fever was similar in the two studies: it occurred in
22% of patients vs 24% of patients in AMC 048. A phase 3 comparison
trial between the AMC 048 and the SC-EPOCH-RR regimen would be
difficult to conduct because of the rarity of this disease. A large ongoing
national confirmatory phase 2 trial (CTSU 9177/AMC 086) of an
outpatient regimen of EPOCH-R in BL is currently enrolling patients
and includes those with HIV.
In our study, we prospectively analyzed the incidence of cytology-
negative but flow cytometry–positive occult leptomeningeal disease.
By using the flow cytometric techniques available at the time, which
were specified by protocol, none of the 12 cytology specimens studied
were flow cytometry positive. In contrast, Hegde et al27 using similar
techniques reported that 11 (22%) of 51 patients had positive multicolor
flow cytometry in the absence of positive cytology. Their study popu-
lation had 91% untreated DLBCL with only 9% BL. HIV infection was
documented in 54% of those patients. Despite aggressive schedules of
direct installation of CSF chemotherapy, including 7 via lumbar punc-
ture and 3 via Ommaya reservoir, 5 patients (45%) had CNS relapse and
died. In contrast, in patients at increased risk of CNS involvement but
with negative flow cytometry results, the relapse risk was only 8%
(3 of 40). In AMC 048, our CNS relapse rate was very low (n 5 1) and
occurred in a patient with CNS baseline involvement. This may reflect
the use of systemic high-dose methotrexate and cytarabine in our
regimen, which was not part of the EPOCH study. Given our low rate of
CNS relapse, it is not clear that the currently available multiparameter
flow with higher sensitivity would yield a different result.
Given that only 19 (76%) of 25 patients had BL after central pa-
thology review, a sensitivity analysis demonstrated that outcomes for
confirmed BL did not differ from those with other histologies. More-
over, although dose intensification rather than CHOP-based therapy
is important for BL, its benefit for other histologies, such as DLBCL
with c-MYC rearrangement, or B-cell lymphoma (unclassifiable)
with features intermediate between DLBCL and BL, is less clear.
Preliminary data from an ongoing prospective study suggests that
EPOCH-R is efficacious for DLBCL with MYC or both MYC and
BCL-2 translocation.28 Nonetheless, it is possible that these 5 patients
may have been overtreated on AMC 048.
Because we were interested in identifying mechanisms of chemo-
therapy resistance, we studied p53 mutations and the chemotherapy
MODIFIED CODOX-M/IVAC-RITUXIMAB FOR HIV-BURKITT 165
efflux pump referred to as the multidrug resistance protein. Although
p53 staining was nearly dichotomized in our study, it was not predictive
of outcome, perhaps because of the small study size. None of the
samples stained for multidrug resistance. In our study, protein expres-
sion of MUM1/IRF4A, a gene of plasma cell differentiation, also failed
to confer a worse prognosis. Further investigations of these markers of
potential drug resistance in larger studies are warranted.
Finally, with respect to HAART, its use was at the discretion of the
individual investigator. At study entry, 26 of 31 patients were receiving
HAART. The protocol specified that physicians could continue or dis-
continue therapy at the initiation of chemotherapy. In addition, HAART
could be discontinued as needed for toxicity. Of note, HAART regimens
were exclusive of zidovudine, given its myelosuppression. HIV replica-
tion 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 were found to have detectable HIV viral loads during
the study. Of 8 patients who were not receiving antiretroviral therapy at
baseline, 2 began antiretroviral therapy during the study. We cannot make
any definitive conclusions about the role of HAART regarding outcomes.
Concurrent vs discontinued HAART therapy is a controversial area of
investigation. Fearing drug interactions, the National Cancer Institute in-
vestigators discontinued HAART therapy during EPOCH for HIV-
associated NHL (largely DLBCL); 5-year PFS and OS were 79% and
80%, respectively.29 With HAART reinitiation, HIV suppression and base-
line CD4 were regained within 6 months. Because HIV viral suppression
and immune reconstitution correlate with sustained disease-free survival,30
HAART reinitiation is highly desirable and all patients completing BL
treatment receive HAART even if it is interrupted during chemotherapy.
In summary, in AMC 048, we were able to aggressively treat HIV-
infected patients with BL and achieve high rates of long-term disease
remission with a modified intensive CODOX-M/IVAC plus rituximab
(CODOX-M/IVAC-R) regimen that minimized drug-related toxicity.
Although CTSU 9177/AMC 086 is investigating an outpatient regimen
of EPOCH-R in BL, the modified AMC 048 version of CODOX-
M/IVAC-R may better serve patients who present with CNS disease
or are at high risk for CNS relapse (eg, patients with bone marrow,
testicular, or multiple extranodal sites), because it contains high-dose
cytarabine and methotrexate, drugs that cross the blood-brain barrier.
Consequently, AMC 048 represents a reasonable treatment option in
the appropriate setting, possibly irrespective of HIV status.
Acknowledgments
This trial was supported by Grant No. U01CA121947 from the
National Cancer Institute for the AIDS Malignancy Consortium.
Authorship
Contribution: A.N., J.Y.L., E.C., R.A., and L.K. designed and
performed the research, analyzed the data, and wrote the paper; and
R.B., E.R., L.R., and N.W.-J. performed the research, analyzed the
data, and wrote the paper.
Conflict-of-interest disclosure: The authors declare no competing
financial interests.
A complete list of members of the AIDS Malignancy Consortium
can be found in the supplemental Data.
Correspondence: Ariela Noy, Memorial Sloan Kettering Cancer Cen-
ter, 1275 York Ave, New York, NY 10065; e-mail: noya@mskcc.org.
 From www.bloodjournal.org by guest on September 25, 2019. For personal use only.
166 NOY et al
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 From www.bloodjournal.org by guest on September 25, 2019. For personal use only.

2015 126: 160-166

doi:10.1182/blood-2015-01-623900 originally published
online May 8, 2015

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 Baiocchi, Erin Reid, Lee
Ratner, Nina Wagner-Johnston and Lawrence Kaplan

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