CHICAGO—There is no standard of care for patients with HIV-associated non-Hodgkin lymphoma, a major cause of death in HIV-infected individuals, and researchers continue tweaking regimens to improve outcomes without increasing toxicity.
In two multicenter Phase II trials presented here at the ASCO Annual Meeting, researchers substituted liposomal doxorubicin for doxorubicin in commonly used regimens in an effort to improve efficacy and decrease anthracycline-associated cardiomyopathy.
The bottom line: In one study the substitution did not appear to improve efficacy; in the other, it was not clear what role liposomal doxorubicin played in response rates because the regimen also included high dose rituximab.
“At present, data [from these two trials] do not suggest an efficacy benefit for liposomal doxorubicin,” said Lawrence D. Kaplan, MD, Director of the Lymphoma Program at the University of California, San Francisco Medical Center, a discussant at a poster-discussion session on Lymphoma and Plasma Disorders where the studies were presented.
The first trial treated diffuse large B-cell lymphoma with R-CHOP (rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, and prednisone); the second, in Burkitt’s lymphoma, used R-CODOX-M/IVAC (high-dose rituximab, cyclophosphamide, vincristine, liposomal doxorubicin and high-dose methotrexate alternating with ifosphamide, etoposide, and high dose Ara-C).
State of the Art
Dr. Kaplan prefaced his comments on these trials with some background: “We’ve come a long way in the past 15 years in the management of HIV-associated lymphoma, and much of the credit goes to treatment of the underlying HIV,” he said. “Prior to the introduction of effective antiretroviral treatment, complete response rates with earlier chemotherapy regimens were 50% or lower, and fewer than 20% of patients survived beyond two years.”
Overall survival was a dismal 11% with the BEACOP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) regimen, he said.
The introduction of HAART (highly active anti-retroviral therapy) brought modest improvements in response rates with CHOP-like regimens, and the introduction of rituximab has helped improve that.
In the most recent AIDS Malignancy Consortium (AMC) study (Sparano J et al: Blood 2010;115:3008-3016), he explained, patients received dose-adjusted R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) with either concurrent or delayed rituximab. With concurrent rituximab the complete response rate was 73%, two-year progression-free survival was 66%, and overall survival was 70% at two years—a dramatically different improvement over previous regimens, Dr. Kaplan said.
Outcomes in that trial were strongly dependent on CD4 lymphocyte count, he added.
“We are now routinely able to administer high-dose chemotherapy with peripheral blood stem cell support, and have good outcomes, but despite that, we have to be aware of the fact that outcome is still dependent on underlying immune function and HIV. Those whose HIV is less well controlled are more difficult to treat, and outcomes are not as good.”
Liposomal Doxorubicin in DLBCL
The first study Dr. Kaplan discussed was the AMC 047 trial of R-CHOP with liposomal doxorubicin (DR-CHOP) in newly diagnosed AIDS-associated B-cell non-Hodgkin’s Lymphoma patients.
First author on this study was Alexandra M. Levine, MD, Chief Medical Officer and Professor of Hematology/HCT at City of Hope Comprehensive Cancer Center. Of the 40 patients with advanced-stage disease, 80% had Stages III/IV. The median CD4 count was relatively low for this population—119, Dr. Kaplan said.
Patients received pegylated-liposomal doxorubicin at 40 mg/m2, rituximab at 375 mg/m2, cyclophosphamide at 750 mg/m2, vincristine at 1 mg/m2, and prednisone.
“Importantly, CNS prophylaxis was targeted to patients with advanced extranodal disease,” Dr. Kaplan said.
The preliminary results were disappointing, he said, citing a 47.5% complete response rate, although one-year overall survival was 81%.
The authors concluded that “the primary results of the DR-COP regimen do not indicate equivalent efficacy to EPOCH-based regimens in AIDS-related lymphoma.”
Dr. Kaplan concurred: “I don’t think we see anything here to suggest that the addition of liposomal anthracycline provided any efficacy benefit.”
He did note that there were only four CNS recurrences, all in patients not prophylaxed.
And only one patient died of infection due to progressive multifocal leukoencephalopathy, despite use of rituximab, which has been associated with that complication in past studies.
…and in Burkitt’s Lymphoma
The second Phase II multicenter trial Dr. Kaplan discussed tested the R-CODOX—M/IVAC regimen in HIV-negative and HIV-positive patients with untreated Burkitt’s lymphoma. The regimen used dose-dense high-dose rituximab (500 mg/m2), and pegylated-liposomal doxorubicin (40 mg/m2) in place of doxorubicin.
The first author was Stephanie A. Gregory, MD, Professor of Medicine and Director of the Section of Hematology and Stem Cell Transplantation at Rush University Medical Center in Chicago.
There were only three HIV sero-positive patients among the total of 12 discussed here, and two of those died of disease progression, “so this is not really an HIV study,” Dr. Kaplan said.
Low-risk patients received three CODOX-M cycles, while high-risk patients received four alternating cycles of CODOX-M and IVAC.
The authors reported an “excellent” complete response rate of 82%; two-year progression free survival was 73%, and overall survival was also 73%.
Dr. Gregory’s results compare favorably to prior studies, Dr. Kaplan said, “but it is impossible to determine the effect of either of the interventions because they were introduced simultaneously,” Dr. Kaplan said.
“The addition of rituximab is likely to be of benefit, and I doubt if there is anyone here who would leave it out of a regimen for Burkitt’s lymphoma patients,” but the rationale for higher-dose rituximab is unclear.
No Standard Regimen
Dr. Kaplan said that in previous Phase II DLBCL studies, R-EPOCH consistently outperformed R-CHOP regimens. R-CHOP did achieve a more favorable outcome vs EPOCH in one trial, he added, but that may have reflected a more favorable population of patients with CD4 counts higher than 200.
He said the substitution of pegylated doxorubicin in R-CHOP may overcome resistance, as does infusional EPOCH, and also may be easier to administer than the 96-hour EPOCH infusion.
While infusional regimens such as EPOCH might have greater efficacy, “some people consider use of liposomal doxorubicin in CHOP to be an easy way of administering EPOCH,” Dr. Kaplan said. “But clearly there is a lot more going on in EPOCH than just simple continuous infusion doxorubicin.
“We need more data for EPOCH, and we await the results of the randomized Phase III CALBG 50303 study comparing R-CHOP versus EPOCH-R in de novo DLBCL.”