By Heather Lindsey
Rituximab is safe and improves survival in patients with HIV-associated non-Hodgkin lymphoma (HIV-NHL), according to a recent pooled analysis (Blood 2013;122:3251-3262). Additionally, intensive chemotherapy regimens and concurrent use of combination antiretroviral therapies (cART) with chemotherapy are effective treatment options in this patient population.
The study brings “clarity into what has mostly been accepted as standard of care, without having Level 1 evidence,” said Stefan Barta, MD, MS, the study's lead author and a medical oncologist specializing in hematological malignancies at Montefiore Einstein Center for Cancer Care and Assistant Professor in the Department of Medicine (Oncology) at Albert Einstein College of Medicine.
Asked for her opinion for this article, Ann S. LaCasce, MD, a medical oncologist in the Adult Lymphoma Program at Dana-Farber Cancer Institute and Director of the Dana-Farber/Partners CancerCare Hematology-Medical Oncology Fellowship Program, said, “It’s an important paper in that it evaluates a large number of patients for a relatively rare problem for which there are not large randomized trials. It’s nice to have the patient-level data collected.”
The study covers a lot of ground, said Stephen M. Ansell MD, PhD, a hematologist/oncologist in the Department of Hematology at the Mayo Clinic Rochester. One of the challenges in this area of research is that “many of the studies on which practice is based are quite small and contain conflicting data,” he said.
“This paper is a large, pooled analysis of multiple studies with patient-specific data and helps to clarify some of the questions around which there has been some uncertainty.”
The researchers (senior author was Joseph A. Sparano, MD) conducted a systemic review of the literature using PubMed and Embase and searched online conference abstracts for prospective Phase II or III studies of HIV-positive patients with newly diagnosed NHL conducted between January 1, 1990 and October 31, 2010.
The team identified 42 trials, 19 of which had patient-level data on 1,546 participants. Two trials were Phase III studies, while the remaining were Phase II. Three quarters of patients were enrolled in the cART era, 84 percent were men, 69 percent had diffuse large B-cell lymphoma (DLBCL), 69 percent had an intermediate-high to high-risk prognosis, and 86 percent had CD4 counts of 50 or more cells/µL.
Thirty-five percent of patients took rituximab; 41 percent received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); and 16 percent underwent less dose-intense regimens. Another 11 percent received infusional etoposide, prednisone, infusional vincristine, infusional doxorubicin, and cyclophosphamide (EPOCH); 12 percent received cyclophosphamide, doxorubicin, and etoposide (CDE); 10 percent received dose-intense doxorubicin, cyclophosphamide, vindesine, bleomycin; and prednisolone (ACVBP); and another 10 percent had the LNHIV91 regimen.
After adjusting for age, gender, CD4 count, and several other factors in a multivariate analysis, the results showed that rituximab was associated with an increased complete response rate (odds ratio [OR] 2.89), progression-free survival (hazard ratio [HR], 0.50), and overall survival (HR 0.51).
Additionally, rituximab was significantly associated with better outcomes only in those patients who had CD4 counts of 50 or more cells/µL.
In univariate and multivariate analysis, dose-reduced or modified CHOP and vincristine/steroids were associated with significantly poorer clinical outcomes.
In comparison with use of CHOP, dose-intense regimens -- namely ABCVP and other intensive combinations -- were associated with improved outcomes, but were not always statistically significant. Specifically, ACVBP was associated with a significantly better complete response (OR 1.70) and progression-free survival (HR 0.72), while intensive regimens were associated with significantly better progression-free survival (HR 0.35) and overall survival (HR 0.54).
In a univariate analysis, infusional CDE was associated with a reduced complete response rate, while a multivariate analysis indicated that this association wasn’t as strong and that the regimen improves overall survival (HR 0.49).
Infusional EPOCH had a significantly higher complete response rate (OR 1.73) and better progression-free survival (HR 0.57) and overall survival (HR 0.59,) in the univariate model, but not when adjusted for other variables such as rituximab.
When the researchers analyzed only patients with diffuse large B-cell lymphoma, EPOCH was found to be associated with significantly better overall survival compared with use of CHOP in a multivariate analysis (HR 0.33). In the subset of patients with either Burkitt’s lymphoma or Burkitt-like lymphoma, treatment with either ABCVP/LNHIV91 or intensive regimens showed improved progression-free survival compared with infusional CDE or EPOCH (HR 0.25).
With a univariate analysis, investigators also found that using cART with chemotherapy was associated with significantly higher complete response rates and overall survival. However, on multivariate analysis, this association was only significant for a complete response (OR 1.89) and trended toward better overall survival.
Data Confirm Rituximab Use
LaCasce said that the paper confirms much of what oncologists have already experienced -- for example, that rituximab is beneficial in HIV-positive patients with NHL, except in patients with CD4 counts of less than 50.
One key takeaway message, Barta said, is that physicians should use rituximab for CD4-positive B cell lymphomas. In patients with a CD4 count of less than 50, the drug does not appear to have the same benefit, he said, adding that whether it is harmful is still questionable.
Physicians have been concerned about increased toxicity and decreased immunity in patients taking chemotherapy and rituximab together, but the researchers found no increased risk of HIV-related complications, Ansell noted.
Overall, Barta said, the results showed that patients with HIV-NHL treated with aggressive regimens do very well.
Ansell noted that the paper addressed many questions about the best chemotherapy regimen to use in HIV-NHL patients, particularly whether physicians should use an intensive or moderate-intensity combination. A concern has been that ACVBP and more aggressive treatments are sometimes difficult to tolerate, but the study found that infusional EPOCH, which is more moderate, provides a better overall survival in large B cell lymphoma, which many NHL patients have, he explained.
The rationale behind EPOCH being superior is that infusional therapies expose aggressive cancer cells to chemotherapy for a longer and sustained period of time, making the treatment better at killing the malignancy, said Adil J. Akhtar, MD, a hematologist/oncologist and Chief of Clinical Operations for Beaumont Health System. AIDS lymphomas are especially aggressive and rapidly dividing, he said.
LaCasce said she hopes that the results of the national randomized NCT00118209 study comparing CHOP and rituximab with EPOCH and rituximab will provide more information in the next year or two on using these agents. “It’s a lot more onerous to give continuous infusion chemotherapy to patients,” she said. “Many patients require hospitalization for five days.”
Barta said that in addition to the pooled analysis, he and his colleagues have unpublished data indicating outcomes can be excellent in patients with Burkett lymphoma who can tolerate more intensive therapy-- specifically, multiagent dose-intense regimens and ACVBP-based regimens. In the past, CHOP has been a common treatment in this population but may be inadequate in immunocompetent patients, he noted.
The researchers also found that using cART while patients are receiving induction chemotherapy is also beneficial. “If patients have just found out that they are HIV-positive and have HIV lymphoma, they can safely start on antiretroviral therapy,” he said. “In our analysis, we were able to show that it is probably beneficial to take antiretroviral therapy during chemotherapy and that it certainly wasn’t harmful, which is a question many oncologists were not quite sure about.”
LaCasce noted that there has been some controversy about whether to use this approach should be used in HIV-positive NHL patients. NCI data supports withholding antiretroviral therapy to avoid drug-drug interactions and to maintain dose intensity, she said, citing a study published last month in the New England Journal of Medicine (2013:369:1915-1925).
The paper also adds to prior data from the AIDS Malignancy Consortium and others on continuing antiretroviral therapy in patients undergoing chemotherapy, she said, referring to JCO 2013;31:58-64 and NEJM 2006;355:2238-2296.
Akhtar added that concurrent use of cART and chemotherapy may result in better outcomes for patients because their HIV is under better control and they are in better physical shape.
In an editorial accompanying the Barta et al study (Blood. 2013;122:3244-3246), long-time HIV-associated malignancies researcher Alexandra M. Levine, MD, Chief Medical Officer at City of Hope National Medical Center, noted that having a “fully clean” data set from which to derive final treatment recommendations, based on level 1 evidence,” is unlikely: “HIV-infected patients, as well as the oncologists who treat them, tend to feel very strongly about use of concurrent chemotherapy with cART and/or use of rituximab,” she wrote. “These inherent beliefs have confounded the ability to enroll patients on prospective, randomized trials.”
Barta noted that the analysis should “encourage researchers to enroll patients with HIV lymphomas in clinical trials that are geared toward immunocompetent patients -- In most trials, being HIV positive is an exclusion criteria.” Patients with adequately controlled HIV can tolerate intensive therapies and should not be excluded from lymphoma trials, he said.
Further research, he added, should also evaluate HIV-related lymphoma and the role of oncogenic viruses, which appear to result in more aggressive features in these patients. And Ansell said, studies investigating novel agents that can be incorporated into frontline treatment to improve outcomes are also needed because a sizable population of patients with HIV-NHL will relapse.
Finally, noted Akhtar, the ongoing Phase III clinical trial (NCT00118209) comparing R-CHOP and R-EPOCH in lymphomas will be able to confirm the current study's findings on these regimens.