Double hit lymphoma (DHL) describes patients whose lymphoma tumors exhibit mutations on two significant genes, where most lymphoma patients have a mutation on only one. Currently found primarily in diffuse large B-cell lymphoma (DLBCL), DHL patients often respond poorly to the standard R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and thus face poor prognoses, including a median overall survival of 12 months or less. Though a relatively rare subtype, the poor outcomes for DHL patients has prompted the focus of researchers, including several studies recently published in Blood and during the 2014 ASH Annual Meeting.
Retrospective Analysis of DHL Patients Identifies Key Predictive Factors for Patient Prognosis
The results of a multi-center, comprehensive effort to analyze patients with double hit lymphoma suggests that a subset of DHL patients may be cured, and provides some important data on effective treatment plans. The study, published in the October 9, 2014 issue of Blood, was the result of a large scale collaboration which included several Lymphoma Research Foundation (LRF) grantees and Scientific Advisory Board (SAB) members.
Collaborators on this study examined retrospective patient data and tissue samples from 311 patients diagnosed with DHL at 23 North American academic medical centers between 2000 and 2012. The researchers created a novel prognostic index specifically for DHL patients, which classified patients as either low-, intermediate-, or high-risk, depending on a number of common factors known to cause poorer survival outcomes for DHL patients. They found that although 121 of the patients included in the study could be classified as high-risk, 41 percent of those patients achieved a two year overall survival rate, suggesting that it is possible for even this group to achieve a positive outcome. In the meantime, 90 percent of the 14 patients identified as low-risk achieved a survival rate of better than 8 years, indicating that the prognostic index created by the researchers may be a useful tool in better identifying DHL patients with favorable prognosis.
Additionally, those patients treated with DA-EPOCH-R (dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab), a more intensive induction regimen than the standard R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) demonstrated an improved likelihood of achieving a complete remission, and longer progression-free survival. The data also suggested that there was no difference in survival rates between patients who underwent a stem cell transplant during their first remission and those who did not undergo any treatment during that period. This data suggests that the key predictive factor of a positive outcome in DHL is whether a patient is able to achieve a complete remission with induction therapy of any type, and that further study of DA-EPOCH-R and other intensive inductions therapies versus R-CHOP in DHL patients is needed.
The large number of medical centers in the study necessitated contributions from a number of authors, including LRF Scientific Advisory Board (SAB) members Andrew M. Evens, DO of Tufts Cancer Center, Kristie Blum, MD, of Ohio State University, Christopher Flowers, MD of Winship Cancer Center at Emory University, Oliver Press, MD, of Fred Hutchinson Cancer Center, Andrew Zelenetz, MD of Memorial Sloan Kettering Cancer Center, and former SAB member Julie Vose, MD of University of Nebraska Medical Center. 2014 LRF Scholars Ryan Cassaday, MD of University of Washington, and Jonathon Cohen, MD of Winship Cancer Center, also contributed to the study.
The full text of the Blood publication may be accessed through the Blood website.
2014 ASH Annual Meeting Features DHL Education Program, Reviews of Treatment Strategies
The Annual Meeting of the American Society of Hematology (ASH), held in San Francisco in December 2014, featured several presentations on double hit lymphoma. Reflecting the growing awareness of DHL as a subtype with specific prognosis and treatment options, a special double hit lymphoma session was included in ASH’s education program. The session, which included a presentation from SAB Member Kieron Dunleavy, MD of the National Cancer Institute, reviewed the basic diagnostic, biologic, and clinical aspects of DHL, as well as current and possible future therapies.
In a similar approach to the October Blood study, a poster presentation at ASH examined the relative effectiveness of the most commonly used immunochemotherapy regimens. Researchers performed a retrospective analysis previously published studies featuring DHL patients who received dose intensive (DI) regimens (multiple small doses of chemotherapy in a short period of time), intermediate dose regimens (such as DA-R-EPOCH), or standard dose regimens (such as R-CHOP). 401 patients across 11 studies were identified, making this study the largest retrospective analysis of DHL outcomes to date. Researchers examined both the overall survival and progression free survival rates for all three regimens. The results of their analysis suggested that, though dose-escalated chemotherapy (both the DI and intermediate dose regimens) showed a significant improvement in progression free survival over R-CHOP — over 20 months average progression free survival for the two dose-escalated regimens vs. 13.9 months average for R-CHOP — the overall survival rate did not show a statistically significant difference.
The researchers, which included LRF SAB Member Andre Goy, MD of John Theurer Cancer Center and LRF Scholar Jonathon Cohen, MD, of Winship Cancer Center at Emory University, suggest that this study shows the need for additional research into strategies for DHL patients.
One of these possible new strategies was discussed in the Clinical Autologous Transplantation poster session, researchers at Oregon Health and Science University reported results of an analysis of 16 double and triple hit lymphoma patients treated with DA-EPOCH-R followed by consolidative autologous stem cell transplant, a treatment plan that is relatively recent in high risk diffuse large b-cell lymphoma. The researchers reported that 91 percent of the 16 patients reached the two year overall survival mark and remain in remission, with only one patient relapsing six months post-transplant. These results suggest autologous stem cell transplants following DA-EPOCH-R or other immunochemotherapy regimens are an effective treatment strategy for DHL, and warrant further study.