Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with high rates of relapse and survival rates that rarely extend beyond two years. However, researchers from the Weill Cornell Lymphoma Program have recently published a study in Cancer Discovery, with the potential to change the standard of care for patients with DLBCL. This study focused on the use of azacitidine (Vidaza), a targeting therapy designed to reawaken the molecular mechanisms that typically trigger cell death but are switched off as lymphoma progresses. Researchers found a resurgence in the death signal on the resumption of chemotherapy for those DLBCL patients treated with azacitidine in advance of chemotherapy.
As the study’s senior investigator Dr. Leandro Cerchietti, the Raymond and Beverly Sackler Research Scholar and assistant professor of medicine at Weill Cornell Medical College noted, “To have any hope for helping patients with aggressive lymphoma, we need to make this resistant cancer sensitive to treatment. We found we could do this by reprogramming the cancer to a more benign disease, which can then respond to chemotherapy…By pre-treating patients with a low-dose of azacitidine — a targeted drug approved for use in myelodysplastic syndrome — we achieved a profound and stable degree of reprogramming and chemosensitization that was very surprising to us.”
In the proof of concept, phase 3 study led by Dr. Peter Martin, patients received low doses of azacitidine five days in advance of standard chemotherapy. 11 patients achieved a complete remission of cancer, while 10 remained cancer-free for up to 28 months.
Study collaborator, Dr. Ari Melnick commented, ”In this remarkable study, Dr. Cerchietti discovered an important new disease mechanism that causes chemotherapy resistance in aggressive lymphomas, developed a new treatment regimen and completed the first clinical trial, demonstrating that his findings are true and directly relevant to those patients with the most severe forms of this tumor.”
The implications for this study are far ranging. Dr. Cerchietti explained, ”Oncologists have long believed that using high doses of an anti-cancer drug is the best strategy. Our study shows that is not the case in this kind of lymphoma, and suggests this new approach can potentially be translated to other tumor types.”
Researchers plan on expanding the study to additional DLBCL patients in a multi-center clinical trial, while studying pre-treatment strategy options in other tumor types and lymphomas.
Please look to this space for further updates. A full listings of available clinical trials can be found here.
Following up on an earlier breakthrough confirming the feasibility of shutting down the Bc16 protein — an important master regulatory transcription factor that is the key to survival for diffuse large-B cell lymphoma and other aggressive B-cell lymphomas– Weill Cornell’s Dr. Ari Melnick and other researchers recently completed a study where five doses of the experimental drug eradicated human lymphoma in mice.
Published online in the journal Cell Reports, the researchers described specifically how Bc16 promotes the survival of DLBCL, before detailing how the Weill Cornell developed Bc16 inhibitor effectively gums up the protein. Initially developed by Dr. Melnick nine years ago, the interim period has seen him working to improve the design for use by DLBCL and other lymphoma patients, collaborating with other world class researchers to understand how both Bc16 and its inhibitor functions.
The researchers found that Bc16 has two independent functions required for the survival of DLBCL. Dr. Melnick described how the first function, “builds a huge shopping mall-style complex”. This complex rests on top of a stretch of the genome. Through this binding Bcl6 deactivates the DNA, prohibiting genes from producing RNA and proteins. As Dr. Melnick noted, “Bcl6 acts like a barcode reader. When it sees that barcode — the DNA sequence — it attaches there”.
He went on, “Normally, the protein complex goes away after an immune reaction has been successfully mounted against the pathogen. But when it doesn’t, and remains stuck to the genes, DLBCL can result. That’s because Bcl6 is inhibiting genes that stop cells from dividing and that sense damage to the genome. We now know the genes that Bcl6 is repressing and how that helps lymphoma develop and survive.”
According to Dr. Melnick the second function, “acts like a switch on railroad track that routes a train in one direction or another. One track is needed when antibodies are required for an immune response, while the other keeps B cells in a constant state of division.”
Importantly the researchers were surprised to find that both the complex and the train switch attach to the Bcl6 protein at the same site. “They fit into the same keyholes on Bcl6,” Dr. Melnick said. “There are two identical binding sites on the protein surface.”
As Dr. Melnick exclaimed, “This is wonderfully serendipitous — our drug just happens to be able to overcome both of the biological mechanisms that are key to survival of aggressive lymphoma,” before adding that the inhibitor completely eradicated DLBCL in mice in a short time, with no detectable side effects.
The team is conducting additional research toward an investigational new drug application from the federal Food and Drug Admission.
ASCO 2013: Effectiveness of Entecavir and Lamivudine in Preventing Reactivation of Hepatitis B in HBsAg-Positive Patients with Untreated DLBCLPosted: June 17, 2013
Patients with DLBCL and a history of hepatitis B are at increased risk from the reactivation of a viral infection following treatment with R-CHOP. Many guidelines recommend that patients at risk of hepatitis B reactivation receive anti-viral prophylaxis while receiving R-CHOP, but do not specify which drug should be used. At the recent annual meeting of the American Society of Clinical Oncology in Chicago, Dr. He Huang from Sun Yatsen University Cancer Center presented the results of a trial comparing two of the most commonly used drugs: entecavir and lamivudine.
Study subjects included patients receiving R-CHOP for previously untreated DLBCL and evidence of active infection (HBsAg-positive). Of the 121 HBsAg-positive patients, 61 were randomly assigned to entecavir and 60 to lamivudine. The primary endpoint was the incidence of HBV-related hepatitis; the secondary endpoint was chemotherapy disruption due to hepatitis.
The entecavir group had significantly lower rates of hepatitis, hepatitis B reactivation, and disruption of chemotherapy. The study concluded that for HBsAg-positive DLBCL patients receiving R-CHOP, entecavir was more effective in preventing hepatitis B reactivation, and should be considered the standard for primary preventive therapy in advanced stages of the disease.
ASCO 2013: Impact of Interval Between Diagnoses and Initiation of Curative Chemotherapy on Survival of Patients with Diffuse Large B-cell LymphomaPosted: June 12, 2013
A common question arising among patients with newly diagnosed DLBCL is how soon to begin treatment. While it is generally considered more appropriate to start chemotherapy sooner rather than later after diagnosis, the exact impact of this time interval on treatment outcomes is unknown. At the recent Annual Meeting of the American Society of Clinical Oncology in Chicago, Dr. Kevin A. Hay from the University of British Columbia presented the results of a retrospective study evaluating the association of patient outcomes with time to initiation of treatment.
Dr. Hay retrospectively divided 793 patients with DLBCL and at least one cycle of R-CHOP into four groups based on the amount of time between initial diagnosis and beginning of therapy. A total of 25% of respondents received R-CHOP within 2 weeks of diagnosis, 31% in 2-4 weeks, 37% in 5-8 weeks, and 7% at longer than 8 weeks. Interestingly, there was no statistically significant difference in survival between the groups. The authors concluded that the timing of chemotherapy initiation appeared to be related to clinical factors (i.e., sicker patients were treated sooner) rather than medical system or socioeconomic barriers. While detrimental outcomes were lacking in those patients who began treatment after 8 weeks, they recommended beginning chemotherapy as soon as possible after an initial diagnosis of DLBCL.
ASCO 2013: Post-therapy Surveillance Imaging has Limited Use in Detection of Relapse of Non-Hodgkin LymphomaPosted: June 10, 2013
Despite the frequent use of routine post-therapy imaging as a means of early detection of lymphoma relapse, there is limited evidence that regular scanning improves patient outcomes. Two groups reported on their experience with surveillance imaging at the recent annual meeting of the American Society of Clinical Oncology in Chicago.
Dr. Quoc Van Truong of the West Virginia School of Medicine retrospectively evaluated 77 patients with non-Hodgkin lymphoma that had relapsed after achieving a complete response with initial treatment. Despite the frequent use of routine imaging, nearly 80% of relapses were detected by patient-reported symptoms and not surveillance imaging. Overall, there was no survival difference between the groups of patients whose relapse had been detected by scans versus those reporting additional symptoms. Additionally, surveillance imaging led to 2 false positive scans resulting in unnecessary invasive procedures.
Dr. Carrie A. Thomas of the Mayo Clinic reported on an analysis of 644 patients with DLBCL seen at the Mayo Clinic or University of Iowa between 2002 and 2009. A total of 537 patients entered post-treatment observation, and 109 of these patients relapsed while 41 died from other causes. At the time of relapse, 68% were symptomatic, 42% had an abnormal physical exam, 55% elevated LDH, and 87% had more than one of these features. Of the 38 patients whose relapse was detected during a planned visit, 26 displayed clinical features of relapse, while the relapse of the other 12 patients was detected by planned surveillance scan. Of these 12 relapses exclusively detected by the planned surveillance scan; 4 presented a low-grade or other subtype and 8 had DLBCL (4 of whom had equivocal/positive scans at the end of treatment). The authors concluded that post-therapy surveillance scans have little value in detecting DLBCL relapse.
These studies add to the growing body of literature suggesting that lymphoma patients that achieve a complete remission from first-line therapy may not benefit from routine imaging. We recommend that patients discuss plans for post-treatment surveillance with their physician.
Dose-Adjusted EPOCH-Rituximab Shows Encouraging Results for Patients with Primary Mediastinal B-Cell LymphomaPosted: April 18, 2013
Initially recognized in the 1980s, primary mediastinal B-cell lymphoma (PMBCL) is a subtype of diffuse large B-cell lymphoma (DLBCL) arising in the thymus. Representing less than 3% of non-Hodgkin lymphoma cases, PMBCL has a skewed age distribution affecting young adults, especially young women. Historically, patients with PMBCL have been treated with mediastinal radiation following chemotherapy based on evidence that chemotherapy alone was insufficient. Despite the high cure rates with this strategy, mediastinal radiation in young patients can be associated with late adverse effects, including premature cardiovascular disease and secondary cancers.
Researchers from the National Cancer Institute (NCI) and their partner institutions recently completed a phase II study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) with no mediastinal radiation complement. In 51 patients with a median age of 30 years, of which 59% were women, the overall survival rate was 97% at the median 5-year follow-up. From these results, researchers suggested that DA-EPOCH-R therapy obviated the need for radiotherapy in patients with PMBCL.
While these results from this phase II study are encouraging, they will need to be confirmed with further research.
Weill Cornell Breakthrough Research: Shutting Down DLBCL Master Protein; Potential for New TreatmentsPosted: March 4, 2013
Reporting in Nature Immunology, Weill Cornell’s Dr. Ari Melnick and his research team have reported an important research breakthrough in diffuse large-B cell lymphoma (DLBCL) that may offer hope for new treatments for aggressive lymphomas.
Dr. Melnick has found that it is possible to shut down the protein Bc16, a powerful master regulatory transcription factor that is the key to survival for many aggressive lymphomas arising from the B-cells.
“The finding comes as a very welcome surprise,” says the study’s lead investigator, Dr. Ari Melnick, Gebroe Family Professor of Hematology/Oncology and director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell.
The protein Bc16 was previously considered too complex to target with individual drugs, because of its centrality in the functioning of the body’s healthy immune cells.
“This means the drugs we have developed against Bcl6 are more likely to be significantly less toxic and safer for patients with this cancer than we realized,” says Dr. Melnick.
DLBCL is the most common subtype of non-Hodgkin lymphoma — the seventh most frequently diagnosed cancer, with many patients resistant to currently available treatments. Presently, there are ongoing clinical trials for those suffering from non-Hodgkin’s lymphoma and other forms of lymphoma at the Weill Cornell Lymphoma Center.
The full press release can be read here.
At the 16th Annual International Congress on Hematologic Malignancies, Dr. John Leonard, the director of the Lymphoma Program at Weill Cornell Medical College, discussed several novel therapies currently under investigation for DLBCL. Today OncLive published an article, “Beyond R-CHOP-21: What’s New in Diffuse Large B-Cell Lymphoma” summarizing Dr. Leonard’s discussion.
“The current standard for patients with advanced diffuse large B-cell lymphoma (DLBCL) is R-CHOP-21 (21-day rituximab-cyclophosphamidedoxorubicin- vincristine-prednisone). However, while this regimen cures approximately two-thirds of patients, a significant fraction of patients will still relapse, and the prognosis for these patients is poor.”
Approaches being evaluated include substituting an alternate chemotherapy regimen for CHOP in combination with rituximab; R-EPOCH (rituximabetoposide- prednisone-vincristine-doxorubicin-cyclophosphamide); and adding a new agent to R-CHOP-21.
Click here to read the full article in in OncLive.
Dr. John Leonard, Director of the Weill Cornell Lymphoma Program, was on the panel of experts participating in Cancer Care’s Connect Education Workshop, “Update on Diffuse Large B-Cell Lymphoma” on October 5.
Click the player below to listen to the workshop, or click here to download the discussion on the Cancer Care website.
Weill Cornell’s Dr. John Leonard will be on the panel of experts participating in Cancer Care’s telephone workshop “Update on Diffuse Large B-Cell Lymphoma” on Wednesday, October 5 from 1:30 to 2:30 pm, Eastern Time.
The workshop is free of charge. No phone charges apply. However, pre-registration is required to secure a place on the call. Click here for more information and to register for the workshop.