Updates on DLBCL from the International Conference on Malignant Lymphoma

LUGANO, Switzerland—The session on diffuse large B-cell lymphoma (DLBCL) at the 10th International Conference on Malignant Lymphoma included presentations on the value of PET scans in mid-treatment, the effects of intensifying the dose of rituximab in a dose-dense R-CHOP-14 regimen, and evidence that three major subtypes of DLBCL differ by genetic pathways. PET Useful in Limited DLBCL The role of radiotherapy in limited-stage DLBCL is still under debate, but a Canadian study has shown that patients with negative FDG-PET scans after three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) have an excellent outcome without radiotherapy. The study would appear to confirm the role of positron-emission tomography (PET) in the management of low-risk patients with DLBCL. Laurie H. Sehn, MD, Clinical Associate Professor at the University of British Columbia and a medical oncologist with the British Columbia Cancer Agency, Vancouver, said a standard treatment for limited-stage DLBCL combines three cycles of chemotherapy and involved-field radiation therapy, but that studies recently have shown that four cycles of CHOP alone can be sufficient for low-risk elderly patients. In British Columbia, she noted, researchers have been recommending since 2005 that all patients treated with limited-stage DLBCL (Stage I/II, no B-symptoms, and mass less than 10 cm and encompassable within a radiation field) undergo a PET scan following three cycles of R-CHOP. With that retrospective data, the team attempted to identify chemotherapy-sensitive patients who may be treated with chemotherapy alone, regardless of clinical factors. PET-negative patients were offered one additional cycle of R-CHOP, while those who were PET-positive went on to receive involved-field radiotherapy. The data presented here were on 65 patients—median age was 67; 58% were male; 58% had Stage I disease, 42% had Stage II; and 57% had at least one extranodal site.FigureWith a median follow-up of 17 months, 48 patients (74%) were PET-negative while 17 (26%) were PET-positive after three cycles of R-CHOP. No clinical factors were found to be predictive of PET status, Dr. Sehn said. Of the 48 PET-negative patients, 46 completed treatment with one additional cycle of chemotherapy alone (one received radiotherapy due to poor chemotherapy tolerance and one died of toxicity). Only one of the 48 PET-negative patients has relapsed (but is alive with lymphoma after salvage therapy). All 17 PET-positive patients received involved-field radiotherapy. Three have relapsed (all out of field), and two of those died from lymphoma. The two-year estimated progression-free survival rate is 97% for PET-negative and 83% for PET-positive patients; and the two-year overall survival rate is 97% for PET-negative and 76% for PET-positive patients. Dr. Sehn concluded that patients with limited-stage DLBCL who are PET-negative after three cycles of R-CHOP have an excellent outcome following four cycles of R-CHOP alone. “Mid-treatment PET scanning can be used to identify patients who can be spared the long-term toxicity of radiation,” Dr. Sehn said. Session co-moderator Bertrand Coiffier, MD, agreed with the findings. “Negative PET scanning is very predictive,” he said, adding that patients with localized, limited-stage disease who are PET-scan negative could probably avoid the complications of radiation therapy if they respond very well to R-CHOP. “PET-scan positive patients may have to go to more intensive therapy, but radiation in those cases might not be sufficient.” Dr. Coiffier, Chief of Hematology at Hospices Civils de Lyon and Professor at Université Claude Bernard in Pierre Benite, France, said that PET scanning is valuable in DLBCL, but in other lymphomas, such as peripheral lymphoma, it is yet to be appreciated. Dose-Dense Rituximab Intensifying the rituximab dose in R-CHOP in elderly patients with poor-prognosis DLBCL resulted in higher serum levels and in higher complete response (CR) and event-free survival rates, in a clinical trial from Germany. But high-risk patients, who benefited most from the dose-dense approach, also had a higher degree of toxicity. Michael Pfreundschuh, MD, Director of the Department of Internal Medicine of Saarland University Hospital in Homburg/Saar, speaking for the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL), said that while six to eight cycles of CHOP in combination with rituximab is widely accepted as the standard of care for aggressive lymphomas, the optimal dose and number of rituximab applications have not yet been determined. He said previous pharmacokinetic studies by the same group had shown that the biweekly concomitant application of CHOP and rituximab does not achieve a plateau of rituximab trough levels until the fifth cycle. In the study, which was supported by F. Hoffmann-La Roche Ltd., in order to achieve high rituximab levels early, the number of rituximab applications was increased: Elderly patients with aggressive CD20+ BCL received six cycles of biweekly CHOP-14 combined with 12 applications of rituximab at 375 mg/m2. Radiotherapy was planned to sites of initial bulk and/or extranodal involvement. The control group was 306 patients treated in the RICOVER-60 trial with six cycles of CHOP-14 and eight applications of rituximab. Dr. Pfreundschuh reported that among the 124 study patients evaluable for response, plateau trough serum levels were achieved by Day 1 of the first chemotherapy cycle and higher rituximab levels were maintained throughout the treatment compared with eight biweekly applications.Figure: Laurie H. Sehn, MD: “Mid-treatment PET scanning can be used to identify patients who can be spared the long-term toxicity of radiation.”“Despite a less favorable study population, dose-dense R-CHOP-14 patients achieved a somewhat higher CR rate than the control arm, 82 percent versus 78 percent, but event-free and overall survival were not different compared with eight biweekly applications of rituximab.” When analyzed by International Prognostic Index (IPI) group, dose-dense study patients with low-risk disease (IPI of 1-2) at 24 months had almost the same complete response rate as low-risk controls (83% vs 84%, respectively), and event-free survival (77% vs 78%, respectively). However, among poor-prognosis patients (IPI of 3-5) at 24 months the dose-dense regimen resulted in a better event-free survival rate (68% vs 58%). But toxicity was significant, with seven Grade 3/4 infections, seven cases of interstitial pneumonia, and three deaths among the first 20 patients. Because of the three therapy-associated deaths, subsequent patients received prophylaxis with levofloxacin, acyclovir, and cotrimoxazol, and infection rates decreased by approximately half, with no further deaths. In his comments after the session, Dr. Coiffier noted that dose-dense R-CHOP “had a lot of toxicity for the elderly patients, and the benefit for the patients is not completely sure. “There is no benefit for good-risk patients, only for high-risk patients, and it is there you will observe the toxicity,” he continued. “We need a longer follow-up and more data to conclude on that.” Distinguishing Molecular Pathways in DLBCL And researchers from the National Cancer Institute's Center for Cancer Research brought data showing that subtypes of gene expression in DLBCL arise by distinct oncogenetic pathways—findings, they said, that may be a significant step forward in individualized gene-specific treatment for lymphoma patients. The study showed that novel copy number abnormalities in DLBCL had significantly different frequencies in the three subtypes, said Georg Lenz, MD, a fellow in the Staudt Laboratory in the Metabolism Branch of the NCI's Division of Cancer Treatment and Diagnosis. The three subtypes studies were germinal-center B-cell-like DLBCL, activated B-cell-like DLBCL, and primary mediastinal BCL, said Dr. Lenz, speaking on behalf of the NCI's Lymphoma/Leukemia Molecular Profiling Project. An analysis of 203 DLBCL biopsy samples by high-resolution, genome-wide copy number analysis coupled with gene-expression profiling defined minimal common regions that were recurrently altered in copy number, and identified those that dysregulated the expression of their constituent genes. Dr. Lenz reported that: Amplification of the oncogenic mir-17-92 microRNA cluster and deletion of the tumor-suppressor PTEN were recurrent in germinal center B-cell-like DLBCL, but did not occur in activated B-cell-like DLBCL. Conversely, deletion of the INK4a/ ARF tumor-suppressor locus, gain of chromosome arm 18q, and trisomy 3 occurred almost exclusively in activated B-cell-like DLBCL and were associated with inferior outcome within this subtype (Bcl2 and NFATC1 are candidate oncogenes affected by the chromosome 18 aberrations). And an amplicon (DNA generated by polymerase or ligase chain reaction) found on chromosome 19 was detected in 20% of activated B-cell-like DLBCL but in only 3% of germinal center B-cell-like DLBCL and primary mediastinal B-cell lymphoma. The gene most upregulated by this amplicon was the transcription factor SPIB. The researchers found that knockdown of SPIB by RNA interference was toxic to activated B-cell-like DLBCL cell lines, but not to germinal center B-cell-like DLBCL, primary mediastinal BCL or myeloma cell lines. This strongly implicates SPIB as an oncogene involved in the pathogenesis of activated B-cell-like DLBCL, Dr. Lenz said.

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