Andrew D. Zelenetz, MD, professor of medicine at Cornell University Weill Medical College, vice chair of medical informatics at Memorial Sloan Kettering Cancer Center and chair of the NCCN Non-Hodgkin’s Lymphoma (NHL) Expert Panel, said the choice of treatment for patients with diffuse large B-cell lymphoma (DLBCL) has rapidly moved beyond R-CHOP.
According to Zelenetz, MD, PhD, treatment options for all patients with diffuse large B-cell lymphoma (DLBCL) have rapidly moved beyond R-CHOP. the need to select which specific signaling pathway to target is based on the primary cancer cells and mutational status. The NCCN DLBCL guidelines update the diagnostic and imaging immunohistochemistry (IHC) protocol to include MYC expression, which is essential for the diagnosis of DLBCL. In addition, the guidelines emphasize the need for fluorescence in situ hybridization (FISH) to detect MYC rearrangements in order to select specific patients, and Dr. Zelenetz noted that these alterations are not only relevant to pathologists, but have important clinical implications. New data have emerged over the past few years suggesting that diffuse large B-cell lymphoma with MYC combined with BCL2 rearrangements (referred to as secondary mutation lymphoma, which occurs in approximately 6% of the DLBCL patient population) is associated with a particularly poor prognosis. Additional new data suggest that MYC-synchronous BCL2 protein expression as indicated by IHC (in approximately 30% of DLBCL patients) is a strong predictor of poor prognosis in DLBCL patients treated with R-CHOP (rituximab in combination with cyclophosphamide, adriamycin, vincristine, and prednisone). zelenetz, MD, emphasizes that there is no evidence-based standard of care for the above patients and that to conduct prospective trials. In the early course of the disease, MYC expression inhibitors may play an important role in the treatment of secondary mutant lymphomas. Dr. zelenetz said that for imaging, emerging data suggest that we should revisit the role of imaging in DLBCL. For follow-up imaging in patients with early-stage disease who develop a complete response after completing induction chemotherapy, the updated guidelines state that repeat CT scans should not be used routinely and should only be used when a clinical indication is present. These changes in the guidelines reflect that the use of surveillance imaging should be limited, especially for patients with limited disease. Current and future treatment options after the updated 2014 NCCN
NHL guidelines state that the best first-line treatment options for primary mediastinal B-cell lymphoma (PMBL) are more controversial than for other subtypes of NHL. However, the new edition of the guidelines lists three different options for PMBL. These include R-CHOP regimen sequential radiotherapy (RT)
and DA-EPOCH-R (dose-adjusted pedialyte glycosides, adriamycin, cyclophosphamide, vincristine, prednisone and rituximab), a level 2A recommendation; R-CHOP
sequential ICE (isocyclophosphamide, carboplatin, pedialyte glycosides) with or without RT, level 2B recommendation, however Dr. zelenetz acknowledged that there were no data suggesting a benefit from RT. In the phase II study that included 67 patients with PMBL, after a median duration of follow-up of 5 years, DAEPOCH-R treatment yielded an event-free survival rate of 93% and an overall survival rate of 97%. Dr. zelenetz acknowledges that these results offer hope, but because the study included only 67 subjects, more data support is needed before recommending DAEPOCH-R as the standard of care for PMBL. Based on the benefits in terms of progression-free survival and overall survival outcomes reported by Peyrade et al, for patients with poor left ventricular function, the updated guidelines recommend a reduced-dose immunotherapy regimen, R-mini-CHOP
（According to Dr. Zelenetz, the curve trends well in the group of patients as young as 80 years old, and morphologic heterogeneity means that DLBCL is more difficult to treat. Immunohistochemical models integrating factors such as CD10, BCL6 and IRF4/MUM1 can be used to differentiate between GCB and non-GCB subtypes. Dr. zelenetz acknowledged that even in the rituximab era, we have not been able to overcome the heterogeneity of tumors. In addition, the molecular pathways of GCB and non-GCB DLBCL subtypes are completely different. As an example, the
EZH2 mutations are only seen in the GCB subtype, and 22% of DLBCL patients have these mutations. Small molecule EZH2 inhibitors, currently in clinical trials, can prevent cell proliferation and activation of EZH2 mutated cells. Primary cells may play an integral role in guiding the choice of future treatment options for DLBCL. zelenetz, MD, focused on new data in the areas of lenalidomide for non-GCB subtypes and ibrutinib (a Bruton tyrosine kinase inhibitor) for the ABC subtype of relapsed/refractory diffuse large B-cell lymphoma. In a retrospective analysis of 44 cases of relapsed refractory DLBCL, a significant difference in clinical response to lenalidomide was found between non-GCB and GCB subtypes. In fact, the overall remission rate for the GCB subtype was a pitiful 9%, while the non-GCB subtype was higher than 50%. Several studies are evaluating the efficacy of lenalidomide plus RCHOP regimens. A phase 2 study that included 70 patients evaluated the efficacy of ibrutinib in relapsed/refractory DLBCL. Researchers confirmed that ibrutinib produced clinically meaningful remission rates in patients with the ABC subtype, but not in other molecular subtypes
(41% vs. 23%). An ongoing study compares the efficacy of R-CHOP with or without ibrutinib specifically in patients with non-GCB DLBCL. Dr. zelenetz concluded that lenalidomide and ibrutinib appear to overcome the adverse effects of non-GCB DLBCL, although intensive conventional chemotherapy could achieve the same results at a lower cost. However, the results were not mature enough to be included in the NCCN guidelines. new guidelines for primary cutaneous CD30-positive T-cell lymphoproliferative lesions in general, cutaneous lymphoma is a complex slow-growing T-cell disease with relatively inert B-cell disease and precancerous lesions. Primary cutaneous CD30
New guidelines for primary cutaneous CD30-positive T-cell lymphoid proliferative disorders
CD30-positive lymph node cutaneous infiltrative lesions can be classified as benign, progressive, or malignant. clinicopathologic correlation is essential, according to Dr. zelenetz. expression of CD30 is not a predictor of good or poor prognosis. It is necessary to distinguish between primary cutaneous CD30-positive mesenchymal large cell lymphoma and LYP because they share a similar immunophenotype.
LyP is at one end of the expression spectrum, primary cutaneous CD30-positive mesenchymal large cell lymphoma is at the other end, and many phenotypes lie between them.LyP
The clinical and pathologic features of LyP include 100% spontaneous regression with papular lesions less than 1 cm, whereas the features of cutaneous CD30-positive mesenchymal large cell lymphoma include infrequent spontaneous relapses, larger or deeper lesions, and multiple lesions that may occur singly or in groups or clusters. patients with LyP and primary cutaneous ALCL have an excellent prognosis, with 10-year disease-specific survival rates of 100% and 96%, respectively. The prognosis for patients with LyP and primary cutaneous ALCL is very good, with 10-year disease-specific survival rates of 100% and 96% respectively. The exception is primary cutaneous ALCL with extensive extremity involvement. This is a more aggressive subtype that usually presents with local RT and systemic treatment refractoriness and a poor prognosis. The first step in the treatment of primary cutaneous CD30-positive T-cell lymphoproliferative disorders is to differentiate between primary and CD30
+The treatment of patients with LyP depends on the presence or absence of symptoms. An observation strategy is preferred in patients with asymptomatic limited lesions. zelenetz, MD, emphasizes the importance of not overtreating these tumors. Spontaneous remission is very common, and in our experience
LyP mortality rate is zero. For those patients with extensive lesions who develop symptoms, methotrexate, phototherapy, systemic retinoids, and topical steroids are listed as treatment options. Topical steroids are effective but not efficacious, and the use of bexarotene is limited. zelenetz, MD, noted that for primary cutaneous ALCL, it is important to distinguish it from the cutaneous appearance of systemic ALCL. Primary cutaneous mesenchymal large cell lymphoma is characterized by a skin-only presentation with or without regional lymph node involvement, an inert disease process, and frequent recurrence of cutaneous lesions but little progression to extracutaneous loci. Treatment depends on the patient’s presentation. surgical excision with or without RT is indicated in patients with substantial lesions, while methotrexate is the treatment of choice for multifocal lesions. rT, systemic retinoic acid, pralatrexate, and an observation strategy (if asymptomatic) are also listed as options. t-cell large granular lymphocytic leukemia according to Dr. zelenetz, T-cell large granular lymphocytic leukemia ( TLGLL)
is another rare and typically inert disease usually seen in 2% and 5% of patients with chronic leukemia. It is often associated with autoimmune diseases, particularly rheumatoid arthritis, and may also be associated with B-cell malignancies. the NCCN guidelines show that
TLGLL diagnosis requires cytologic analysis of peripheral blood smears, flow cytometry detection of peripheral blood, bone marrow aspiration and biopsy, and adequate immunophenotypic analysis results. a trained medical pathologist and flow cytometer specialist needs to properly interpret the above results, and is important for the treatment of rheumatic diseases, Dr. zelenetz noted. As with other inert lymphomas, the
TLGLL should also be treated at the time of indication. Indications include severe neutropenia (absolute neutrophil count <0.5 x 109/L), moderate neutropenia with recurrent infections, symptomatic or transfusion-dependent anemia, and
TLGLL-induced autoimmune disease, B symptoms, etc. In the absence of a treatment indication, a watchful waiting strategy is reasonable. zelenetz, MD, noted that early intervention does not alter the natural history of the disease. For patients requiring treatment, first-line regimen options include methotrexate, cyclophosphamide, and cyclosporine A, with or without steroids. While all of these options have reasonable effects, and some of them also elicit lasting effects, they are largely based on retrospective, single-institution experience and involve a limited number of patients. Studies of alemtuzumab in patients with refractory disease have shown an overall remission rate of almost 60%, with remission durations ranging from 6 to 24 months. Finally, Dr. zelenetz said that a response may not be seen for several weeks, but treatment should be continued as long as it is tolerated without any side effects.