June 2014, Vol 3, No 4

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Updated NCCN Guidelines for Non-Hodgkin Lymphoma Note Controversy Related to B-Cell Disease Management: Cell of Origin May Soon Influence Treatment Decisions


The updated guidelines from the National Comprehensive Cancer Network (NCCN) for the management of non-Hodgkin lymphoma (NHL) include new strategies in the management of diffuse large B-cell lymphoma (DLBCL) and new guidelines for T-cell lymphoproliferative disorders.

The updates were presented by Andrew D. Zelenetz, MD, PhD, vice chair, medical informatics, department of medicine, Memorial Sloan Kettering Cancer Center, New York, at the 2014 NCCN Conference.

The guidance for primary mediastinal B-cell lymphoma (PMBL) states that optimal first-line therapy is more controversial than for other subtypes of NHL and includes the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, plus rituximab) regimen; and R-CHOP followed by the ICE
(ifosfamide, carboplatin, and etoposide) regimen.

The coexpression of the MYC protein and the BCL2 protein predicts poor outcomes for a group of patients with DLBCL. This “double hit” by immunohistochemistry represents approximately 30% of patients. There is no evidence-based standard of care for patients with this MYC/BCL2 coexpression lymphoma, who “really need to go on prospective clinical trials,” said Zelenetz.

Dose-adjusted EPOCH-R, although effective at improving survival in patients with MYC-positive DLBCL, needs to be validated as a treatment for this subgroup of patients with DLBCL.

The new guidelines for induction therapy for stage I or stage II nonbulky DLBCL no longer distinguish between risk factors that are present and those that are not present, because there is no evidence to support a differential management of patients with favorable or unfavorable risk factors, Zelenetz said, even though patients with such risk factors have worse outcomes.

PMBL: 3 Treatment Options Produce Excellent Outcomes
Currently, 3 treatment options are included in the guidelines for the management of patients with PMBL:

  • R-CHOP followed by radiation therapy
  • Dose-adjusted EPOCH-R with optional radiation
  • R-CHOP for 4 cycles, followed by ICE, with optional radiation

In a 2013 study by Dunleavy and colleagues, dose-adjusted EPOCH-R without radiation therapy was associated with an event-free survival of 100% over a median of 3 years of follow-up in 16 patients involved in a retrospective analysis. The 51 patients in the prospective cohort had an event-free survival of 93% over 5 years. Of note, dose-adjusted EPOCH-R had no significant impact on cardiac function. “I would argue that with a total of 67 patients, we need more data before we call this the standard of care,” said Zelenetz.

“Given the demographics of this disease with high incidence in young women, avoidance of radiation is preferred,” he said. Hence, avoiding radiation is an option.

“R-mini-CHOP” an Option in Older Patients
In patients aged >80 years with comorbidities, “R-mini-CHOP” has been added as a treatment option for patients with DLBCL.

This regimen consists of dose-attenuated rituximab (375 mg/m2), a reduced dose of cyclophosphamide (400 mg/m2), halving of the usual doxorubicin dose (25 mg/m2), and a 1-mg flat dose of vincristine, as was established in a prospective study by Ballester and colleagues in their evaluation of 150 patients aged >80 years with DLBCL.

Therapy Based on Cell of Origin
In the not-too-distant future, the cell of origin may influence the treatment choice. In this respect, the more promising results have been achieved with non–germinal center B-cell lymphoma (non-GCB), Zelenetz noted, discussing several specific examples in this setting.

  • Lenalidomide plus R-CHOP ameliorates the negative effect of the non-GCB phenotype and is well tolerated, including in elderly patients
  • Ibrutinib has shown clinically meaningful response rates in relapsed or refractory non-GCB, which is consistent with an essential role of B-cell receptor signaling in this subtype of disease
  • Bortezomib added to R-CHOP has also had success in early studies in the treatment of non-GCB DLBCL and is now under investigation in 3 large-scale randomized trials for this purpose
  • The sequence of R-CHOP and ICE may be a more cost-effective way to achieve these same results in non-GCB tumors, Zelenetz said.

What’s New in T-Cell Lymphoma?
Two new guidelines in T-cell lymphoma have been constructed for primary cutaneous CD30+ lympho­proliferative disorders and large granular lymphocytic leukemia.

For the lymphomatoid papulosis subtype of primary cutaneous CD30+ lymphoproliferative disorders, the primary treatment depends on the extent of the disease. Observation is preferred for asymptomatic patients with limited lesions, with the option to use topical steroids or phototherapy. For patients with extensive lesions or who have symptoms, weekly methotrexate, phototherapy, systemic retinoids, topical steroids, and topical nitrogen mustard are options.

For patients with primary cutaneous anaplastic large-cell lymphoma (ALCL), surgical excision with or without radiation therapy is considered primary therapy for patients with solitary or grouped ALCL lesions. Weekly methotrexate, radiation therapy, systemic retinoids, observation (if asymptomatic), or interferon alpha-2b are options for primary therapy for patients with multifocal ALCL lesions.

For patients with T-cell large granular lymphocytic leukemia, the most common indications are cytopenias. If patients with indolent disease are asymptomatic, the recommended management strategy is obser­vation. The preference for symptomatic patients is enrollment into a clinical trial, “but many things work,” said Zelenetz.

Immunosuppressive therapy with methotrexate or cyclophosphamide, or cyclosporine A without steroids, all have reasonable activity. Persistence is crucial when using cyclosporine A, Zelenetz said, because responses may not be observed for several weeks.

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