NCCN Guidelines Reflect Recent FDA Approvals for Hematologic Malignancies

Published: Wednesday, Feb 13, 2019
 Meletios A. Dimopoulos, MD
Meletios A. Dimopoulos, MD
New options for patients with hematologic malignancies stemming from recent FDA approvals are making an impact on treatment strategies recommended in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology.

The guidelines, which take into consideration the clinical evidence that the FDA evaluated in approving novel agents and new indications for existing drugs, are commonly used as a baseline in helping oncology specialists decide on which treatments are best for their patients.1

Waldenström Macroglobulinemia

The FDA recently approved ibrutinib (Imbruvica) plus rituximab (Rituxan) for the treatment of Waldenström macroglobulinemia (WM), or lymphoplasmacytic lymphoma, a rare form of B-cell lymphoma that is characterized by bone marrow infiltration by lymphoplasmacytic cells.2 The approval expands the label of ibrutinib in WM from its currently approved use as monotherapy to include the first nonchemotherapy combination in this malignancy.

Due to the rarity of this disease, there have only been a small number of studies that evaluate patients with this malignancy, and treatment strategies are relatively limited. New data from the phase III iNNOVATE trial, which evaluated the combination in 150 patients with both previously untreated or relapsed/refractory disease, has expanded the treatment options available for these patients.3

Patients were randomized to receive either ibrutinib or placebo, with all patients receiving rituximab. The 30-month progression-free survival (PFS) was significantly higher for the patients in the ibrutinib arm than for those receiving the placebo (82% vs 28%, respectively). The median PFS had not been reached in the ibrutinib arm by the median follow-up of 26.5 months, which was an improvement over the median PFS of 20.3 months experienced by the placebo group (P <.001). In addition, patients receiving the ibrutinib combination had an 80% lower risk of disease progression or death (P <.001).3 These data indicate the efficacy and superiority of the combination therapy over that of rituximab monotherapy in treatment-naïve patients as well as those with recurring disease.

The lead author of the study, Meletios A. Dimopoulos, MD, chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine, remarked, “We believe now that we have a new standard of care for the treatment of this disease.”

Prior to the introduction of this new therapy, the NCCN guidelines had recommended rituximab-based therapies for the treatment of WM.4 Rituximab is a monoclonal antibody that targets the lymphocyte antigen CD20, which is a protein that is expressed on the surface of infiltrating lymphoplasmacytic cells.

Rituximab has been somewhat successful as a monotherapy, with response rates between 25% and 45%. Combination therapies have resulted in improved outcomes, however, and preferred combination therapies include rituximab with bortezomib (Velcade) plus dexamethasone, rituximab with cyclophosphamide plus dexamethasone, and rituximab with bendamustine.

Ibrutinib is a Bruton tyrosine kinase (BTK) inhibitor that has been effectively used as a single-agent therapeutic in this patient population.5 BTK is critical to the maturation of B cells and contributes to the proliferation of B-cell malignancies like WM. Previous NCCN guidelines considered single-agent ibrutinib to be in the category of “other recommended regimens” for primary treatment of WM and a “preferred regimen” for patients who received previous treatment for the disease.4 Two clinical trials in WM determined overall ibrutinib response rates between 70% and 100% in patients with mutations in MYD88 or CXCR4, 2 genes that are often mutated in the disease.6,7 Notably, patients in the iNNOVATE trial benefitted from ibrutinib/rituximab therapy regardless of MYD88 or CXCR4 mutational status.3

The ibrutinib/rituximab approval motivated updates to the NCCN guidelines for WM/lymphoplasmacytic lymphoma. These updates include the addition of ibrutinib plus rituximab as a category 2A therapy under “Other Recommended Regimens” for first-line therapy and in the “Preferred Regimens” category for patients who have received prior treatment.

The NCCN evidence blocks for this new recommended combination therapy indicate that although it is expensive, it is very effective, with a long-term survival advantage, mild or rare significant toxicities, and quality evidence supporting clinical use despite few trials.8 Evidence blocks are a visual representation of 5 key measures that provide important information about recommendations contained with the guidelines.9


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TitleExpiration DateCME Credits
Oncology Consultations®: The Advancing Role of CAR T-Cell Therapies in Hematologic MalignanciesApr 30, 20191.5
Advances in™ Diagnostic Guidelines for Effective Clinical Decision - Making in the Management of Hematologic MalignanciesApr 30, 20191.5
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