FDA Approves Subcutaneous Administration of Rituximab for Three Lymphoma Types

On June 22, 2017, the United States Food and Drug Administration (FDA) approved subcutaneous injection of rituximab plus hyaluronidase human for people with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). Subcutaneous administration refers to the method of delivering a drug under the skin rather than directly into a vein as performed during intravenous (IV) administration.

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Administration of rituximab under the skin tends to take less than 10 minutes, whereas the traditional IV method can last several hours. The technique also allows for fixed dosing, which can reduce preparation time and excess drug waste, and may be more cost effective than IV infusion.

The approved treatment is to be employed only after patients have received at least one cycle of intravenous rituximab.

Approval comes based on the results of a series of clinical trials demonstrating comparable safety and efficacy outcomes across subcutaneous and intravenous administration.

Dr. Richard Furman Examines Future of CLL Risk Assessment

At OncLive’s State of the Science Summit on Hematologic Malignancies, Dr. Richard Furman, director of the Chronic Lymphocytic Leukemia (CLL) Research Center at Weill Cornell Medicine, discussed how medical oncologists should be using prognostic markers to make risk assessments in order to determine individualized treatments for their patients with CLL.

SOSS_Richard_FurmanDr. Furman noted that current CLL therapies are effective, but they often lead to complications. CLL patients treated with standard chemotherapy drug combination fludarabine, cyclophosphamide, rituximab (FCR) are often prone to developing treatment resistance or Richter’s transformations (RT), in which their CLL transforms into a more aggressive diffuse large B-cell lymphoma (DLBCL). They may also succumb to infectious complications, adverse events, or secondary malignancies.

Because of the risks associated with FCR treatment, Dr. Furman suggested a movement toward treatment agents that are not as toxic, such as ibrutinib. But even with ibrutinib, patients can develop resistance to treatment. For example, in cysteine481-to-serine mutations, the amino acid in Bruton’s tyrosine kinase (BTK) that ibrutinib binds to is changed from a cysteine to a serine, prohibiting ibrutinib from continuing to bind. This results in inadequate ibrutinib coverage and enables CLL cells to escape treatment and survive.

According to Dr. Furman, a large number of CLL patients will have excellent responses and enjoy very long progression free survivals. What is important is to identify those who will not and to devise a treatment strategy that can improve their outcomes. Currently, interphase FISH (demonstrating deletion 11q or 17p), NOTCH1 mutation, or certain V genes help identify those patients who will progress on currently novel agents or have a risk of Richter’s transformation. In the future, stimulated karyotyping, or evaluating changes in the chromosomes after stimulation of the CLL cells, will also be of great importance.

The CLL team at Weill Cornell Medicine and NewYork-Presbyterian is currently investigating an early intervention trial in which patients at risk of developing Richter’s transformation or resistance to BTK inhibitors receive intervention before the mutations have a chance to develop. Our team is also looking into the use of combination therapies, such as ibrutinib and venetoclax, in treatment of CLL patients.

Additionally, Dr. Furman pointed out that prognostic markers are dependent upon the setting in which they’re used. Those used for FCR, such as minimal residual disease (MRD), don’t necessarily apply to ibrutinib. He said that prognostic markers are traditionally based upon responses, but we now need to start looking at them from a progression-free survival (PFS) perspective.

To hear more from Dr. Furman about the outlook of CLL prognostic markers, check out this short OncLive clip:

FAT1 Mutations Influence Time to First Treatment in Untreated CLL

john-allan-mdBy John Allan, M.D.

Despite recent strides in mapping the mutational landscape of chronic lymphocytic leukemia (CLL) there is still limited information regarding the clinical impact of some less common gene mutations in the treatment of CLL. As next generation sequencing (NGS) has become more readily available physicians have more information about their patient’s genome, but this information is often lacking in context.

Using a commercially available NGS platform researchers from Weill Cornell Medicine identified a high prevalence of mutations in the FAT1 gene in people with CLL. FAT1 plays a role in regulating WNT signaling and tumor suppression and mutations have previously been associated with leukemia. Given the prevalence of FAT1 mutations in our CLL database and evidence suggesting FAT1 contributes to tumor growth, researchers investigated the clinical impact of FAT1 mutations.

Altogether 172 patients were included in the study. Nineteen (11%) patients were found to have a FAT1 mutation and 153 (89%) were lacking the mutation. In total 21 mutations were identified with 17 being unique. No significant differences were found between groups based on age or co-occurrence of high risk mutations, although 17p deletions occurred significantly more in mutated FAT1 patients (24%) compared to people lacking the mutation (7%). Mutated FAT1 patients had a significantly shorter TTFT at 50 months compared to 143 months for people lacking the mutation.

Researchers identified a higher prevalence of FAT1 mutations in untreated CLL patients than previously reported. FAT1 was found to associate with the 17p deletion, but no other high-risk mutations. We also found a vast difference in TTFT between mutated FAT1 and those lacking the mutation, although there was no difference in response rates when treated with novel agents.

These findings suggest that FAT1 mutations may be more common in patients, who have yet to receive treatment than commonly supposed. Results warrant additional research to investigate the influence of FAT1 mutations and association with the 17p deletion.