Raising the Bar: 4 Drugs for CLL

Several new drugs for the treatment of chronic lymphocytic leukemia (CLL) are considered major advances: 2 have been approved and 2 are under review by the US Food and Drug Administration (FDA). At the recent Chemotherapy Foundation Symposium, experts discussed ibrutinib, idelalisib, ofatumumab, and obinutuzumab.^1,2

“Ibrutinib and idelalisib are 2 potent BCR [B-cell receptor] pathway inhibitors that are highly effective in both untreated and treated CLL,” stated Morton Coleman, MD, Weill Cornell Medical Center, New York City.

Idelalisib is a phosphatidylinositol 3-kinase (PI3K) inhibitor that achieves dramatic nodal responses in patients with CLL; but along with nodal shrinkage, white blood cell counts rise when treatment is first initiated.

In one study, the nodal response rate was 81%, while the overall response rate (ORR) was 72% due to lymphocytosis. Median progression-free survival (PFS) was 17 months, and overall survival is not yet reached in heavily treated poor-prognosis patients with CLL.

Idelalisib has been studied in combination with rituximab as well as with bendamustine. Both combinations achieved about a 90% response in the lymph nodes, with a concomitant rise in lymphocyte count, although less so than when idelalisib is used as a single agent.

A study of idelalisib plus rituximab as frontline therapy in 64 patients with CLL achieved an ORR of 97%. Partial response rate was 67% in patients with p53 abnormalities. The major adverse effect was grade 3 diarrhea in 15 patients (23%).³

A pivotal study of idelalisib is now ongoing in the United States and the drug is under review by the FDA.

The same response pattern—a robust lymph node response with increased lymphocytosis—is seen with the Bruton’s tyrosine kinase inhibitor ibrutinib. This drug is also under review by the FDA.

A phase 1b/2 study included 116 patients with CLL/small lymphocytic leukemia treated with ibrutinib monotherapy; some were relapsed/refractory and some were treatment naive. The best ORR was 84% in treatment-naive patients and 88% in relapsed/refractory patients. At 26 months, 96% of treatment-naive patients are still part of the study and PFS was 75% for the relapsed/refractory patients. These outcomes were observed in patients with poor-prognosis cytogenetics, including deletions in 17p and 11q.^1,4

“These are amazing results,” Coleman said.

Grade 3 and 4 adverse events included pneumonia and diarrhea, but the diarrhea is less intense than with idelalisib, Coleman noted.

Ibrutinib and ofatumumab were combined in a phase 2 trial, in which the ORR was 100%. Sustained improvement was observed among patients with pretreatment cytopenias.⁴

A pivotal study of ibrutinib is planned.

Ofatumumab and Obinutuzumab
“Both ofatumumab and obinutuzumab [anti-CD20 monoclonal antibodies] have a great future and an important place in the treatment of CLL,” said Kanti Rai, MD, Hofstra North Shore-LIJ School of Medicine, Hempstead, New York.

Rituximab was the first anti-CD20 antibody to be approved a number of years ago for the treatment of hematologic malignancies. Ofatumumab was approved in the past few years, and approval was granted to obinutuzumab in November 2013.

Ofatumumab has good activity in CLL as a single agent and in combination with other drugs. Recent studies show that ofatumumab can replace rituximab in the fludarabine/cyclophosphamide/rituximab regimen for patients with CLL.

A phase 2 trial confirmed comparable high activity and safety of the O-FC (ofatumumab/fludarabine/cyclophosphamide) regimen as frontline treatment of previously untreated CLL. Investigators are moving forward with this regimen using the 1000-mg dose of ofatumumab.

Idelalisib in combination with ofatumumab versus idelalisib alone is in phase 1/2 testing. The combination of ofatuzumab and lenalidomide has been extremely effective as frontline therapy for CLL, Rai said.

The pivotal trial of obinutuzumab plus chlorambucil showed superiority of this combination versus rituximab plus chlorambucil. The ORR was 75% with obinutuzumab/chlorambucil versus 65.9% with rituximab/chlorambucil. Complete response was achieved in 22% versus 8%, respectively; and median PFS was 23 months versus 16 months (P <.0001). Neutropenia was reported in 34% versus 25%, respectively, and grade 3 to 5 adverse events in 67% versus 48%.

“Ofatumumab and obinutuzumab have each demonstrated good activity in CLL as single agents. Now ongoing trials are showing that combinations with each of these drugs are extremely promising,” Rai said.

References
1. Coleman M. Ibrutinib and idelalisib in CLL. Presented at: 2013 Chemotherapy Foundation Symposium; November 6, 2013; New York, NY. http://chemotherapyfoundationsymposium.org/CMS/2013archives/110613_008_coleman.
2. Rai K. Anti-CD20 monoclonal antibodies in therapy of CLL: obinutuzumab and ofatumumab.
Presented at: 2013 Chemotherapy Foundation Symposium; November 6, 2013; New York, NY. http://chemotherapyfoundationsymposium.org/CMS/2013archives/110613_009_rai.
3. O’Brien SM, Lamanna N, Kipps T, et al. A phase II study of the selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor idelalisib (GS-1101) in combination with rituximab (R) in treatment-naive patients (pts) 65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). J Clin Oncol. 2013;31(15 suppl):Abstract 7005.
4. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42.