Vemurafenib/Rituximab Combo Reaches 100% CR Rate in Hairy Cell Leukemia

Enrico Tiacci, MD

The combination of vemurafenib (Zelboraf) and rituximab (Rituxan) in patients with relapsed/refractory hairy cell leukemia was proven to be safe and non-myelotoxic, producing durable and deep responses that in turn could provide an effective chemotherapy-free option in this heavily pretreated population, according to findings of a study presented during the 2017 ASH Annual Meeting.

Complete responses (CRs) were achieved in all 27 patients evaluable for efficacy, which included 2 patients who had incomplete platelet recovery.

Enrico Tiacci, MD, lead author of the study, said that the results warrant further study of this combination, potentially in the frontline setting. Although patients with hairy cell leukemia initially respond well to standard of care chemotherapy, up to 50% will relapse and become less responsive, resulting in a need for new therapeutic regimens, he added.

OncLive: Can you provide an overview of this study?

How was the study designed?

In an interview with OncLive, Tiacci, associate professor, Institute of Hematology, Ospedale S. Maria della Misericordia, University of Perugia, discussed the high potential with the combination of vemurafenib and rituximab in relapsed/refractory patients with hairy cell leukemia.Tiacci: We conducted this study to improve on the previous trial with vemurafenib alone in patients with hairy cell leukemia who are either refractory to standard chemotherapy with purine analogs or have relapsed multiple times following chemotherapeutics. In the prior trial with vemurafenib in this setting of relapsed/refractory patients, we obtained almost 100% overall response rates, including about one-third of the patents achieving a CR. Even in complete responders, residual disease persisted in the bone marrow. Therefore, the aim of this current trial is to improve on these results by adding another agent to vemurafenib with a completely different mechanism of action, such as rituximab, to try to get more CRs. That is the rationale of the study.We enrolled 31 patients who were either primary or refractory to purine analogs, and about one-fourth of them were primary refractory to standard chemotherapy. The other three-fourths of patients had received a median of 3 lines of prior therapies, including purine analogs. This was a single-center phase II study.

Vemurafenib was administered at a dose of 960 mg twice daily for 8 weeks. In addition, there are 2 concomitant doses of intravenous rituximab at the standard dose of 375 mg/m2 on days 1 and 15. Also, [sequential] rituximab was given after vemurafenib dosing [4 times every 2 weeks]

What were the results?

After these 2 cycles, there was a response evaluation and, if the patient was in complete remission, we stopped the drug. Otherwise, they would undergo a third cycle of vemurafenib and rituximab and another 4 doses of sequential rituximab.Strikingly, all 27 patients so far evaluable for efficacy obtained a CR versus only 35% on the previous trial. About two-thirds of these CRs were negative for minimal residual disease (MRD) in the bone marrow by immunohistochemistry flow cytometry and pathological complete response (pCR) for the BRAF mutation—which is the genetic cause of hairy cell leukemia.

There were no new unexpected toxicities from the combination, so we observed some fusion-related reactions and neutropenia that are known to be side effects of rituximab. We observed the usual toxicities with vemurafenib that we have seen previously, such as rash, warts, and photosensitivity, that were mostly grade 1/2 and transient.

The fact that we achieved MRD negativity in two-thirds of CRs is expected to translate into a much longer progression-free survival (PFS) than we observed with vemurafenib alone in the previous trial. In the previous trial, the PFS was around 10 months. In the current trial, the median follow-up is almost 1.5 years and only 1 of 27 evaluable patients progressed. We are continuing to follow these patients to see how long the PFS will hold.

What is the take-home message from this study?

Among the 16 patients who obtained MRD negativity and underwent subsequent bone marrow evaluation during the following 15 months, only 1 lost the MRD-negative status, which is very encouraging. Vemurafenib plus rituximab is a safe, chemotherapy-free regimen that quickly produces deep and durable responses in heavily pretreated patients with hairy cell leukemia. It can be helpful in difficult situations, such as patients with an active infection with cytopenia. It can be very helpful to deliver treatment during an active infection, which chemotherapy cannot do. It has the further distinct advantage of having a short and fixed duration. It is clearly superior to monotherapy with either vemurafenib or rituximab, and it has the potential to challenge chemotherapy in the frontline setting.

Hairy cell leukemia responds very well to chemotherapy with purine analogs initially, but up to 50% of patients eventually relapse and become progressively less responsive to these drugs, whose cumulative myelotoxicity and immune suppression cause some concern. Here is where this combination regimen is very helpful and may even spare chemotherapy to all patients in the frontline setting. However, that has to be tested in a randomized fashion, which we are thinking about doing.

Tiacci E, De Carolis L, Zaja F, et al. The chemotherapy-free combination of vemurafenib and rituximab produces deep and durable responses in relapsed or refractory hairy cell leukemia (HCL) patients. In: Proceedings from the 59th ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 409.