SAMHD1 Expression Not Associated With Outcome in Mantle Cell Lymphoma With Cytarabine Combo Treatment

Expression or mutations in sterile alpha motif and histidine-aspartic domain-containing protein 1 (SAMHD1) does not appear to be linked with failure-free survival (FFS) or complete remission (CR) rates in patients with mantle cell lymphoma (MCL) who are treated with high-dose cytarabine-based chemotherapy, according to the results of a new study.¹

The report, published in the International Journal of Cancer, also found that while high expression of the protein appears to mediate resistance to cytarabine in lab-based experiments, the problem only seems to apply to cytarabine monotherapy and not to combination therapy that includes cytarabine. The findings suggest oncologists treating patients with MCL do not need to limit the use of cytarabine in patients based on SAMHD1 anomalies.

A diagnosis of MCL comes with a difficult prognosis, but in recent years, 2 studies have been published that have made a considerable difference in the treatment choices made by oncologists and patients. The European Mantle Cell Lymphoma Network’s MCL Younger trial² found that the addition of high-dose cytarabine to treatment regimens improves outcomes for patients with MCL who are ages 65 and younger. The network’s MCL Elderly trial,³ meanwhile, showed that rituximab (Rituxan) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) led to more favorable outcomes in patients over the age of 65 who were unfit for high-dose therapy. That study also showed that rituximab maintenance therapy improved overall survival (OS).

SAMHD1 has been proposed as a possible biomarker for cytarabine response in patients with MCL. Corresponding author Sascha Dietrich, MD, of the University of Heidelberg, and colleagues, explained that high expression of SAMHD1 can theoretically counteract cytarabine by enhancing hydrolysis of the active metabolite in cytarabine. Similar drugs, such as fludarabine, may also have limited efficacy in hematologic malignancies of patients with high expression of SAMHD1, the authors said.

At the same time, SAMHD1 has also been found to be a tumor suppressor, and reduced suppression of SAMHD1 has been linked with Sézary syndrome and lung carcinoma, along with other adverse outcomes.

Dietrich and colleagues decided to try and better understand whether cytarabine- or fludarabine-based induction therapy led to negative outcomes in patients with MCL and SAMHD1 expression. They used data from 189 patients in the MCL Younger and Elderly trials to identify patients with SAMHD1 mutations and quantify expression levels of the protein. All of the patients had received polychemotherapy with cytarabine or fludarabine. The investigators also treated B-cell lymphoma cell lines with cytarabine, fludarabine, and other drug combinations to see whether and how varying levels of SAMHD1 expression affected responses to the drugs.

The results were similar and suggested SAMHD1 expression did not affect outcomes.

The authors calculated a rate of SAMHD1 mutations of 7.1% among 182 patients assessed. The presence of such mutations did not have a statistically significant effect on FFS (P = .47). This was carried through even when adjusted for Mantle Cell Lymphoma International Prognostic Index (HR, 1.5; P = .25).

Similarly, the team found SAMHD1 expression levels did not have a significant impact. “We found that SAMHD1 expression was not associated with the CR rate or with FFS in patients treated with high-dose cytarabine- or fludarabine-containing regimes,” Dietrich and colleagues wrote.

The investigators noted that their findings differed from earlier studies, but in the previous research the patients received consolidation with single-agent high-dose cytarabine. They noted that when those authors investigated CR rates following acute myeloid lymphoma induction therapy with cytarabine and anthracycline, the correlation between SAMHD1 expression and CR was no longer statistically significant. In the current study, the subjects all received combination therapies.

That point was underscored by the other facet of the study. When Dietrich and colleagues looked at SAMHD1 expression in B-cell lymphoma cell lines, they found the response to cytarabine as a single agent was inversely related to SAMHD1 expression (P < .0001). When cytarabine was combined with other chemotherapeutics, the effect was reversed.

“We conclude that this might explain why we did not observe a significant association between SAMHD1 protein expression and the outcome of MCL patients upon cytarabine-based treatment,” the authors said.

Another potential factor is the use of myeloablative conditioning using the BEAM regimen (carmustine, etoposide, cytarabine, melphalan). Dietrich and colleagues said such therapy might have the effect of diluting and further overcoming cytarabine resistance; however, their study did not consider such conditioning in their assay. The investigators said their study was exploratory in nature, and thus they said they cannot rule out that some effect of SAMHD1 on outcomes in MCL might be possible.

_References:

_{1. Roider T, Wang X, Hüttl K, et al. The impact of SAMHD1 expression and mutation status in mantle cell lymphoma: An analysis of the MCL Younger and Elderly trial. Int J Cancer. 2021;148(1):150-160. doi:10.1002/ijc.33202}

_{2. Hermine O, Hoster E, Walewski J, et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open- label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016;388(10044):565-575. doi:10.1016/S0140-6736(16)00739-X}

_{3. Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-cell lymphoma. N Engl J Med 2012;367:520-531. doi:10.1056/NEJMoa1200920}