The first-generation Bruton tyrosine kinase inhibitor ibrutinib has long been of interest in treating patients with primary diffuse large B-cell lymphoma of the central nervous system due to the disease’s reliance on chronic active B-cell receptor signaling.
Mark Roschewski, MD
The first-generation Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica) has long been of interest in treating patients with primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (CNS) due to the disease’s reliance on chronic active B-cell receptor (BCR) signaling. However, ibrutinib monotherapy may impair innate immunity and could necessitate fungal prophylaxis to prevent Aspergillus infections. As such, investigators are looking to ways to manage the safety concerns while providing efficacy with combination approaches.
Results from an ongoing phase 1 dose-escalation study (NCT02203526) of ibrutinib and temozolomide (Temodar), etoposide, liposomal doxorubicin, dexamethasone, rituximab (Rituxan) (TEDDI-R regimen) with isavuconazole in patients with relapsed or refractory primary CNS lymphoma aimed to determine if a long-term deep clinical response could be achieved without the need for fungal prophylaxis. Patients received isavuconazole at 200 mg twice a day for 3 days prior to ibrutinib, given at one of 3 dose levels, plus up to 6 cycles of TEDDI-R with intrathecal cytarabine. All patients were monitored for fungal injections. The primary end point was maximum tolerated dose for ibrutinib in the treatment regimen. In total, 13 patients were enrolled and 12 were evaluable for response.
Of the 8 patients who received at least 4 cycles of treatment, 100% received complete remission while the other 4 participants remain on therapy. Of the patients who received complete remission, 75% remain in remission while 25% relapsed in the first 3 months after halting treatment. The estimated progression-free survival rate at 1 year is 60% and the estimated overall survival rate is 100%.
No dose-limiting toxicities were observed with treatment up to 560 mg ibrutinib safely administered. Grade 3 or higher infections were observed in 8% of cycles but no Aspergillus infections were observed.
Study author Mark Roschewski, MD, a senior clinician and clinical director of the Lymphoid Malignancies Branch at the National Cancer Institute Center for Cancer Research, discussed the early results of this study in an interview with Targeted Oncology.
TARGETED ONCOLOGY: Why was this treatment regimen explored in this patient population?
Roschewski: Sure, so we have been interested in drugs like ibrutinib, those that target the Bruton tyrosine kinase pathway for CNS lymphoma for a long time. This regimen this TEDDI-R regimen was developed here at the National Cancer Institute [NCI] based on primarily ibrutinib, it but then the chemotherapy agents all penetrate the CNS. And it's a regimen that we modeled after the way we attack lymphoma. It's not in the brain, meaning multiple different chemotherapy drugs, non-overlapping toxicities, and using combination. So this has been something we've been developing here, the first iteration of this combination has been published and the data were promising and we saw that a lot of times patients responded and the responses were durable. But the problem we had [was that] there was toxicity. And specifically, we were getting too many aspergillosis infections. Aspergillosis is not something you would normally see. And it was a surprise. So, it required us to modify the regimen to use medicines that were sort of treating fungal infections before we even started the treatment. So that's what this abstract is showing, is the first group of patients [who were] treated with both isavuconazole and the TEDDI-R regimen, as it was previously published.
TARGETED ONCOLOGY: What were the findings from the trial thus far?
Roschewski: So, the first important thing we showed is that [with the] use of the isoconazole, we haven't yet seen any fungal infections, which is good. So, we've reduced that to a manageable toxicity level. And the other finding of this abstract is that you can safely give up to 560 mg of ibrutinib with isavuconazole. So those drugs do interact. And the chemotherapy interacts with isavuconazole. So, the drug levels are probably higher. But the toxicity is still quite manageable. There is some hematologic toxicity to be aware of and there's some mucositis and some hand-foot syndrome, which are not things you would see with other regimens. But this is a group of patients who typically don't have very good options for treatment. And at least in the first 13 patients, we're seeing that almost all of them, 12 of the 13 actually, went into complete response, which is a really high number. The results are still pretty early, but considering that most things often don't work in this situation, it's pretty exciting.
TARGETED ONCOLOGY: What are the next steps for this?
Roschewski: The study has actually been amended to include patients that are untreated. So, we now have a cohort of patients with primary CNS lymphoma who have not received treatment that are eligible for TEDDI-R and we're still working out the safety of this regimen in the relapse setting, we want to treat some more patients. All the patients that have had TEDDI-R, or at least the majority, have been treated at one institution, the NCI and so we also want to export the regimen to other centers. So, we have some plans for this protocol to be expanded in a multicenter way so that other centers that treat these patients can also get some familiarity with the regimen, and so we can confirm that it's safe and feasible outside of the NCI.
TARGETED ONCOLOGY: What kind of challenges still exist in this space that we still need to overcome?
Roschewski: We don't know if regimens like this can cure patients. I mean, this is aggressive lymphoma. So, the goal is should always be cure. Historically, the cure rates have not been high enough. I think the [difficulty with] CNS lymphomas is balancing the ability to get cure with the amount of toxicity that you have to achieve to get there. And what I mean by that is a lot of the chemotherapy regimens and curative approaches will include autologous stem cell transplant, which has a lot of toxicity, and even TEDDI-R has toxicity. So, the field is sort of focused on how do we incorporate these highly active novel agents, and get active regimens, and maybe even a regimen that can be given outpatient, such as TEDDI-R to be delivered to patients more broadly. And what we know about the disease is it includes a lot more patients as they age. And so, the toxicity is critical in that we have to be able to have a regimen that's tolerable even for patients in their 70s or 80s. Because that's not true of autologous stem cell transplant, and it's probably true of TEDDI-R, I think, once we get it worked out to its optimal levels.
TARGETED ONCOLOGY: What are your key takeaways from this?
Roschewski: Well, I think the key takeaway is that it's a safe regimen and it doesn't, when you use antifungals, you don't have the same risk of aspergillosis, which is probably the most important thing. And the second thing is [that it is] highly active. It's not 100% effective, but it is pretty high. And so, I think it's something that could be used in patients that don't have other good treatment options, because all these drugs are otherwise available to us.
Roschewski M, Melani C, Lakhotia R, et al. Phase 1 Study of Escalating Doses of Ibrutinib and Temozolomide, Etoposide, Liposomal Doxorubicin, Dexamethasone, Rituximab (TEDDI-R) with Isavuconazole for Relapsed and Refractory Primary CNS Lymphoma. Presented at: 2020 American Society of Hematology Annual Meeting and Exposition; Dec ember 5-8, 2020; Virtual. Abstract 2110.