Primary Central Nervous System Lymphoma (Extranodal ABC). Primary CNS lymphoma (PCNSL) (HIV-negative) is a rare disease representing less than 3% of all non-Hodgkin lymphoma. Most (90%) are diffuse large B-cell lymphomas (DLBCL) and epidemiological studies show an increasing incidence. These tumors commonly harbor MYD88 and CD79B mutations and are ABC DLBCL. Based on our work showing that BCR signaling in ABC DLBCL is sensitive to ibrutinib, we instituted a study of ibrutinib in PCNSL. We developed a unique regimen, termed DA-TEDDi-R, comprised of active agents that enter the CNS including temozolomide, etoposide, liposomal doxorubicin, dexamethasone, and rituximab. We completed a phase Ia study to assess safety and PK. Preliminary data shows ibrutinib achieves active concentrations in the CNS, has 90% single agent response rate and DA-TEDDi-R has led to long term remissions in patients with refractory PCNSL. The molecular findings from the phase II ibrutinib study, which included primarily nodal ABC DLBCL, raised the hypothesis that ABC DLBCL that is dependent on BCR signaling, such as those with CD79B/A mutations with or without MYD88 mutations (i.e. genetic BCR signaling) present in 23% of ABC DLBCL, and those without identifiable mutations (non-genetic BCR signaling) present in 33% of ABC DLBCL may be hyper-addicted and highly responsive to BTK inhibition. To explore this hypothesis, we turned to a rare extranodal ABC DLBCL, primary CNS lymphoma (PCNSL), which has CD79B mutations in 53% of cases with both CD79B and MYD88 mutations in 37% of cases, suggesting PCNSL is hyper-addicted to BCR signaling. Notably, other extranodal ABC DLBCL such as leg-type, breast and testicular DLBCL also harbor high rates of dual mutations, suggesting extranodal ABC DLBCL is highly dependent on BCR-signaling whereas nodal ABC DLBCL is more heterogeneous. We performed a phase IB study of ibrutinib alone followed by ibrutinib and DA-TEDDi-R chemotherapy. Ibrutinib was administered for a 14-day window during which time we performed PK and obtained a response estimate. Following the ibrutinib window, patients received ibrutinib with DA-TEDDi-R with repeated cycles every 21 days for a total of 6 cycles. Eighteen enrolled patients had a median (range) age of 66 (49-87) years, and performance status of 1 (1-3). Five patients were untreated, whereas 13 (72%) were relapsed (2) or refractory (11) and received a median (range) of 2 (1-6) prior treatments. Among 18 patients on the ibrutinib window study, all but one patient (17/18; 94%) had disease reductions and 83% (15/18) responded and this was independent of prior treatment. Sixteen patients began DA-TEDDi-R treatment, and of 14 evaluable patients, 86% (12/14) achieved complete responses. Research FDG-PET scans were negative in all CR patients and in 6 of 9 CRu patients. Eight (57%) patients, including 5 with refractory disease, continue to be progression-free at a median (range) of 15.5 (8-27) months follow-up. Considering all 13 patients with relapsed/refractory disease, the median progression-free survival is 15.3 months, while the overall survival median was not reached with 51.3% of patients alive at one year. Refractory PCNSL patients have few effective treatment options and a median survival of around 2 months. Though the present results are based on a limited number of patients, the high CR rate of DA-TEDDi-R in refractory PCNSL suggests it may significantly improve the outcome of this disease. The high efficacy of ibrutinib and the pivotal role of doxorubicin in the cure of systemic DLBCL suggests both agents play an important role in the outcome of DA-TEDDi-R. An unexpected finding was the development of invasive aspergillosis in 7/18 (39%) patients; proven (3), probable (1) or possible (3). To assess the role of BTK in Aspergillus fumigatus immune surveillance, we analyzed the outcome of invasive aspergillosis in Btk knockout (Btk-/-) and wild-type (Btk+/+) mice. Btk-/- mice exhibited significantly greater mortality (27%) after Aspergillus fumigatus infection compared to Btk+/+ mice (0%) (p = 0.013 by exact log-rank test), as well as greater weight loss, and more severe lung tissue damage and fungal burden assessed by histology, indicating a contribution of BTK to the innate immune control of Aspergillus infection. These findings suggest ibrutinib impairs fungal immune surveillance, a deficit that may be exacerbated by co-administration of dexamethasone and/or chemotherapy. Indeed, we found that Btk-/- mice have a higher mortality during pulmonary aspergillosis, demonstrating a role for BTK in innate fungal immune surveillance. Mechanistically, macrophages provide the first line of defense against fungi. These considerations suggest that inhibition of BTK by ibrutinib contributed to the high incidence of aspergillosis, perhaps in concert with glucocorticoids. We have modified our protocol to investigate the addition of voriconazole to prevent aspergillosis. Upon completion of this extended phase IB study, we will institute a multi-center phase II trials to assess the efficacy of DA-TEDDi-R in relapsed/refractory and untreated PCNSL. Based on this study, we have now begun a second phase I to obviate the occurrence of fungal infections. Thus far we have observed no fungal infections and the regimens continues to be very active.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011654-05
Application #
10014751
Study Section
Project Start
Project End
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Budget End
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
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