Despite unprecedented clinical activity in mantle cell lymphoma (MCL), primary and acquired resistance to ibrutinib is common. The outcomes and ideal management of patients who experience ibrutinib ...failure are unclear. We performed a retrospective cohort study of all patients with MCL who experienced disease progression while receiving ibrutinib across 15 international sites. Medical records were evaluated for clinical characteristics, pathological and radiological data, and therapies used pre- and postibrutinib. A total of 114 subjects met eligibility criteria. The median number of prior therapies was 3 (range, 0-10). The Mantle Cell Lymphoma International Prognostic Index (MIPI) scores at the start of ibrutinib were low, intermediate, and high in 46%, 31%, and 23% of patients, respectively. Of patients with available data prior to ibrutinib and postibrutinib, 34 of 47 and 11 of 12 had a Ki67 >30%. The median time on ibrutinib was 4.7 months (range 0.7-43.6). The median overall survival (OS) following cessation of ibrutinib was 2.9 months (95% confidence interval CI, 1.6-4.9). Of the 104 patients with data available, 73 underwent subsequent treatment an average of 0.3 months after stopping ibrutinib with a median OS of 5.8 months (95% CI, 3.7-10.4). Multivariate Cox regression analysis of MIPI before postibrutinib treatment, and subsequent treatment with bendamustine, cytarabine, or lenalidomide failed to reveal any association with OS. Poor clinical outcomes were noted in the majority of patients with primary or secondary ibrutinib resistance. We could not identify treatments that clearly improved outcomes. Future trials should focus on understanding the mechanisms of ibrutinib resistance and on treatment after ibrutinib.
•Patients with mantle cell lymphoma who progressed during treatment with ibrutinib have a poor outcome.•There are no therapies that appear to be uniquely successful in the postibrutinib setting. The postibrutinib setting is an unmet need.
Introduction
The United States Food and Drug Administration approved ibrutinib for treatment of patients with mantle cell lymphoma (MCL) that have received at least one prior therapy based on a phase ...II trial demonstrating a 68% response rate with a median progression-free survival of 13.9 months (Wang et al, NEJM 2013). Despite this significant efficacy, recent data suggest that primary or secondary resistance to ibrutinib is common and the mechanisms of ibrutinib resistance are varied (Chiron et al, Cancer Discovery 2014). The outcomes of MCL patients with ibrutinib resistance have not been previously reported, and the ideal management of patients with ibrutinib-resistant MCL is not known.
Methods
Following IRB approval, we performed a retrospective cohort study of all patients with MCL at WCMC and OSU that had experienced disease progression while receiving ibrutinib in a clinical trial or in routine clinical use. We evaluated historical medical records for clinical, pathological, and radiological data. Time-to-event statistics were estimated using the Kaplan-Meier method.
Results
We identified 32 subjects (19 male, 13 female) with primary or acquired ibrutinib resistant MCL. The median age at start of ibrutinib was 70 years (range 50-83), and the median number of prior therapies was 3 (0-9), including 2 patients with no prior therapy. The median time from diagnosis to start of ibrutinib was 32.5 months (range 0-223). Of the 30 patients that had received prior treatment, all had received rituximab, 21 had received bendamustine, 19 received bortezomib, 10 received an IMiD, 5 had received cytarabine, 5 had received methotrexate, 4 had received a purine analog, 2 received a PI3K inhibitor, and 1 had received an mTOR inhibitor. Five had undergone prior stem cell transplantation (3 auto, 2 allo). Only 11/30 patients had responded to their prior treatment, with a median time of 2.5 months between the prior treatment and ibrutinib. Four of 18 patients with morphology evaluated within 6 months of start of ibrutinib had blastoid MCL, and 11/19 patients had a previously reported Ki67 of >30%. The MIPI scores were as follows: 18 high risk, 5 intermediate risk, and 8 low risk, 1 not evaluable. Best response to ibrutinib was reported as follows: PD 20, SD 2, PR 6, CR 2, not evaluable 2. The median time on ibrutinib was 2.5 months (range 0-11). Among 27 patients with available follow-up data, 19 received treatment following ibrutinib with a median time of 0 months between stopping ibrutinib and starting subsequent treatment. The MIPI scores at start of subsequent therapy were as follows: 11 high risk, 3 intermediate risk, 3 low risk, and 2 unknown. Subsequent treatments included the following: 11 rituximab, 6 lenalidomide, 6 alkylator, 3 bendamustine, 2 anthracycline, 1 bortezomib, 1 purine analog. Two patients underwent allogeneic stem cell transplantation. Six of 17 patients evaluated for response demonstrated an objective response to subsequent treatment, including 2 patients that received bendamustine, 2 patients that received lenalidomide (one in combination with bendamustine), one that received an anthracycline, and one that received a purine analog. The median overall survival following cessation of ibrutinib was 4 months (95% CI 2-10 months). Both patients that underwent allogeneic stem cell transplantation died, one at 4 months from toxicity and one at 5 months from disease progression. Twelve patients were still alive, including four patients with more than 6 months of follow up (17, 22, 25, and 32+ months). There was no clear association between number of prior therapies, response to ibrutinib, morphology, Ki67 prior to ibrutinib, response to ibrutinib, duration of ibrutinib, or choice of subsequent therapy and OS.
Conclusions
In a group of patients with highly treatment-resistant MCL, primary and secondary ibrutinib resistance was associated with poor clinical outcomes, with limited duration of response to subsequent therapy and short overall survival. As yet, there are no identifiable predictors of clinical outcome following development of ibrutinib resistance, nor are there any clear signs that specific therapies might be particularly effective in this setting. Additional investigation into the outcomes of these patients is warranted. Clinical trials evaluating combinations with ibrutinib should be prioritized, as should trials of novel agents in the post-ibrutinib setting.
Martin:Janssen: Honoraria. Maddocks:Pharmacyclics: Advisory Board Other, Research Funding. Furman:Pharmacyclics: Consultancy, Speakers Bureau. Jones:Pharmacyclics: Consultancy, Research Funding. Ruan:Pharmacyclics: Speakers Bureau; Janssen: Speakers Bureau. Blum:Janssen, Pharmacyclics : Research Funding.
The Horizontal Wind Model (HWM) has been updated in the thermosphere with new observations and formulation changes. These new data are ground‐based 630 nm Fabry‐Perot Interferometer (FPI) ...measurements in the equatorial and polar regions, as well as cross‐track winds from the Gravity Field and Steady State Ocean Circulation Explorer (GOCE) satellite. The GOCE wind observations provide valuable wind data in the twilight regions. The ground‐based FPI measurements fill latitudinal data gaps in the prior observational database. Construction of this reference model also provides the opportunity to compare these new measurements. The resulting update (HWM14) provides an improved time‐dependent, observationally based, global empirical specification of the upper atmospheric general circulation patterns and migrating tides. In basic agreement with existing accepted theoretical knowledge of the thermosphere general circulation, additional calculations indicate that the empirical wind specifications are self‐consistent with climatological ionosphere plasma distribution and electric field patterns.
Key Points
The horizontal wind model has been updated
New data fill observational gaps
Empirical specifications are consistent with ionospheric models
Neisseria gonorrhoeae has the capacity to acquire iron from its human host by removing this essential nutrient from serum transferrin. The transferrin binding proteins, TbpA and TbpB constitute the ...outer membrane receptor complex responsible for binding transferrin, extracting the tightly bound iron from the host-derived molecule, and transporting iron into the periplasmic space of this Gram-negative bacterium. Once iron is transported across the outer membrane, ferric binding protein A (FbpA) moves the iron across the periplasmic space and initiates the process of transport into the bacterial cytosol. The results of the studies reported here define the multiple steps in the iron transport process in which TbpA and TbpB participate. Using the SUPREX technique for assessing the thermodynamic stability of protein-ligand complexes, we report herein the first direct measurement of periplasmic FbpA binding to the outer membrane protein TbpA. We also show that TbpA discriminates between apo- and holo-FbpA; i.e. the TbpA interaction with apo-FbpA is higher affinity than the TbpA interaction with holo-FbpA. Further, we demonstrate that both TbpA and TbpB individually can deferrate transferrin and ferrate FbpA without energy supplied from TonB resulting in sequestration by apo-FbpA.
Neisseria gonorrhoeae
has the capacity to acquire iron from its human host by removing this essential nutrient from serum transferrin. The transferrin binding proteins, TbpA and TbpB constitute the ...outer membrane receptor complex responsible for binding transferrin, extracting the tightly bound iron from the host-derived molecule, and transporting iron into the periplasmic space of this Gram-negative bacterium. Once iron is transported across the outer membrane, ferric binding protein A (FbpA) moves the iron across the periplasmic space and initiates the process of transport into the bacterial cytosol. The results of the studies reported here define the multiple steps in the iron transport process in which TbpA and TbpB participate. Using the SUPREX technique for assessing the thermodynamic stability of protein-ligand complexes, we report herein the first direct measurement of periplasmic FbpA binding to the outer membrane protein TbpA. We also show that TbpA discriminates between apo- and holo-FbpA; i.e. the TbpA interaction with apo-FbpA is higher affinity than the TbpA interaction with holo-FbpA. Further, we demonstrate that both TbpA and TbpB individually can deferrate transferrin and ferrate FbpA without energy supplied from TonB.
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