Roeker, Lindsey

Abstract Early-phase clinical trials of Bruton’s tyrosine kinase (BTK) degraders have demonstrated efficacy in patients with BTK inhibitor-resistant chronic lymphocytic leukemia (CLL). How clinical resistance to BTK degraders arises is unknown. Here we sequenced serial CLL samples from patients enrolled in the phase I trials of zelebrudomide and bexobrutideg and observed recurrent expansion of preexisting BTK A428D mutations at relapse. Unlike previously studied BTK inhibitor resistance mutations, BTK A428D conferred pan-resistance to BTK inhibitors and degraders. In the absence of BTK-directed therapies, however, cells bearing BTK A428D exhibited a competitive disadvantage. A crystal structure of BTK A428D revealed that the mutant aspartate clashes with the adenine ring of ATP and the adenine-mimetic moiety of BTK inhibitors and degraders. Combining BTK degraders with venetoclax mitigated the expansion of BTK A428D. These results provide the molecular basis for clinical resistance to BTK degraders and will inform the development of next-generation BTK degrader therapies.

Abstract Advancements in the understanding of chronic lymphocytic leukemia (CLL) have transformed patient care, leading to the development of novel targeted therapies. Traditionally, patient fitness for treatment was based on the tolerability of chemoimmunotherapy such as fludarabine–cyclophosphamide–rituximab. As the CLL patient population is predominantly older, age has historically been a major factor in how a physician selects a patient's treatment. However, as a patient's fitness goes beyond age, the definition of patient fitness should also evolve. Here, we provide suggestions for the current best practice on assessing fitness for treating CLL. Considerations for treatment include assessment of polypharmacy, history of infections, cardiovascular and renal comorbidities, functional status, cognitive and psychological status, nutritional status, and social support. The flow of assessments can start with a typical clinical evaluation followed by geriatric, cardiovascular, and renal reviews, if needed, and include collecting a patient's full history to evaluate their risk of complications with specific CLL treatments. The severity of a patient's cardiovascular profile can range from low to high risk; for those at high risk, collaboration with a cardiologist is recommended. Geriatric assessment is advised to determine baseline frailty and resilience to tolerate treatments, to avoid inappropriate treatment or undertreating patients based on chronological age, and to align the patient's fitness status with the most optimal treatment. Continuous monitoring and assessment, regardless of therapy, are recommended. Patient preferences are also integral to this decision‐making process. Looking beyond a patient's age and basing treatment selection on their fitness is key in the new era of treatment in CLL.

Abstract Although Bruton tyrosine kinase inhibitors (BTKis) are generally well tolerated and less toxic than chemotherapy alternatives used to treat lymphoid malignancies, BTKis like ibrutinib have the potential to cause new or worsening hypertension (HTN). Little is known about the optimal treatment of BTKi-associated HTN. Randomly selected patients with lymphoid malignancies on a BTKi and antihypertensive drug(s) and with at least 3 months of follow-up data were sorted into 2 groups: those diagnosed with HTN before BTKi initiation (prior-HTN), and those diagnosed with HTN after BTKi initiation (de novo HTN). Generalized estimating equations assessed associations between time varying mean arterial pressures (MAPs) and individual anti-HTN drug categories. Of 196 patients included in the study, 118 had prior-HTN, and 78 developed de novo HTN. Statistically significant mean MAP reductions were observed in patients with prior-HTN who took β blockers (BBs) with hydrochlorothiazide (HCTZ), (−5.05 mmHg; 95% confidence interval [CI], 10.0 to −0.0596; P = .047), and patients diagnosed with de novo HTN who took either an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) with HCTZ (−5.47 mmHg; 95% CI, 10.9 to −0.001; P = .05). These regimens also correlated with the greatest percentages of normotensive MAPs. Treatment of HTN in patients taking a BTKi is challenging and may require multiple antihypertensives. Patients with prior-HTN appear to benefit from combination regimens with BBs and HCTZ, whereas patients with de novo HTN appear to benefit from ACEi/ARBs with HCTZ. These results should be confirmed in prospective studies.

Background: Familial transthyretin amyloidosis is a disease caused by misfolded transthyretin aggregates that can impair multiple organ systems. Liver transplantation is the first-line treatment for familial transthyretin amyloidosis. Research Question: Our objective is to study outcomes and survival among patients with familial transthyretin amyloidosis after transplantation. Design: All patients undergoing orthotopic liver transplant for familial transthyretin amyloidosis at Mayo Clinic between 1997 and 2012 were reviewed. Baseline clinical characteristics, organs transplanted, and posttransplant clinical course were assessed. Results: Of the 40 patients, 7 patients had the V30M mutation and 33 had other mutations. Nineteen patients received liver only, 19 liver and heart, and 2 combined liver, heart, and kidney transplants. The 5-year overall survival was 85% for those receiving multiple organ transplant and 52% for those receiving liver transplant only ( P = .057). There was no difference in overall survival based on mutation (V30M vs other mutations), but survival was confounded by varied disease involvement and organs transplanted. Those who had early death (≤24 months from liver transplant) had a higher incidence of baseline peripheral neuropathy, autonomic neuropathy, lower modified BMI, and higher alkaline phosphatase. Discussion: Outcomes of orthotopic liver transplant in familial transthyretin amyloidosis are variable due to heterogeneity in mutations and patient status at the time of transplant. Familial transthyretin amyloidosis can progress, despite liver transplantation. Patients receiving combined liver, heart/kidney transplant demonstrated improved survival compared to liver transplant alone.

Shapiro syndrome and periodic hypothermia have been reported approximately fifty times in the literature. Shapiro syndrome is defined as the constellation of periodic hypothermia and hyperhidrosis along with agenesis of the corpus callosum by Shapiro et al. in 1969. Periodic hypothermia is a more broad diagnosis with a number of proposed mechanisms; it occurs in patients without structural brain abnormalities. Hematologic abnormalities beyond iron-deficiency anemia have not been documented in any of the reported cases of Shapiro syndrome or periodic hypothermia. Though accidental and therapeutic hypothermia have been associated with thrombocytopenia, this is, to our knowledge, the first reported case of periodic intrinsic hypothermia causing bicytopenia. In this report, we present the case of a patient with Shapiro syndrome who experienced cyclic bicytopenia mirroring hypothermic episodes. We address the differential diagnosis of bicytopenia, review the mechanisms proposed for cytopenias related to hypothermia, and propose possible mechanisms for the finding in this case.