Treon et al provide early clinical data supporting a theoretical rationale for continuing ibrutinib in patients receiving the drug during COVID-19 illness.
Bruton tyrosine kinase inhibitors (BTKi) and venetoclax are currently used to treat newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). ...However, most patients eventually develop resistance to these therapies, underscoring the need for effective new therapies. We report results of the phase 1 dose-escalation portion of the multicenter, open-label, phase 1/2 TRANSCEND CLL 004 (NCT03331198) study of lisocabtagene maraleucel (liso-cel), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory CLL/SLL. Patients with standard- or high-risk features treated with ≥3 or ≥2 prior therapies, respectively, including a BTKi, received liso-cel at 1 of 2 dose levels (50 × 106 or 100 × 106 CAR+ T cells). Primary objectives included safety and determining recommended dose; antitumor activity by 2018 International Workshop on CLL guidelines was exploratory. Minimal residual disease (MRD) was assessed in blood and marrow. Twenty-three of 25 enrolled patients received liso-cel and were evaluable for safety. Patients had a median of 4 (range, 2-11) prior therapies (100% had ibrutinib; 65% had venetoclax) and 83% had high-risk features including mutated TP53 and del(17p). Seventy-four percent of patients had cytokine release syndrome (9% grade 3) and 39% had neurological events (22% grade 3/4). Of 22 efficacy-evaluable patients, 82% and 45% achieved overall and complete responses, respectively. Of 20 MRD-evaluable patients, 75% and 65% achieved undetectable MRD in blood and marrow, respectively. Safety and efficacy were similar between dose levels. The phase 2 portion of the study is ongoing at 100 × 106 CAR+ T cells. This trial was registered at clinicaltrials.gov as NCT03331198.
•Liso-cel was associated with manageable toxicities and rapid and deep responses in patients with relapsed/refractory CLL/SLL.•With successful manufacturing of liso-cel for patients with CLL/SLL and the encouraging phase 1 results, a phase 2 study is underway.
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Chimeric antigen receptor (CAR) T cells have emerged as a promising class of cell-based immunotherapy in refractory malignancies. Neurotoxicity represents a common and potentially life-threatening ...adverse effect of CAR T cells, and clinical experience is limited. Here, we describe the clinical presentation and management of 25 adult patients who presented with neurotoxic syndromes after CAR T-cell therapy at the Massachusetts General Hospital. This cohort includes 24 patients treated with CD19-directed CAR T cells for non-Hodgkin lymphoma (n = 23) and acute lymphoblastic leukemia (n = 1), and 1 patient treated with α-fetoprotein–directed CAR T cells for hepatocellular carcinoma (n = 1). Twelve of the 25 patients (48%) developed grade 1-2 neurotoxicity and 13 patients (52%) presented with grade 3-4 neurotoxicity. We found that lower platelet counts at time of CAR T-cell infusion were associated with more severe neurotoxicity (P = .030). Cytokine release syndrome occurred in 24 of 25 patients (96%). Serum levels of ferritin peaked with onset of neurologic symptoms, and higher ferritin levels were associated with higher neurotoxicity grade. Grade 3-4 neurotoxicity correlated negatively with overall survival (OS) (P = .013). Median OS of the entire cohort was 54.7 weeks. Eight patients (32%) with grade 3-4 neurotoxicity were deceased at database closure, whereas none died with neurotoxicity grade 1-2. High pretreatment lactate dehydrogenase was frequently encountered in lymphoma patients with grade 3-4 neurotoxicity and correlated negatively with progression-free survival (P = .048). We did not find evidence that steroid use ≥7 days altered the patient's outcome when compared with <7 days of steroids. Management of CAR T cell–mediated neurotoxicity warrants evaluation in prospective clinical trials.
•Neurotoxicity after CAR T cells is associated with cytokine release syndrome; serum levels of inflammatory markers correlate with severity.•Grade 3-4 neurotoxicity is a negative prognostic factor for OS, and a short course of steroids does not appear to alter outcome.
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Phosphatidylinositol 3-kinase p110δ (PI3Kδ) inhibitors are efficacious in B-cell malignancies. Immune-related adverse events might be mitigated with intermittent dosing. We aimed to evaluate the ...safety and antitumour activity of zandelisib, a potent novel PI3Kδ inhibitor, with continuous or intermittent dosing as monotherapy or in combination with rituximab, in patients with relapsed or refractory B-cell malignancy.
We conducted a first-in-patient, dose-escalation and dose-expansion, phase 1b trial at ten treatment centres across Switzerland and the USA. Eligible patients were aged 18 years or older with relapsed or refractory B-cell malignancy (limited to follicular lymphoma or chronic lymphocytic leukaemia during dose escalation) and an Eastern Cooperative Oncology Group performance status of 0–2, and had received at least one previous line of therapy and no previous PI3Kδ inhibitor treatment. In the dose-escalation study, participants received oral zandelisib once daily (60 mg, 120 mg, or 180 mg; we did not evaluate four additional planned dose levels). The 60 mg dose was further evaluated as monotherapy or with intravenous rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3–6, using a continuous daily schedule or intermittent dosing therapy (days 1–28 of cycles 1–2 and days 1–7 of subsequent cycles) in 28-day cycles. Treatment was continued until evidence of disease progression, intolerance, or withdrawal of consent by the patient. Primary endpoints were safety (dose-limiting toxicities and maximum tolerated dose), minimum biologically effective dose, and a composite endpoint to assess the activity of each dose level, and were analysed by intention to treat. The zandelisib monotherapy and zandelisib–rituximab combination cohorts have completed accrual, but accrual to a cohort evaluating zandelisib with zanubrutinib is ongoing. This study is registered with ClinicalTrials.gov, NCT02914938.
Between Nov 17, 2016, and June 2, 2020, 100 patients were assessed for eligibility and 97 were enrolled and received zandelisib monotherapy (n=56) or zandelisib plus rituximab (n=41), with zandelisib administered on either a continuous schedule (n=38) or with intermittent dosing (n=59). No dose-limiting toxicities were observed, the objective of determining the maximum tolerated dose was abandoned, and antitumour activity was similar across the evaluated doses activity (objective responses in 11 92%; 95% CI 61·5–99·8 of 12 patients at both 60 mg and 120 mg doses, and in five 83%; 95% CI 35·9–99·6 of six patients at 180 mg). With a median duration of exposure of 15·2 months (IQR 3·7–21·7), the most common grade 3–4 adverse events were neutrophil count decrease (ten 17% of 59 patients in the intermittent dosing group and four 11% of 38 in the continuous dosing group), diarrhoea (three 5% and eight 21%), pneumonia (one 2% and six 16%), alanine aminotransferase increase (three 5% and two 5%), and colitis (two 3% and one 3%). 26 (44%) of 59 patients in the intermittent dosing group and 29 (76%) of 38 patients in the continuous dosing group had grade 3–4 adverse events. Treatment-related serious adverse events occurred in eight (21%) patients in the continuous dosing group and five (8%) patients in the intermittent dosing group. There were no treatment-related deaths.
Zandelisib 60 mg once daily on an intermittent dosing schedule was safe, with low frequency of grade 3 or worse adverse events, warranting the ongoing global phase 2 and phase 3 trials.
MEI Pharma.
Castleman disease is an uncommon lymphoproliferative disorder characterized as either unicentric or multicentric. Unicentric Castleman disease (UCD) is localized and carries an excellent prognosis, ...whereas multicentric Castleman disease (MCD) is a systemic disease occurring most commonly in the setting of HIV infection and is associated with human herpesvirus 8. MCD has been associated with considerable morbidity and mortality, and the therapeutic landscape for its management continues to evolve.
The available medical literature on UCD and MCD was reviewed. The clinical presentation and pathological diagnosis of Castleman disease was reviewed, along with associated disorders such as certain malignancies and autoimmune complications.
Surgical resection remains the standard therapy for UCD, while systemic therapies are required for the management of MCD. Rituximab monotherapy is the mainstay of therapy; however, novel therapies targeting interleukin 6 may represent a treatment option in the near future. Antiviral strategies as well as single-agent and combination chemotherapy with glucocorticoids are established systemic therapies. The management of Castleman disease also requires careful attention to potential concomitant infections, malignancies, and associated syndromes.
UCD and MCD constitute uncommon but well-defined clinicopathologic entities. Although UCD is typically well controlled with local therapy, MCD continues to pose formidable challenges in management. We address historical chemotherapy-based approaches to this disease as well as recently developed targeted therapies, including rituximab and siltuximab, that have improved the outcome for newly diagnosed patients. Ongoing research into the management of MCD is needed.
We examined the activity of bortezomib, dexamethasone, and rituximab (BDR) in patients with symptomatic, untreated Waldenström macroglobulinemia (WM).
A cycle of therapy consisted of bortezomib 1.3 ...mg/m(2) intravenously; dexamethasone 40 mg on days 1, 4, 8, and 11; and rituximab 375 mg/m(2) on day 11. Patients received four consecutive cycles for induction therapy and then four more cycles, each given 3 months apart, for maintenance therapy. Twenty-three patients received a median of seven cycles of treatment.
Median bone marrow disease involvement declined from 55% to 10% (P = .0004), serum immunoglobulin M levels declined from 4,830 to 1,115 mg/dL (P < .0001), and hematocrit increased from 29.8% to 38.2% (P = .0002) at best response. The overall response rates and major response rates were 96% and 83% with three complete responses, two near complete responses, three very good partial responses, 11 partial responses, and three minor responses. Responses occurred at a median of 1.4 months. With a median follow-up of 22.8 months, 18 of 23 patients remained free of disease progression. Peripheral neuropathy was the most common toxicity, and it resolved to grade < or = 1 in 13 of 16 patients at a median of 6.0 months. Four of the first seven treated patients developed herpes zoster, resulting in the institution of prophylactic antiviral therapy.
The results demonstrate that BDR produces rapid and durable responses, along with high rates of response and complete remissions in WM. Herpes zoster prophylaxis is necessary with BDR, and reversible peripheral neuropathy was the most common toxicity leading to premature discontinuation of bortezomib in 61% of patients. Exploration of alternative schedules for bortezomib administration that includes weekly dosing should be pursued.
A 55-year-old man was evaluated for a mediastinal mass, which was identified during an evaluation for waxing and waning fevers, night sweats, and fatigue. He had mediastinal lymphadenopathy with low ...FDG uptake, splenomegaly, anasarca, elevated inflammatory marker levels, hypoalbuminemia, anemia, and thrombocytopenia. A diagnosis was made.
IMPORTANCE: Anthracyclines treat a broad range of cancers. Basic and retrospective clinical data have suggested that use of atorvastatin may be associated with a reduction in cardiac dysfunction due ...to anthracycline use. OBJECTIVE: To test whether atorvastatin is associated with a reduction in the proportion of patients with lymphoma receiving anthracyclines who develop cardiac dysfunction. DESIGN, SETTING, AND PARTICIPANTS: Double-blind randomized clinical trial conducted at 9 academic medical centers in the US and Canada among 300 patients with lymphoma who were scheduled to receive anthracycline-based chemotherapy. Enrollment occurred between January 25, 2017, and September 10, 2021, with final follow-up on October 10, 2022. INTERVENTIONS: Participants were randomized to receive atorvastatin, 40 mg/d (n = 150), or placebo (n = 150) for 12 months. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of participants with an absolute decline in left ventricular ejection fraction (LVEF) of ≥10% from prior to chemotherapy to a final value of <55% over 12 months. A secondary outcome was the proportion of participants with an absolute decline in LVEF of ≥5% from prior to chemotherapy to a final value of <55% over 12 months. RESULTS: Of the 300 participants randomized (mean age, 50 SD, 17 years; 142 women 47%), 286 (95%) completed the trial. Among the entire cohort, the baseline mean LVEF was 63% (SD, 4.6%) and the follow-up LVEF was 58% (SD, 5.7%). Study drug adherence was noted in 91% of participants. At 12-month follow-up, 46 (15%) had a decline in LVEF of 10% or greater from prior to chemotherapy to a final value of less than 55%. The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002). The odds of a 10% or greater decline in LVEF to a final value of less than 55% after anthracycline treatment was almost 3 times greater for participants randomized to placebo compared with those randomized to atorvastatin (odds ratio, 2.9; 95% CI, 1.4-6.4). Compared with placebo, atorvastatin also reduced the incidence of the secondary end point (13% vs 29%; P = .001). There were 13 adjudicated heart failure events (4%) over 24 months of follow-up. There was no difference in the rates of incident heart failure between study groups (3% with atorvastatin, 6% with placebo; P = .26). The number of serious related adverse events was low and similar between groups. CONCLUSIONS AND RELEVANCE: Among patients with lymphoma treated with anthracycline-based chemotherapy, atorvastatin reduced the incidence of cardiac dysfunction. This finding may support the use of atorvastatin in patients with lymphoma at high risk of cardiac dysfunction due to anthracycline use. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02943590
BTK inhibitors (BTKi) are highly effective in B-cell malignancies. Acalabrutinib and zanubrutinib have exhibited favorable safety profiles when compared with ibrutinib. We identified all ...published/presented randomized trials comparing a second-generation BTKi with ibrutinib and reconstructed individual patient-level, censored time-to-event data for adverse events to evaluate the impact of second-generation BTKi on safety outcomes including atrial fibrillation/flutter AF, hypertension, bleeding, diarrhea, and infection. 1386 pts from ELEVATE-RR (
= 533), ALPINE (
= 652), and ASPEN (
= 201) trials were included in the analyses. Acalabrutinib or zanubrutinib were associated with significant reductions in cumulative event rates of AF (HR 0.28, 95% CI 0.18-0.42,
< 0.001), bleeding (HR 0.65, 95% CI 0.52-0.81,
< 0.001), diarrhea (HR 0.61, 95% CI 0.47-0.78,
< 0.001), hypertension (HR 0.40, 95% CI 0.27-0.61,
< 0.001), and infections (HR 0.83, 95% CI 0.70-0.98,
= 0.032). In summary, zanubrutinib and acalabrutinib have a favorable safety profile among pts with r/r B-cell malignancies. These data support use of acalabrutinib or zanubrutinib as preferred BTK inhibitors for approved indications.
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