Laboratory Tumor Lysis Syndrome Research Articles

A retrospective review of rasburicase utilization in pediatric and adult patients across a large health system.

This study aimed to characterize rasburicase dosing and duration. Secondary objectives included characterizing the indication of rasburicase and identifying the utilization of prophylactic therapy for tumor lysis syndrome (TLS). This retrospective review included patients 0 to 89 years old admitted between 1 January 2021 and 31 December 2021, and received at least one dose of rasburicase. Patients were excluded if they were >89 years old, pregnant, lactating, or received rasburicase outpatient. A total of 192 patients, 176 adults and 16 pediatric patients were included in the retrospective review. Of the total population, 184 received a fixed dose of rasburicase and 8 patients received a weight-based dose (0.15 mg/kg/dose) of rasburicase. The average dose administered was 3.4 mg for fixed and 2.99 mg for weight-based dosing. Nearly half (49.5%) the patients received rasburicase for an elevated uric acid but did not meet Cairo-Bishop criteria for TLS. Only 42.2% received at least one dose of allopurinol within 5 days prior to rasburicase and 18.8% received aggressive hydration within 72 h prior to rasburicase. The majority of rasburicase administered was ordered as fixed dose for a uric acid level ≥7.5 mg/dL. Most patients did not meet criteria for laboratory or clinical TLS and less than half the patients received prophylactic allopurinol and/or aggressive hydration. These study results are supported by recent literature for fixed dose rasburicase as a safe and economical dosing strategy compared to weight-based dosing.

Low incidence of tumor lysis syndrome in elderly patients with chronic lymphocytic leukemia treated with venetoclax under real-world conditions: results from the prospective observational VeRVe study.

Venetoclax is active in both frontline and relapsed/refractory settings for the treatment of chronic lymphocytic leukemia (CLL). Although the prevalence and severity of tumor lysis syndrome (TLS) are well characterized in clinical trials, laboratory and clinical TLS remain relatively unexplored in real-world clinical practice.In this prospective, real-world observational study, we aimed to determine the incidence and outcomes of TLS in patients with CLL receiving venetoclax outside a clinical trial. The study (VeRVe) was conducted in centers in Austria, Germany, and Switzerland.Two hundred and thirty-nine patients were treated according to local label with at least one dose of venetoclax. Patient demographics, baseline characteristics, and blood chemistry at baseline were documented, and descriptive statistical analyses were conducted.Seventy eight patients (33%) were treated with venetoclax monotherapy, 101 (42%) with venetoclax in combination with rituximab and 60 (25%) with venetoclax in combination with obinutuzumab. In all cases, the TLS risk mitigation strategy adhered to the ramp-up protocol. Median age was 73 years and 66% of patients were male. The majority of patients (75%) had relapsed/refractory CLL, 63/192 (32.8%) patients tested had a del(17p) and 93/134 (69.4%) patients tested had unmutated immunoglobulin heavy chain variable region gene (IGHV). Clinical TLS occurred in 5 patients (2.1%) and laboratory TLS occurred in 15 patients (6.3%). Ten patients received specific treatment, of which 6 were hospitalized. There were no deaths due to a TLS event and venetoclax was well-tolerated. Of the 5 clinical TLS events reported, none were fatal or resulted in renal failure (NCT03342144, registered on Nov 10, 2017).

Incidence of Laboratory Tumor Lysis Syndrome in CAR T-Cell Recipients

Incidence of Laboratory Tumor Lysis Syndrome in CAR T-Cell Recipients

Laboratory and clinical features of tumor lysis syndrome in children with non-Hodgkin lymphoma and evaluation of long-term renal functions in survivors

ObjectiveThe purpose of our study is to investigate the laboratory and clinical features of tumor lysis syndrome (TLS) and acute kidney injury (AKI) in childhood non-Hodgkin lymphomas (NHL) and to reveal their impact on long term kidney function in survivors.MethodsOur single-center retrospective study included 107 patients (0-18 years old) with NHL who were admitted and treated at our hospital between 1998 and 2020. The relationship between TLS and age, gender, histopathological subgroup, tumor stage, lactate dehydrogenase (LDH) level at presentation, bone marrow and kidney involvement were assessed. The long-term renal functions of the patients were investigated.Results80.3% of the patients were male with a median age of 9.8 years. The most common detected histopathological subgroup was Burkitt lymphoma. Hyperhydration with or without alkalinisation, and allopurinol were used in first-line treatment and prophylaxis of TLS. Laboratory TLS and clinical TLS was observed in 30.8% and 12.1% of patients, respectively. A significant correlation was found between young age, advanced stage, high LDH level at presentation, and TLS. AKI was observed in 12.1% of the patients. When the glomerular filtration rate values of the patients at the first and last admissions were compared after an average of 6.9 years, a mean decrease of 10 mL/min/1.73 m2 was found. It was not, however, found to be statistically significant.ConclusionLower age, advanced stage, and high LDH level at presentation were found to be risk factors for TLS in our study. Long-term renal function loss was not observed in the survivors who received early and careful prophylaxis/treatment for TLS. The survivors are still being followed up.

Tumor Lysis Syndrome in Patients with AML Initiated on Venetoclax-Based Treatment without a Dose Ramp-up

Introduction Treatment with the combination of a hypomethylating agent (HMA) and venetoclax (VEN) is the standard of care for older patients (pts) with acute myeloid leukemia (AML). Venetoclax, an oral BCL-2 inhibitor, was initially approved for the treatment of chronic lymphocytic leukemia (CLL). In the early, pivotal studies assessing VEN safety, tumor lysis syndrome (TLS) was found to be a dose-limiting, potentially fatal toxicity. Dosing modifications were made to allow for safer initiation of the drug and, ultimately, a dose ramp-up was included in the dosing recommendation for CLL. Given the risk for TLS with VEN initiation for CLL, it was hypothesized that the risk would be the same, or potentially greater, when treating pts with AML. Therefore, studies of VEN in AML have included a dose ramp-up. Although reported rates of tumor lysis syndrome in these studies have been much lower than expected, a dose ramp-up for pts with AML is included in the package insert for VEN and continues to be utilized in clinical trials. Methods We conducted a retrospective analysis of pts ≥18 years of age with newly diagnosed or relapsed/refractory AML treated with a standard dose hypomethylating agent (HMA), either azacitidine or decitabine, and VEN without a dose ramp-up (initiated at 400mg daily or 100mg daily if on concomitant voriconazole or posaconazole) at Thomas Jefferson University Hospital from January 1, 2018- August 1, 2021. The primary objective of this study was to determine the rate of laboratory and clinical TLS within 72 hours after chemotherapy initiation, as defined by the Cairo-Bishop criteria (Table 1). The secondary objectives were (1) to identify clinical and laboratory risk factors for the development of TLS in pts with AML who were treated with HMA-VEN without a VEN dose ramp-up and (2) to compare rates of TLS in pts with AML who were treated with HMA-VEN without a VEN dose ramp-up to historical rates of TLS in pts who underwent a VEN dose ramp-up. In the Phase 3 study of azacitidine and venetoclax the rate of TLS during the VEN dose ramp-up period (days 1-3 of treatment) was 1% (DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629.). Results Ninety pts were included in the analysis. Seventy-one pts had newly diagnosed AML and 19 had relapsed/refractory disease. The majority of pts (58/90, 64%) had adverse risk disease by 2017 European LeukemiaNet Criteria. Median baseline white blood cell count at the time of therapy initiation was 3.25 (range 0.5-161.4). Sixty-one pts (68%) were receiving allopurinol prophylaxis at the time of HMA-VEN administration. Eighteen pts (20%) had a history of underlying renal disease. Fifteen pts (17%) were on medications, such as thiazide diuretics, aspirin, or levodopa, that can increase the risk of TLS at the time of treatment. Zero pts met the defined criteria for laboratory or clinical TLS. One pt developed acute kidney injury and one pt developed a cardiac arrhythmia (atrial fibrillation) but neither had concomitant evidence of laboratory TLS. Discussion In this retrospective study of 90 pts with newly diagnosed or relapsed/refractory AML who were treated with HMA-VEN without a VEN dose ramp-up no pts developed clinical or laboratory tumor lysis syndrome. This is comparable to the rate of TLS (1%) seen in the registration trial of HMA-VEN where pts were treated with VEN 100 mg on day 1, 200 mg on day 2, and 400 mg on day 3 and thereafter. Starting pts with AML on full dose VEN on day 1, regardless of white blood cell count, renal function, or concomitant medications, appears safe and could be implemented in clinical practice and clinical trials moving forward. This would simplify dosing for pts, pharmacists, and providers and allow for easier initiation of therapy.

Monotherapy with Second-Generation BCL2 Inhibitor Sonrotoclax (BGB-11417) Is Well Tolerated with High Response Rates in Patients with Relapsed/Refractory Marginal Zone Lymphoma: Data from an Ongoing Phase 1 Study

Background: Marginal zone lymphoma (MZL) is an uncommon type of non-Hodgkin lymphoma (NHL) that is generally considered incurable, with most patients experiencing a relapse after remission. Development of novel MZL therapies that are effective and tolerable is needed. Sonrotoclax (BGB-11417) is a next-generation BH3 mimetic which binds and inhibits BCL2 with a potency >10x that of venetoclax in biochemical assays. BGB-11417-101 (NCT04277637) is an ongoing, first-in-human, phase 1/1b dose-escalation and dose-expansion study looking at a wide array of B-cell malignancies. Previous interim analyses indicate sonrotoclax is well tolerated as monotherapy at all doses tested, up to 640 mg once daily (QD). This analysis investigated the safety, tolerability, and efficacy of sonrotoclax in patients with relapsed/refractory (R/R) MZL. Methods:Patients with R/R MZL received sonrotoclax (dose escalation: 40, 80, 160, 320, or 640 mg QD) with a 3-day ramp-up to the intended dose, followed by expansions at 640 mg and 320 mg. Dose-limiting toxicity (DLT), predefined in the protocol for each dose cohort, was evaluated during dose ramp-up through day 21 at the intended dose. The primary objective was to determine the safety and tolerability of sonrotoclax; a secondary objective for the expansion phase was to evaluate the activity of BGB-11417 as measured by the overall response rate (ORR, defined as partial response [PR] or better). Responses were assessed per Lugano criteria 2014. Adverse events (AEs) were reported per CTCAE v5.0 and tumor lysis syndrome (TLS) was assessed per Howard (2011) criteria. Results: As of April 24, 2023, 13 patients with MZL had received sonrotoclax across dose-escalation and -expansion cohorts (n=1, 40 mg; n=2, 160 mg; n=10, 640 mg). Overall, median age was 73 years (range: 54-85) and the median number of prior treatments was 1 (range: 1-3). Four patients progressed on Bruton tyrosine kinase inhibitors (BTKi), of which three had BTKi as last prior therapy. Dose escalation occurred per protocol at all defined doses. The maximum tolerated dose was not achieved with a maximum assessed dose of 640 mg; one DLT of febrile neutropenia was observed in the 160 mg cohort. Dose expansion was completed with the recommended phase 2 dose of 640 mg. Median follow-up was 7.8 months (range, 2.6-36.6 months). Treatment-emergent AEs (TEAEs) occurring in ≥20% of patients were nausea (39%) and pyrexia, diarrhea, and constipation (31% each). The most common grade ≥3 TEAEs were neutropenia, febrile neutropenia/neutropenic sepsis, and TLS (n=2 [15%] each). Five patients discontinued treatment (n=3, progressive disease; n=1, AE [infection]; n=1, withdrawal). No TEAEs leading to death occurred. Two patients in the 640-mg cohort experienced laboratory TLS following the initial ramp-up dose. The first patient (baseline: nodes, 60 mm; spleen, 21 cm; white blood cells [WBC], 46.9 × 10 9/L) had laboratory TLS (elevated potassium, phosphate, and urate) after a 160 mg dose, which resolved within 24 hours with intravenous hydration and supportive care without sequela or dose modification. Following a protocol amendment, patients with circulating tumor cells received an additional 3-day ramp-up starting at 40 mg. A second patient (baseline: nodes, 28 mm; spleen, 20 cm; WBC, 352 × 10 9/L) had laboratory TLS (elevated phosphate and urate) after initial 40- and 80-mg doses. Both episodes resolved within 24 hours without sequela or change in dosing. Overall, 12 patients were assessable for response; ORR was 67% (n=8), including four patients (33%) with complete response (CR). Nine of the 10 patients treated at 640 mg were assessable for response, where the ORR was 78% (n=7), including four patients (44%) who achieved a CR (Figure). Responses of PR or better were observed in all four patients with previous progression on BTKi (n=3, CR; n=1, PR). Conclusions: These data confirm sonrotoclax monotherapy had a tolerable safety profile across all doses tested and encouraging antitumor activity in patients with MZL. Two patients had laboratory TLS following the initial doses that resolved. No clinical TLS were observed, indicating that TLS can be mitigated with current measures, including revised ramp-up. An exploratory 320-mg cohort is currently enrolling.

A Phase 2 Study of Minimal Residual Disease (MRD)-Adapted Front Line Venetoclax and Obinutuzumab in Fit Patients with Chronic Lymphocytic Leukemia (CLL): Effect of Obinutuzumab on Tumor Lysis Syndrome (TLS) Risk and Safety of Outpatient Venetoclax Dose Escalation

Introduction: Venetoclax (V) / Obinutuzumab (O) is an effective one-year fixed duration therapy for patients (pts) requiring first-line CLL treatment (tx). In CLL14, tumor lysis syndrome (TLS) risk assessment (including lymph node measurements by imaging and ALC) was required once prior to tx initiation, and O's impact on TLS risk prior to introduction of V was not a pre-planned study endpoint. Therefore, TLS prophylaxis (ppx) and tx setting for V dose escalation did not account for the possibility that O may decrease TLS risk prior to V escalation. Based on this approach, 22% of pts in the CLL14 study were high risk for TLS, thus requiring hospitalization for intensive laboratory monitoring during V dose escalation. (Fischer, NEJM 2019) We hypothesized that cycle (C) 1 of O would significantly decrease TLS risk prior to V escalation and that all pts, regardless of TLS risk category, could safely undergo a standard 5-week V dose escalation in the outpatient setting. Methods: We are conducting a Phase 2 study (NCT04447768) designed to examine the efficacy of a minimal residual disease (MRD)-adapted approach to V/O combination for fit pts in the front-line setting (study schema, Figure 1). A planned secondary study endpoint is to evaluate the effect of O monotherapy in C1 on TLS risk. Here we present interim results of TLS risk modification for the first 80 patients. Per protocol, TLS risk assessment including CT imaging and ALC measurement was performed at two defined timepoints: (1) prior to C1 day (D) 1 and (2) immediately prior to V initiation on C1D22. Key eligibility criteria: adult pts with CLL requiring first line tx per iwCLL guidelines, CIRS score ≤ 6, adequate heme function (Hgb ≥8 g/dL, ANC ≥1 x 10 9/L, Plt ≥30 x 10 9/L), creatinine clearance >50 mL/min. O was administered on C1 D1/2, 8 and 15. Per protocol, pts underwent V dose escalation in the outpatient setting, regardless of TLS risk. For pts with low and medium (med) tumor burden, TLS ppx was per FDA label. For pts who remained high TLS risk at the time of V initiation, TLS ppx throughout dose escalation included allopurinol to start at least 3 days prior to V initiation, sevelamer to start 12 hours prior to V initiation, and oral intake of ≥2 L water daily. On days of dose escalation, ppx additionally included kayexalate, rasburicase, and IV normal saline on D1 and D2 of each dose escalation. TLS labs were monitored according to FDA label guidance. Statistical analysis of TLS risk and adverse events was descriptive. Results: As of 5/2023, 80 pts have enrolled in this study. Seventy-eight pts completed the 5-week V ramp-up. Two pts were removed after receiving at least one dose of O but before repeat assessment of TLS risk and initiation of V (1 death unrelated to tx/disease, 1 patient with recurrent grade 3 (G3) O infusion-related reaction (IRR) leading to consent withdrawal). Median pt age was 57.5 years, 68% male, 95% white. Prior to tx initiation, TLS risk categories were low: 16%, med: 58%, and high: 26% (n=80). Change in TLS risk from baseline to C1D22 is detailed in Figure 2. Of the 20 pts who had sequential assessments with high baseline TLS risk, TLS risk after C1 O (C1D22) was low: 55%, med: 35%, high: 10%. For pts with med TLS risk at baseline with sequential assessments (n=45), TLS risk at C1D22 was low: 82%, med: 18%. One patient developed laboratory TLS on C1D3 following administration of O; no clinical TLS was observed. All pts accomplished V dose escalation in the outpatient setting with no observed laboratory or clinical TLS as defined by Howard Criteria. Grade 3 / 4 tx emergent AEs that occurred in >5% between C1D1 and C3D1 included neutropenia (35% G3, 11% G4), IRR (11% G3, 0% G4), and thrombocytopenia (9% G3, 3% G4). Conclusions: A single cycle of O effectively reduced TLS risk prior to introduction of V escalation with most pts achieving low or med TLS risk by C1D22. Notably, 90% of pts with high pre-tx TLS risk converted to low or med risk following C1 of O allowing for outpatient V escalation per FDA label. Further, we demonstrate that V dose escalation can be safely accomplished in the outpatient setting with close monitoring regardless of TLS risk. With this strategy, we observed no laboratory or clinical TLS during V dose escalation. Eliminating the need for hospitalization during V dose escalation may enhance patient and provider convenience and decrease the economic burden of this regimen. This study is ongoing; efficacy results of this MRD-guided approach to V/O are forthcoming.

Primary Analysis and Results of Bendamustine, Rituximab, and Venetoclax (BR-VEN) for Initial Treatment of Mantle Cell Lymphoma in Subjects over 60 Years of Age (PrE0405)

Background Mantle cell lymphoma (MCL) is an incurable form of aggressive non-Hodgkin lymphoma. Treatment choice at diagnosis is based on tolerability of cytarabine and high-dose chemotherapy. With a median age of 60-70 years, many patients are ineligible for aggressive treatment. Bendamustine and rituximab (BR) is a reasonable treatment option (E1411, Smith MR et al. ASH 2022) for this patient population and venetoclax (VEN) has shown pre-clinical evidence of synergy with chemoimmunotherapy. PrECOG 0405 was designed to evaluate the addition of VEN to BR in previously untreated patients with MCL aged over 60 years. Methods Eligible patients included those that were previously untreated and diagnosed with MCL as defined as the presence of t(11;14) by FISH or cyclin D1 expression by IHC. Patients must have been at least 60 years of age or older on D1C1 of therapy with a good performance status (ECOG 0-2). Adequate marrow and organ function was required, specifically a creatinine clearance of ≥ 40 mL/min. Treatment administration is summarized in Figure 1. Dose of bendamustine was either 90mg/m 2 D1&2; or, for subjects over the age of 75 years, 70mg/m 2 was allowed per investigator discretion. VEN was dose escalated during Cycle 1 to 200mg. At the time of C2, BR was repeated and VEN was also escalated to 400mg. With C2-6, VEN 400mg PO daily was given D1-10 only. Primary endpoint was PET-negative complete response (CR) rate at end of treatment (EOT) by Lugano Criteria. A negative bone marrow biopsy was required to confirm CR if involved at screening. Minimal residual disease (MRD) by next-generation sequencing was performed at the EOT. Maintenance rituximab was encouraged per investigator discretion. This was a single arm study with an original accrual goal of 53 subjects to detect a 15% improvement in CR rate compared to historical data. However, due to slow study accrual during COVID pandemic and preliminary efficacy data from E1411 study, the statistical parameters were updated after 25 subjects had been accrued. The revised accrual goal was 33 patients to obtain 32 eligible and treated patients, which provided 81.8% statistical power to detect a 17% difference in CR rate (from 60% [E1411 data] to 77%) using an exact binomial test with a 1-sided alpha of 11.6%. This combination regimen will be considered promising if 23 or more (out of 32) patients attain CR. Results From January 2020 to March 2022, 33 subjects enrolled and were treated on study. Subject characteristics are listed in Table 1. Seven (21%) unique subjects were treated with 70mg/m 2 of bendamustine during induction cycles. Laboratory tumor lysis syndrome (TLS) was seen in 2/33 during C1 only; clinical TLS was not seen. Treatment was generally well tolerated with treatment-related adverse events (TRAE) of Grade ≥3 and occurring in >10% of subjects being neutropenia (n=5, 15%), thrombocytopenia (n=5, 15%) and lymphopenia (n=9, 27%). Other common non-hematologic TRAE of all grades were nausea/vomiting (n=26, 79%), diarrhea (n=10, 30%), and fatigue (n=17, 52%). There were 4 (12%) instances of COVID-19/COVID-19 pneumonia considered treatment related. Dose adjustments and delays for any drug occurred in 36% and 67% of subjects respectively. 22/33 (66.7%) subjects completed 6 cycles of BR-VEN. Maintenance rituximab was administered in 19/33 (57.6%) of subjects. Overall response rate was 97% (32/33) and PET-negative bone marrow biopsy confirmed CR Rate at EOT was 85% (28/33), achieving the primary endpoint (≥23 CRs). MRD at EOT is under analysis. With a median survival follow up of 21.5 months (mo), Median PFS and OS were not reached; estimated 2-year PFS and OS was 69.7% and 81.1% respectively. During follow up, there have been 6 deaths, 4 from COVID-19 (all in remission), one from influenza A (in remission), and one from disease progression (non-responding pt). There have been 2 other progression events who are alive. Conclusions BR-VEN was generally well-tolerated in this older patient population though GI toxicities were common. With a PET-negative CR rate of 85%, the combination is promising but longer follow-up is needed. There was a competing risk of death related to upper respiratory viruses identified, mostly COVID-19, as has been seen in other BR-based protocols during the COVID-19 pandemic. MRD analysis and survival data will be updated.

Outcomes of Patients with Relapsed/Refractory Lymphoplasmacytic Lymphoma Treated with Venetoclax: A Multicenter Retrospective Analysis

Outcomes of Patients with Relapsed/Refractory Lymphoplasmacytic Lymphoma Treated with Venetoclax: A Multicenter Retrospective Analysis

Preliminary Safety, Pharmacological and Efficacy Data from Patients with Relapsed or Refractory B-Cell Malignancies Treated with the ICP-248, a Next Generation BCL2 Inhibitor

Background: BCL2, a key protein regulator of the apoptotic pathway, is constitutively expressed in various malignancies, which is a hallmark of cancer cell. BCL2 inhibitors have been shown to be safe and effective and are approved for the treatment of patients with chronic lymphocytic leukemia/small cell lymphoma (CLL/SLL) or acute myeloid leukemia (AML). Venetoclax, the first and only approved BCL2 inhibitor, is associated with gastrointestinal toxicities and tumor lysis syndrome (TLS). Therefore, ICP-248 was developed as a potent and highly selective inhibitor of BCL2 and has shown antitumor activity superior to venetoclax in preclinical studies. Preclinical studies of ICP-248 have demonstrated favorable pharmacokinetics profile, broad safety window and excellent safety profile, as well as synergistic effect in anti-tumor activity in combination with Orelabrutinib, a novel and highly selective BTK inhibitor. Methods: ICP-CL-1201 is a phase I study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ICP-248 in patients with relapsed or refractory B-cell malignancies ( ClinicalTrials.gov ID: NCT05728658). The study will be conducted in 2 parts. Part 1 will evaluate ICP-248 as monotherapy at the target dose of 100mg, 200mg, 300mg, 400mg, 500mg and 600mg (once daily and 28 days per cycle) and will explore different ramp-up dosing strategies. Part 2 will evaluate ICP-248 in selected and proposed indications. The dose escalation in Part 1 will follow the 3+3 design with dose-limiting toxicity (DLT) observation window with 49 days. Eligible patients include those with CLL/SLL and B-cell non-Hodgkin lymphomas (NHLs) who failed on available therapy. Key exclusion criteria include CNS involvement, prior exposure to BCL2 inhibitors and clinically significant cardiovascular disease. Adverse events (AEs) are reported per common terminology criteria for AEs (CTCAE) v5.0. Efficacy was evaluated according to the Lugano 2014 or International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria. Minimal residual disease was evaluated with flow or next generation sequencing. Results: As of 30 th July, 2023 (data cutoff date) 3 patents (mantle cell lymphoma [MCL], SLL and CLL) had been enrolled at the dose level of 100 mg QD; age ranging from 53 to 68; follow-up ranging from 1.9 to 4.7 months); median of prior regimen numbers was 3 (range, 1-3; 2 out 3 patients failed on zanubrutinib or pirtobrutinib). ICP-248 demonstrated a favorable PK profile, approximate dose proportionality was observed across the ramp-up stage. No DLTs and SAEs were observed. All the AEs were grade 1 to 2 (mainly neutropenia) without dose interruption and modifications. No TLS including laboratory TLS was observed. Two patients with MCL and SLL were assessed as complete response (CR) at the end of cycle 2, and the CLL patient was assessed as stable disease without sign and symptom of disease and recovering hematology. Undetectable MRD was confirmed in the patient with SLL and MCL. Conclusions: Preliminary results suggest that ICP-248 is safe and well tolerated in relapsed or refractory B-cell malignancies. The favorable clinical pharmacological and safety profiles support current dose ramp up strategy. Preliminary efficacy data demonstrated good response with deep remission. Further assessment of safety and efficacy with additional dose levels and dosing strategies will be pursued in expanded patient population and in the combination with orelabrutinib.

Combination Treatment with Sonrotoclax (BGB-11417), a Second-Generation BCL2 Inhibitor, and Zanubrutinib, a Bruton Tyrosine Kinase (BTK) Inhibitor, Is Well Tolerated and Achieves Deep Responses in Patients with Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (TN-CLL/SLL): Data from an Ongoing Phase 1/2 Study

Background: The combination of BCL2 and BTK inhibitors has shown synergistic activity. The combination of venetoclax, a BCL2 inhibitor, and ibrutinib, a BTK inhibitor, is an effective treatment for CLL/SLL. Sonrotoclax (BGB-11417) is a BH3 mimetic that binds and inhibits BCL2 with potency >10x that of venetoclax in biochemical assays. Zanubrutinib, a next-generation BTK inhibitor, has shown improved PFS with fewer cardiac adverse events (AEs) vs ibrutinib in a randomized study of patients with CLL/SLL (Brown et al. N Engl J Med. 2023). BGB-11417-101 (NCT04277637) is an ongoing, first-in-human, phase 1/1b dose-escalation/expansion study of patients with various B-cell malignancies. In a preliminary report, sonrotoclax, alone or in combination with zanubrutinib, was well tolerated at all doses tested up to 640 mg. This abstract describes the safety and efficacy data from patients with treatment-naïve (TN) CLL/SLL who received the combination of sonrotoclax and zanubrutinib. Methods:Patients received zanubrutinib (320 mg QD or 160 mg BID) 8-12 weeks before starting sonrotoclax using a ramp-up schedule starting from 1 mg to the intended target dosage of 160 mg or 320 mg QD (doubling weekly [W] or 30% increase every day 5 d/week [D]) to mitigate risk of tumor lysis syndrome (TLS). Patients were treated until progression, unacceptable toxicity, or could elect to stop. TLS was assessed per Howard (2011) criteria; mitigation included mandatory oral hydration and antihyperuricemics. Primary endpoint was safety (reported per CTCAEs v5.0); a secondary endpoint was ORR (per iwCLL 2008 criteria) and minimal residual disease assessed in blood by ERIC flow every 24 weeks (uMRD4; <1 CLL cell per 10,000 leukocytes, or <0.01%) was an exploratory endpoint. Results: As of May 21, 2023, 94 patients with TN-CLL/SLL were enrolled (sonrotoclax 160 mg QD, n=41 [26 W, 15 D] and 320 mg QD, n=53 [25 W, 28 D]); 15 patients were still receiving zanubrutinib monotherapy and 79 started sonrotoclax (160 mg, n=32 [25 W, 7 D] and 320 mg, n=47 [24 W, 23 D]). Median follow-up was 8.5 mo (range: 0.6-18.2) for all patients; 160 mg, 12.1 mo (range: 0.6-18.2); 320 mg, 7.0 mo (range: 1.1-14.6). No deaths have occurred, and all patients remain on study. Treatment-emergent AEs (TEAEs) occurring in ≥20% patients who received sonrotoclax plus zanubrutinib (n=79) are listed in theTable; TEAE frequencies were similar between the two sonrotoclax cohorts. Contusion, neutropenia, and low-grade gastrointestinal toxicity were the most common TEAEs; neutropenia was the most common grade ≥3 TEAE (n=13 [17%]). No cases of clinical or laboratory TLS occurred in either ramp-up schedule; no patient experienced atrial fibrillation. One TEAE (cryptococcal meningitis at 11 weeks treated with azoles) led to treatment discontinuation. Sonrotoclax dose holds occurred in 17 patients (22%) for a median duration of 11 days (range: 3-37) and three patients (4%) had dose reduction. The most common TEAEs resulting in dose holds were COVID-19 (n=9 [11%]) and diarrhea (n=3 [4%]). A total of 56 patients had a response assessment. The ORR was 100% (CR: 160 mg, n=9 [36%]; 320 mg, n=6 [19%]). Across all doses, rate of CR increased with time; overall median time to CR was 10.1 mo (range: 5.4, 17.1). No progression was reported in either cohort (Figure). Week 24 blood uMRD4 rates were 50% (n=12/24) in 160 mg and 65% (n=13/20) in 320 mg patients. Week 48 blood uMRD4 rates were 73% in 160 mg (n=11/15) and 100% (n=1/1) in 320 mg; no patient has lost uMRD4. Conclusion: Sonrotoclax (160 mg and 320 mg) in combination with zanubrutinib was well tolerated in patients with TN CLL/SLL. Only one patient discontinued treatment and three patients had dosage reductions. No TLS was seen with either ramp-up schedule. Acknowledging the short follow up, efficacy is encouraging with 100% ORR in assessed patients and no PFS events. High rates of blood uMRD4 occurred early. Based on these data, a phase 3 study assessing this combination is planned.

Ibrutinib Combined with Venetoclax in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Primary Analysis Results from the Randomized Phase 3 Sympatico Study

Background: Ibrutinib (Ibr) is a once-daily Bruton tyrosine kinase (BTK) inhibitor approved in multiple regions for patients (pts) with mantle cell lymphoma (MCL) who have received ≥1 prior therapy. Venetoclax (Ven) is a BCL-2 inhibitor approved in the US for pts with chronic lymphocytic leukemia and previously untreated acute myeloid leukemia. Ibr and Ven have distinct and complementary modes of action, and the combination has shown promising clinical activity in early phase studies in MCL (Tam, N Engl J Med 2018; Wang, J Hematol Oncol 2021). Here, we report the primary analysis results from the multinational, randomized, double-blind, phase 3 SYMPATICO (NCT03112174) study comparing Ibr+Ven vs Ibr + placebo (Pbo) in pts with relapsed/refractory (R/R) MCL. Methods: Pts aged ≥18 y with R/R MCL after 1-5 prior therapies were randomly assigned 1:1 to receive oral Ibr 560 mg once daily concurrently with oral Ven (standard 5-wk ramp-up to a target dose of 400 mg once daily) or Pbo for 2 y, followed by single-agent Ibr until progressive disease (PD) or unacceptable toxicity. Randomization was stratified based on ECOG PS, prior lines of therapy, and tumor lysis syndrome (TLS) risk based on tumor burden and CrCl. The primary endpoint was progression-free survival (PFS) by investigator (INV) assessment using Lugano criteria; pts without PD or death were censored at the last non-PD assessment (per global censoring rules). Additional sensitivity analyses included PFS assessment by independent review committee (IRC) and censoring per US FDA rules (Table). Key secondary endpoints were tested hierarchically in the following order: complete response (CR) rate by INV assessment, time to next treatment (TTNT), overall survival (OS, interim analysis), and overall response rate (ORR) by INV assessment. Results: A total of 267 pts were enrolled and randomly assigned to receive Ibr+Ven (n=134) or Ibr+Pbo (n=133). Median age was 68 y; 96% of pts had an ECOG PS of 0-1, 17% had ≥3 prior lines of therapy, and 22% were at increased risk for TLS. At baseline, pts in the Ibr+Ven vs Ibr+Pbo arms had median ages 69 vs 67 y, high-risk simplified MCL International Prognostic Index score 38% vs 31%, bulky disease ≥5 cm 46% vs 40%, bone marrow involvement 46% vs 41%, splenomegaly 31% vs 25%, and TP53 mutated 30% vs 28%; other baseline characteristics were generally similar between arms. With a median time on study of 51.2 mo, median PFS by INV assessment was significantly longer with Ibr+Ven vs Ibr+Pbo (31.9 vs 22.1 mo), with a hazard ratio (HR) of 0.65 (95% CI, 0.47-0.88; stratified log-rank P=0.0052) (Figure). PFS rates at 24 mo were 57% and 45% with Ibr+Ven and Ibr+Pbo, respectively. PFS benefit with Ibr+Ven vs Ibr+Pbo was generally consistent across prespecified subgroups, including those with blastoid variant or TP53-mutated MCL. Sensitivity analyses of PFS were consistent with the primary analysis (Table). Ibr+Ven significantly improved CR rates (54% vs 32%) and TTNT (median not reached [NR] vs 35.4 mo); at the current 51.2 mo median follow-up, median OS was 44.9 mo with Ibr+Ven vs 38.6 mo with Ibr+Pbo (HR 0.85 [95% CI, 0.62-1.19]) (Table). Median duration of treatment was 22.2 mo for the Ibr+Ven arm and 17.7 mo for the Ibr+Pbo arm; at the time of analysis, 30% of pts in the Ibr+Ven arm and 20% of pts in the Ibr+Pbo arm remained on single-agent Ibr. Grade ≥3 adverse events (AEs) occurred in 84% of pts with Ibr+Ven vs 76% with Ibr+Pbo; the most frequent (occurring in ≥5% of pts) were neutropenia (31% vs 11%), pneumonia (13% vs 11%), thrombocytopenia (13% vs 8%), anemia (10% vs 3%), diarrhea (8% vs 2%), leukopenia (7% vs 0%), MCL (7% vs 12%), atrial fibrillation (5% vs 5%), COVID-19 (5% vs 1%), and hypertension (4% vs 9%). Serious AEs occurred in 60% of pts in each arm. No clinical TLS occurred; laboratory TLS occurred in 5% and 2% of pts in the Ibr+Ven and Ibr+Pbo arms, respectively. COVID-19 deaths occurred in 10 pts in each arm and had no meaningful impact on PFS or OS HRs. Conclusion: The Ibr+Ven combination demonstrated a statistically significant improvement in PFS compared with Ibr+Pbo in pts with R/R MCL; CR rates and TTNT were also significantly improved with Ibr+Ven. OS was numerically but not significantly improved at this interim analysis. The safety profile of Ibr+Ven was consistent with known AEs for each agent, with no new safety signals observed. Overall, these results demonstrate a favorable benefit-risk profile for Ibr+Ven in pts with R/R MCL.

Emergencies in Hematology: Tumor Lysis Syndrome

Emergencies in Hematology: Tumor Lysis Syndrome

Emergencies in Hematology: Tumor Lysis Syndrome

TLS (tumor lysis syndrome) is a serious consequence of haematologic malignancies and their treatment. The condition is defined by laboratory abnormalities alone (laboratory TLS) or in conjunction with clinical consequences such as renal failure, seizures, and arrhythmias (clinical TLS). Clinical TLS is a risk factor for increased morbidity and death in cancer patients, although it may be avoided. As a result, accurate prediction is crucial to the effective management of patients at risk for TLS, and it takes into account both disease characteristics (tumor kind and load) and patient factors (baseline renal insufficiency or hyperuricaemia). In low- and intermediate-risk individuals, water and allopurinol are used to prevent TLS, whereas rasburicase is used in high-risk patients.

Tumor Lysis Syndrome in Adults with Hematologic Malignancies

Introduction: Tumor lysis syndrome (TLS) is a metabolic complication commonly seen in patients with hematologic malignancies, particularly high-grade non-Hodgkin lymphomas and acute leukemia. It is characterized by biochemical abnormalities that can lead to cardiac, neurological, and renal complications that can be fatal. The purpose of our study is to describe the epidemiology, laboratory profile and the outcome of TLS in order to identify patients at risk, and to implement appropriate prophylactic measures to prevent the clinical repercussions. Material and Methods: This work is a retrospective study of all patients who developed a laboratory TLS in hematologic malignancies according to the classification of Cairo and Bishop over a period of 3 years (from November 2019 to November 2022), and whose data were collected at the adult hematology unit of the Mohammed VI University Hospital of Tangiers. Results: The incidence of TLS among hematologic malignancies identified during this period was 3.7%. The underlying disease was acute leukemia in 10 patients (55.6%) and high-grade lymphoma in eight patients (44.4%). TLS was spontaneous in fifteen cases (83%) and chemotherapy-induced in three cases (17%). All our patients presented with hyperphosphatemia. 94% of cases had hyperuricemia, 44% of cases had hypocalcemia, while 6% of cases had hyperkalemia. Lactate dehydrogenase levels were elevated in all cases. Treatment consisted of hyperhydration and administration of hypouricemic agents in all cases. Three patients received hemodialysis. The outcome was favorable in 83% of cases and 17% of cases died during follow-up. Conclusion: TLS is a severe complication, most often seen in highly proliferative hematologic malignancies. The role of the laboratory remains paramount in the diagnosis of TLS and in the biological monitoring after the implementation of appropriate therapeutic measures.

Daily serum phosphate increase as early and reliable indicator of kidney injury in children with leukemia and lymphoma developing tumor lysis syndrome.

Tumor lysis syndrome (TLS) and its most serious complication, acute kidney injury (AKI) are one of the emergency conditions in onco-hematology. It is difficult to predict the degree of kidney involvement. Therefore, we studied children with leukemia and lymphoma treated in four Hungarian tertiary centers (inpatient university clinics) retrospectively (2006-2016) from a nephrological aspect. Data of 31 pediatric patients were obtained from electronic- and paper-based medical records. Physical status, laboratory test results, treatments, and outcomes were assessed. Patients were analyzed according to both "traditional" TLS groupings, as laboratory TLS or clinical TLS, and nephrological aspect based on pRIFLE classification, as mild or severe AKI. Significant differences were found between the changes in parameters of phosphate homeostasis and urea levels in both classifications. Compared to age-specific normal phosphate ranges, before the development of TLS, hypophosphatemia was common (19/31 cases), while in the post-TLS period, hyperphosphatemia was observed (26/31 cases) most frequently. The rate of daily change in serum phosphate level was significant in the nephrological subgroups, but peaks of serum phosphate level show only a moderate increase. The calculated cut-off value of daily serum phosphate level increased before AKI was 0.32mmol/L per ROC analysis for severe TLS-AKI. The 24-h urinalysis data of eight patients revealed transiently increased phosphate excretion only in those patients with TLS in whom serum phosphate was elevated in parallel. Daily serum phosphate level increase can serve as a prognostic factor for the severity of pediatric TLS, as well as predict the severity of kidney involvement. A higher resolution version of the Graphical abstract is available as Supplementary information.

Acute kidney injury in bortezomib-treated patients with multiple myeloma.

The nephrotoxicity of bortezomib, a proteasome inhibitor, has not yet been elucidated, although tumor lysis syndrome (TLS) associated with multiple myeloma (MM) has been reported to increase after introduction of the drug. This study compared the incidence and risk factors for acute kidney injury (AKI) and TLS in patients with MM after bortezomib-based chemotherapy to investigate drug-related nephrotoxicity. From 2006 to 2017, 276 patients who underwent a first cycle of bortezomib-based chemotherapy for MM were identified in a single tertiary hospital. Laboratory TLS was defined according to the Cairo-Bishop definition. Development of AKI was assessed by AKI Network criteria within 7 days of the first chemotherapy. The median (interquartile range) age was 65 (56-72) years, and baseline estimated glomerular filtration rate (eGFR) was 61.3 (34.1-89.1) mL/min/1.73 m2. The incidences of AKI and laboratory TLS were 17% (n=47) and 13% (n=36), respectively. Ten (3.6%) subjects met both AKI and TLS criteria. Multivariate analyses showed that lower eGFR category [30-59, odds ratio (OR) 3.005 (95% confidence interval 1.163-7.976); 15-29, OR 4.225 (1.183-15.000); <15, OR 16.154 (3.831-70.920) vs ≥60, P<.001], lower serum albumin level [per 1 increase, OR 0.479 (0.256-0.871), P=.018], renal amyloidosis [OR 13.039 (4.108-44.041), P<.001] and use of acyclovir during bortezomib treatment [OR 3.689 (1.133-14.469), P=.042] were predictors of AKI. MM stages and β-2-microglobulin were not associated with increased risk of AKI. Regarding laboratory TLS, MM stage and β-2-microglobulin were higher in those with TLS than in others. In multivariate analyses, β-2-microglobulin level [OR 1.204 (1.005-1.461), P=.038] and absence of high-risk chromosome abnormalities [OR 0.143 (0.022-0.588), P=.016] were associated with higher risk of TLS. Development of AKI was often observed in the absence of TLS in patients with MM after treatment with bortezomib. In addition, the risk factors for AKI and TLS varied widely. These findings indicate the potential nephrotoxicity of bortezomib irrespective of TLS in patients with decreased kidney function.

A Retrospective Single-Center Study of Sevelamer Hydrochloride for the Treatment of Hyperphosphatemia in Children With Tumor Lysis Syndrome.

Introduction Tumor lysis syndrome (TLS) is a life-threatening metabolic abnormality. The incidence of TLS depends on the underlying malignancy. In a recent analysis of hematological malignancy, the incidence of clinical TLS in children was 3.8%, laboratory TLS 46.2%, and hyperphosphatemia 32.7%. Sevelamer is effective for the treatment of hyperphosphatemia associated with renal failure; however,there is no clear data that it has the same effect in treating hyperphosphatemiawith TLS. Methods This was a retrospective study among children aged ≤14 years with hematological malignancy who developed TLS and received sevelamer to treat hyperphosphatemia at Princess Norah Oncology Center, King Abdulaziz Medical City (KAMC) in Jeddah from January 2012 to December 2016. Results A total of 34 patients received sevelamer. The majority was male (64%), with a median age of six years. The median sevelamer dose per day was 1600 mg, while the median duration of use was two days. Phosphate level was significantly decreased at different times(24 hours, 48 hours, and 72 hours) during sevelamer usage, p-value <0.001. Conclusion In our study, the use of sevelamer resulted in a significant decrease in phosphate levels. This finding further consolidates the efficacy of sevelamer in treating hyperphosphatemia with TLS. However, further research into the drug's kinetics is recommended.

Repeated photodynamic therapy mediates the abscopal effect through multiple innate and adaptive immune responses with and without immune checkpoint therapy

In combination with immune checkpoint inhibitors, photodynamic therapy can induce robust immune responses capable of preventing local tumor recurrence and delaying the growth of distant, untreated disease (ie. the abscopal effect). Previously, we found that repeated photodynamic therapy (R-PDT) using porphyrin lipoprotein (PLP) as a photosensitizer, without the addition of an immune checkpoint inhibitor, can induce the abscopal effect. To understand why PLP mediated R-PDT alone can induce the abscopal effect, and how the addition of an immune checkpoint inhibitor can further strengthen the abscopal effect, we investigated the broader immune mechanisms facilitated by R-PDT and combination R-PDT + anti-PD-1 monoclonal antibody (αPD-1) in a highly aggressive, subcutaneous AE17-OVA mesothelioma dual tumor-bearing C57BL/6 mice.We found a 46.64-fold and 61.33-fold increase in interleukin-6 (IL-6) after R-PDT and combination R-PDT + αPD-1 relative to PBS respectively, suggesting broad innate immune activation. There was a greater propensity for antigen presentation in the spleen and distal, non-irradiated tumor draining lymph nodes, as dendritic cells and macrophages had increased expression of MHC class II, CD80, and CD86, after R-PDT and combination R-PDT + αPD-1. Concurrently, there was a shift in the proportions of CD4+ T cell subsets in the spleen, and an increase in the frequency of CD8+ T cells in the distal, non-irradiated tumor draining lymph nodes. While R-PDT had an acceptable safety profile, combination R-PDT + αPD-1 induced 1.26-fold higher serum potassium and 1.33-fold phosphorus, suggestive of mild laboratory tumor lysis syndrome. Histology revealed an absence of gross inflammation in critical organs after R-PDT and combination R-PDT + αPD-1 relative to PBS-treated mice. Taken together, our findings shed light on how the abscopal effect can be induced by PDT and strengthened by combination R-PDT + αPD-1, and suggests minimal toxicities after R-PDT.

A Phase 1 Study with the Novel B-Cell Lymphoma 2 (Bcl-2) Inhibitor Bgb-11417 As Monotherapy or in Combination with Zanubrutinib (ZANU) in Patients (Pts) with CLL/SLL: Preliminary Data

Background/introduction: The effectiveness of Bcl-2 inhibitors as a treatment for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was established by the approval of venetoclax in pts with CLL/SLL across all lines of therapy. However, the related adverse events (AEs) and emergence of BCL2 mutations, resulting in resistance, can limit the utility of venetoclax. BGB-11417 is a highly selective Bcl-2 inhibitor with potency >10 times that of venetoclax in biochemical assays. BGB-11417 monotherapy is tolerable, with no maximum tolerated dose (MTD) reached after dose escalation through all planned doses to 640 mg once daily (QD) in pts with non-Hodgkin lymphoma (EHA 2022. Abstract P687). The combination of Bcl-2 and Bruton tyrosine kinase (BTK) inhibitors is tolerable with synergistic activity in CLL and mantle cell lymphoma (MCL) (J Clin Oncol 2019;37:2722-9; N Engl J Med 2019;380:2095-103; EHA 2020. Abstract S158; N Engl J Med 2018;378:1211-23). ZANU, a next-generation BTK inhibitor, has shown favorable activity and safety in pts with CLL/SLL (EHA 2021. Abstract LB1900) and Waldenström macroglobulinemia (Blood. 2020;136(18):2038-2050). BGB-11417-101 is an ongoing first-in-human phase 1/1b dose-escalation/expansion study (NCT04277637). Pts with various B-cell malignancies were enrolled; data from CLL/SLL cohorts are presented here. Methods: In separate monotherapy and combination therapy cohorts, pts received escalating doses of BGB-11417 (40, 80, 160, 320, or 640 mg QD) with a ramp-up to the intended target dose to minimize risk of tumor lysis syndrome (TLS). In combination therapy cohorts, pts received ZANU (320 mg QD or 160 mg twice daily) beginning 8-12 weeks before BGB-11417. Dose-limiting toxicity for each cohort was evaluated by a Bayesian logistic regression model during dose ramp-up through day 21 at the intended dose. AEs were reported per Common Terminology Criteria for AEs v5.0. Minimal residual disease (MRD) was assessed by a European Research Initiative on CLL flow cytometry assay. Results: As of May 15 2022, 50 pts with CLL received treatment: 6 monotherapy (all relapsed/refractory [R/R]) and 44 combination (22 R/R; 22 treatment naïve [TN]). The monotherapy CLL cohort received BGB-11417 doses up to 160 mg. Based on emerging safety data from other cohorts, pts in combination cohorts with R/R CLL received BGB-11417 up to 640 mg and pts with TN CLL received up to 320 mg (data include 8 pts in ZANU pretreatment not yet dosed with BGB-11417). MTD has not yet been reached for any CLL cohort, with dose escalation ongoing. Median follow-up was 11.5 mo (range 8.5-18.3) for monotherapy and 5.8 mo (range 0.2-10.5) for combination. Treatment-emergent AEs (TEAEs) across all doses are listed in the Table. With monotherapy, cytopenias were the most common TEAEs (≥50%), with 33% grade ≥3. With combination, contusion, neutropenia, and low-grade gastrointestinal toxicity were the most common TEAEs (≥22.7%); neutropenia was the most common grade ≥3 TEAE (11.4%) with 5 pts. No pts discontinued monotherapy treatment, and 1 pt discontinued combination treatment (disease progression; Richter transformation). Only 1 high-risk pt with CLL on monotherapy had laboratory TLS that resolved with no intervention (overall laboratory TLS ≤2%). No clinical TLS was reported. Diarrhea was mostly grade 1 and grade ≥3 was not seen. Although efficacy data are early, most pts with CLL/SLL had notable reductions in absolute lymphocyte count (ALC) with responses seen at doses as low as 1 mg (Figure), consistent with improved potency of BGB-11417 vs venetoclax. Four responses (66%, partial response [PR] or better) and 32 responses (72.7%, PR with lymphocytosis or better) were observed with mono- and combination therapy, respectively. MRD data are early: among 4 MRD evaluable pts at 160 mg, 3 pts (2 monotherapy; 1 combination) had a peripheral blood CLL count <10-4 at 24 weeks after BGB-11417 initiation. Conclusion: These preliminary data show BGB-11417, alone or in combination with ZANU, was well-tolerated in most patients. Grade ≥3 neutropenia was uncommon and manageable. Efficacy is supported by the rapid reduction in ALC during ramp-up, and early response data are promising. TLS rates are low; the prophylactic measures and ramp-up schedule seem to adequately mitigate TLS across all dose levels tested. Mature MRD data are forthcoming, and venetoclax-treated CLL/SLL cohorts will soon be open for enrollment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal