Novel BCL-2 Inhibitor Lisaftoclax in Relapsed or Refractory Chronic Lymphocytic Leukemia and Other Hematologic Malignancies: First-in-Human Open-Label Trial

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in western societies, accounting for approximately 7% of non–Hodgkin lymphoma (NHL) cases, 5,000 deaths, and 15,000 newly diagnosed U.S. cases annually (1, 2). Despite recent treatment advances, many patients experience relapse on chemoimmunotherapy.

B-cell lymphoma 2 (BCL-2) is overexpressed in most cases of CLL and plays an important role in its pathogenesis, tumorigenicity, and aggressiveness. The BCL-2 protein (one of the antiapoptotic members of the BCL-2 family) controls apoptosis, and its dysregulation promotes tumor cell survival. Small-molecule inhibitors of BCL-2 can enhance cancer cell apoptosis across many hematologic malignancies (HMs; refs. 3–8).

Structural insights into interactions between proapoptotic and antiapoptotic proteins culminated in the discovery and clinical development of the first BCL-2 homology domain 3 (BH3) mimetic: navitoclax (ABT-263; refs. 9,10). Despite clinical efficacy in advanced cancer, high-grade thrombocytopenia driven by on-target BCL–extra-large (BCL-xL)–mediated platelet inhibition impeded its development (10, 11). Subsequently, venetoclax (BH3-mimetic ABT-199; refs. 12, 13) became the first FDA-approved BCL-2‒selective small-molecule inhibitor (12–16), although hematologic toxicities and tumor lysis syndrome (TLS) remain its clinical challenges.

To address these issues, we have designed lisaftoclax as a novel molecule, with a potent BCL-2 inhibitory and unique pharmacokinetic profile, to enhance efficacy and minimize toxicities. The aim of this first-in-human phase I study was to investigate lisaftoclax in patients with relapsed or refractory HMs.

This phase I multicenter open-label, nonrandomized study investigated the safety, efficacy, and pharmacologic (pharmacokinetic and pharmacodynamic) profiles of lisaftoclax in patients with HMs that are refractory, relapsed, or intolerant or ineligible to therapies with known clinical benefits. Conduct of the trial was consistent with the Declaration of Helsinki, including patient written informed consent and Institutional/Ethical Board Reviews.

Eligible patients were ≥ 18 years of age and had a histologically confirmed diagnosis of a B-cell HM, including CLL, NHL, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large BCL (DLBCL), follicular lymphoma, Waldenström macroglobulinemia, and multiple myeloma. The malignancies were relapsed, refractory or intolerant to, or considered ineligible for therapies that are known to provide clinical benefit, and the patients were required to have adequate function of major organs. Exclusion criteria included previous allogeneic stem-cell transplantation within 1 year, active infection, active central nervous system involvement, and gastrointestinal conditions that could affect the absorption of the study drug. A summary of the representativeness of study participants is outlined in Supplementary Table S1.

For each treatment cycle, lisaftoclax was administered orally once daily for 28 consecutive days. Dose escalation commenced in single-patient cohorts to minimize exposure to subtherapeutic doses and allow for intrapatient dose escalation. Blinding was not used in the study. Disease assessments were performed at baseline, then every two cycles during the first year, followed by every three cycles thereafter.

In TLS intermediate/high-risk groups, defined according to criteria outlined by an expert TLS panel (17), the daily dose ramp-up was initiated at 20 mg on day 1 (D1), followed by 50 mg on D2, 100 mg on D3, 200 mg on D4, and 400 mg on D5 (for the target dose of 400 mg, D5 was also cycle 1 day 1; C1D1). All patients were hospitalized and monitored closely for TLS during the dose ramp-up period. To mitigate the risk of TLS, standard prophylaxis with oral antihyperuricemic agents (rasburicase recommended) and oral hydration was instituted ≥ 72 hours before the first dose, along with intravenous hydration during hospitalization.

For pharmacokinetic analyses, blood samples were collected before lisaftoclax dosing and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours on C1D1 and C1D28. For pharmacodynamic analyses, specimens from patients with CLL/SLL were collected, analyzed, and subjected to BH3 profiling as described previously (18–22).

The primary objective comprised safety assessments including maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included pharmacokinetic characteristics, such as maximum concentration (C_max), systemic exposure (area under the concentration–time curve; AUC) over 28 days, and antitumor effects.

Objective disease assessments, including disease-specific scans, bone marrow biopsy/aspirate, and other appropriate hematologic and biochemical laboratory results, were performed at baseline, and then every 8 weeks beginning at odd cycles (cycles 3, 5, 7, etc.). Minimal residual disease (MRD) was evaluated in patients achieving complete response (CR; ≥ 6 weeks after first achievement of MRD), and then MRD was also assessed every 12 weeks in peripheral blood until achievement of MRD negativity; once MRD negativity was achieved in peripheral blood, MRD assessment was conducted in bone marrow.

This was an open-label, nonrandomized study. Statistical analyses were descriptive, including means, SD, medians, and ranges for continuous variables and frequency counts and percentages for categorical variables. Sex was not included as a biological variable, and attrition rates were not analyzed. Objective response rates (ORR) with 95% confidence interval (CI) values were also calculated. Sample size was not based on formal statistical calculation as there was no formal hypothesis testing. Missing data were not imputed, and all safety analyses were based on the safety population, which was defined as all patients who received ≥ 1 dose of lisaftoclax.

All data associated with this study, including the trial protocol, are present in the article or Supplementary Data. The authors agree to make additional data supporting the results or analyses presented in their article available from the corresponding authors (Y. Zhai and A. Chanan-Khan) upon reasonable request.

As of this study data cutoff date (October 22, 2022), a total of 52 patients were enrolled, and the dose escalation phase was complete. Lisaftoclax was administered orally once a day at doses ranging from 20 mg to 1,200 mg. The median age of the 52 patients enrolled was 68 (range, 39–89) years, and 36 (69.2%) of these individuals were male. Of the 52 patients, 17 (32.7%) remained on treatment and 35 discontinued (n = 23, because of progressive disease; n = 5 each because of physician decision or withdrawal by patient, mainly due to lack of response and switched to other therapies; Supplementary Fig. S1). Patients received a median 7 (range, 1–43) cycles, including 23 (44.2%) with CLL/SLL and 11 (21.2%) with multiple myeloma (Table 1).

Among the 23 patients with CLL/SLL who met the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria for treatment at entry, the mean age was 67 (range, 48–83) and median number of previous treatments 2 (range, 1–3; Table 2). Most patients (n = 17; 73.9%) had intermediate-, high-, or very high-risk disease per the International Prognostic Index and/or adverse prognostic features (n = 21; 91.3%), including unmutated IgVH (n = 10; 43.5%). Prior treatments included anti-CD20 antibody, fludarabine/chemotherapy, and Bruton tyrosine kinase (BTK) inhibitors (BTKis) (Table 2). All patients had experienced disease relapse after 1 or 2 standard-of-care regimens.

Lisaftoclax was well tolerated, with no DLTs at doses of up to 1,200 mg. MTD was not reached. Among lisaftoclax recipients (n = 52) at the time of data cutoff, treatment-emergent neutropenia was observed in 14 (26.9%) with grade ≥ 3 neutropenia in 11 (21.2%); diarrhea in 25 (48.1%); fatigue in 18 (34.6%); nausea in 16 (30.8%); anemia or thrombocytopenia in 15 (28.8% each); constipation in 13 (25.0%); vomiting in 12 (23.1%); headache in 11 (21.2%); peripheral edema or hypokalemia in 9 (17.3% each); and arthralgia in 8 patients (15.4%; Table 3). None of these adverse events led to treatment discontinuation. Among the 23 patients with CLL/SLL in the safety population, 6 (26.1%) had grade 3 or 4 treatment-emergent neutropenia; 3 (13.0%) had increased lipase; and 2 (8.7% each) had thrombocytopenia, pneumonia, and colitis.

Three patients experienced grade 3 or 4 treatment-related hematologic toxicities. One patient receiving lisaftoclax 400 mg experienced grade 3 neutropenia in C1, which led to dose interruption. The absolute neutrophil count recovered to 1.15 × 10⁹/L (10³/μL) after the lisaftoclax dose was held for 8 days (without other interventions), and subsequent treatment (C2 onward) with lisaftoclax was well tolerated. The other patient with CLL who received lisaftoclax 1,200 mg experienced grade 3 neutropenia without dose interruption or growth factor support. Neutrophil count remained stable, and the patient continued through C10. One patient treated with lisaftoclax 1,200 mg had grade 4 treatment-related thrombocytopenia, which led to dose interruption in C6. After the dose was held for 14 days during a splenectomy procedure, the platelet count recovered to 5.9 × 10¹⁰/L, and lisaftoclax 1,200 mg was restarted. One week later, treatment-related grade 4 thrombocytopenia recurred and led to treatment discontinuation during C7. The recommended phase II dose of lisaftoclax monotherapy for patients with CLL/SLL was 600 mg.

There was no evidence of clinical or laboratory TLS with lisaftoclax, even though 74% of the patients were in the TLS intermediate-, high, or very high-risk categories and 85% of the patients were treated at dose levels ranging from 600 to 1,200 mg. One case of grade 1 hyperuricemia was reported in a patient with CLL but recovered with standard TLS prophylaxis. To assess the effects of lisaftoclax on patients at elevated risk of TLS, we evaluated 5 individuals with CLL (CLL-007, CLL-008, CLL-017, CLL-026, and CLL-036) who were treated at respective lisaftoclax doses of 400, 400, 800, 1,000, and 600 mg, and whose baseline mean absolute lymphocyte count (ALC) was > 2.5 × 10⁴/μL. The highest ALC was 104.53 × 10⁹/L (in subject CLL-008). Biochemical changes occurred in certain TLS markers after the first dose of lisaftoclax (as low as 20 mg), but they resolved within 24 hours. On the basis of prespecified criteria, none of these isolated biochemical changes led to a diagnosis of TLS. Detailed TLS marker curves of these 5 patients are shown in Supplementary Fig. S2.

A total of 14 of 22 evaluable patients with CLL/SLL had a partial response (PR) per 2008 iwCLL criteria (23) over a median of 15 (range, 6–43) treatment cycles, for an ORR of 63.6% (95% CI = 41%–83%; Fig. 1). The median time to response was 2 (range, 2–8) cycles. Patients with adverse prognostic features (as noted below) experienced PRs: 66.7% (2/3) with del(17p)/TP53 mutation; 55.6% (5/9) with del(13q); and 80.0% (8/10) with unmutated IgVH. No patients had prior venetoclax treatment, and 10 patients were previously treated with BTKis. Among 4 patients who relapsed to prior BTKi, 1 patient achieved PR after two cycles of treatment with lisaftoclax. In patients with BTKi-intolerant disease, the ORR was 80.0% (4/5 evaluable patients). In the responders, only one patient who achieved PR in C9 progressed in C31, while others maintained their responses by the cutoff date. Among 28 evaluable patients without CLL/SLL, clinical benefit was observed in 14 (50.0%). One patient with multiple myeloma achieved PR, and another carrying t(11;14) exhibited minimal response, after two cycles of treatment. One patient with Waldenström macroglobulinemia exhibited minimal response after 18 cycles. Nineteen patients [8 CLL, 3 each Waldenström macroglobulinemia and follicular lymphoma, 2 multiple myeloma, and 1 each hairy cell leukemia (HCL), Castleman disease, and DLBCL] had stable disease as the best response (Table 4; Fig. 1). No patient experienced a CR.

Rapid reductions in nodal and/or splenic size after lisaftoclax treatment were observed in patients with CLL/SLL (Supplementary Fig. S3). A total of 9 (42.9%) of 21 patients experienced ≥ 70% reductions. A total of 12 patients experienced lymph node shrinkage and a PR after two to eight treatment cycles (Supplementary Fig. S3).

Among 23 patients with CLL/SLL, ALC values decreased markedly after initiation of lisaftoclax treatment. This decrease was noted as early as during the dose ramp-up period (mean decrease 69.4% from ramp-up D1 to C1D1) and was 92.8% at completion of the first cycle (from ramp-up day 1 to C2D1; Supplementary Fig. S4A). Notably, 5 patients at respective doses of 400, 400, 800, 1,000, and 600 mg had a higher risk of TLS at screening (with ALC > 2.5 × 10⁴/μL) and demonstrated rapid decreases in ALC of 89%, 99%, 97%, 96%, and 99%, without evidence of TLS. The median time to 50% ALC reduction was 3 (range, 2–4) days (Supplementary Fig. S4B and S4C). These data show leukemic cell susceptibility to lisaftoclax not only as early as the first dose but also with the lowest starting dose (20 mg). Representative patient data after treatment with different doses of lisaftoclax are presented in Supplementary Figs. S2 and S5A–S5D.

The pharmacokinetic profile of lisaftoclax and mean concentration versus time profiles from different dose cohorts are displayed alongside a representative profile of patient CLL-008 (Fig. 2A). The pharmacokinetic parameters are summarized in Table 5. After a single dose or multiple doses of orally administered lisaftoclax, the median time to reach maximum plasma concentration ranged from 3 to 8 hours across the dose range. A preliminary dose proportionality assessment showed that plasma exposure (C_max and AUC_0–24) generally increased with ascending doses (Fig. 2B), although there was a high interpatient variability [coefficient of variation (CV) ∼ 72%). Lisaftoclax had a plasma elimination half-life (t_1/2) of approximately 3 to 5 hours and a median time to maximum concentration (t_max) of 3 to 6 hours. No significant accumulation was observed after multiple oral daily dosing, with an accumulation ratio of approximately 1. At 400 mg, the steady-state, mean CV% C_max of lisaftoclax was 981 (43%) ng/mL and the AUC_0–24h 10,130 (40%) ng/h/mL.

On-target pharmacodynamic analysis using BH3 profiling was conducted on bone marrow mononuclear cell (BMMC) or peripheral blood mononuclear cell (PBMC) samples collected from patients with CLL (n = 13) or SLL (n = 1) after lisaftoclax treatment. As an indicator of overall mitochondrial priming (the threshold for a cell to commit to apoptosis; ref. 24), BCL-2–like protein 11 (BIM) peptide triggered cytochrome c release in a dose-dependent manner (Fig. 2C), and this phenomenon was greater in PBMCs than BMMCs (Supplementary Fig. S6A and S6B). There was a transient increase in cytochrome c release in PBMCs collected from C1D1 6 hours after lisaftoclax treatment. However, cytochrome c release gradually decreased in samples collected from C1D2 (24 hours) and C1D15 (predosing) and was markedly decreased after the first cycle (C1D28).

Peptides of BCL-2–associated agonist of cell death (BAD), including MS1, HRK-y, and FS1, are specific interaction partners for BCL-2, myeloid-cell leukemia 1 (MCL-1), BCL-xL, and Bfl-1, respectively. The general pattern of cytochrome c loss triggered by these peptides was similar to that observed with BIM peptide (Fig. 2C; Supplementary Fig. S7A). As expected, BCL-2 was the dominant antideath protein in samples from patients with CLL, in which BAD peptide at 0.05 μmol/L triggered 25% to 50% mitochondrial cytochrome c release compared with other peptides at 5 μmol/L (Fig. 2D; Supplementary Fig. S7A).

Further analysis of samples collected across lisaftoclax dose cohorts showed that cytochrome c release induced by BAD (0.1 μmol/L) and MS1 (10 μmol/L) peptides in PBMC samples collected at baseline and C1D15 (predose) were inversely correlated with time to ALC normalization (Supplementary Fig. S7B–S7D). Cytochrome c release by BIM (0.05 μmol/L) peptide treatment in either baseline or post-lisaftoclax treatment PBMCs did not show such a correlation (Supplementary Fig. S7B–S7D). Key peptide responses in patient samples, together with treatment dose cohorts and best clinical responses for patients, are summarized in Supplementary Table S2.

CLL is recognized to be one of the most BCL-2‒dependent HMs. Our clinical study suggests that lisaftoclax (administered via a daily dose ramp-up schedule) is a novel BH3 mimetic. Clinically, the ability to have an abbreviated ramp-up with lisaftoclax can be a significant advantage in expeditiously achieving therapeutic doses, especially by minimizing and averting the risk of TLS and other dose-limiting adverse drug reactions (e.g., thrombocytopenia, neutropenia). The daily (vs. weekly) ramp-up period with lisaftoclax may also be more convenient (“user friendly”) for patients and potentially reduce burdens on the health care system. Among individuals with R/R CLL or SLL, lisaftoclax treatment was associated with an ORR of 63.6% and rapid reduction in ALC even at the lowest dose evaluated (entry level 20 mg) and as early as the first day of dosing. In patients with CLL/SLL and del(17p), preliminary data showed an ORR of 66.7%

Mechanistically, BCL-2 inhibitors rapidly achieve a mitochondrial threshold that triggers apoptosis; thus, their effects are driven by C_max (5). Lisaftoclax was designed as a potent and efficacious BCL-2 inhibitor with a unique pharmacokinetic profile, including a high C_max and a shorter t_1/2 (3–5 hours) compared with venetoclax (26 hours; ref. 25), resulting in a high C_max but relatively low systemic exposure. Although preliminary, our clinical observations evidently support the intended pharmacologic properties of lisaftoclax, with a limited plasma residence and exposure that are likely responsible for its encouraging safety profile. This includes minimal effects of the BCL-2 inhibitor on the risk of TLS (despite an abbreviated dose ramp-up schedule) and a relatively low overall incidence (as well as rapid recovery) of grade 3 or 4 neutropenia (26.1%; 6/23 evaluable patients with CLL/SLL). Furthermore, in contrast to the dual BCL-2/BCL-xL inhibitor navitoclax, lisaftoclax also did not elicit clinically significant changes in platelet counts. These results support the feasibility and overall safety of implementing a more rapid, daily dose ramp-up protocol currently under evaluation with lisaftoclax.

Compared with a weekly ramp-up schedule of venetoclax, the potential 1-month reduction resulting from the shorter lisaftoclax ramp-up period may minimize potentially treatment-limiting adverse drug reactions, including thrombocytopenia, neutropenia, and TLS. While changes in some isolated TLS biochemical markers were observed, they tended to recover within 24 hours, and none constituted a full TLS. At this writing, no patient with CLL/SLL in this study has experienced TLS, even in the TLS high-risk group and in patients receiving high lisaftoclax doses (e.g., 1,200 mg). This minimal risk of TLS with lisaftoclax may differentiate it from other BCL-2 inhibitors and potentially warrants assessments of further reductions in lisaftoclax ramp-up intervals. Additional research using lisaftoclax in patients with different levels of pretreatment tumor burden and kinetics of ALC reductions are warranted to confirm our findings, as these are pivotal risk factors for TLS (16, 26). By one estimate, the risk of developing TLS increases by 32% (P = 0.02) for each decrease of 10 × 10³/μL in ALC (26).

These data are consistent with the clinical observation of rapid reductions in ALC among most patients with CLL/SLL treated with lisaftoclax, indicating that the antileukemic activity of lisaftoclax depends on BCL-2 priming and on-target disruption of BCL-2 complex, a C_max-dependent phenomenon. In lisaftoclax-treated PBMCs, the correlation of BCL-2 complex changes (indicated by BAD peptide response) with the time to ALC normalization seems to be confounded by the ramp-up duration and variation among different lisaftoclax doses (e.g., 4 to 8 days for the 400 to 1,200 mg cohort). At baseline, both BIM and BAD peptide responses were lower in BMMCs (Supplementary Fig. S6A and S6B) than PBMCs, indicating that BMMCs have a higher mitochondrial apoptosis threshold (probably because of the protective microenvironment in bone marrow), clinically correlating with peripheral blood clearing of leukemic cells before those in bone marrow. Cytochrome c release, however, did not show a relationship with lisaftoclax dose. These findings extend and reinforce preclinical observations, including rapid entry into tumor cells, on-target engagement, disruption of BCL-2 complexes, and BAX/BAK-dependent caspase-mediated apoptosis (27).

While recognizing the preliminary nature of our observations, we report an overall encouraging safety profile of lisaftoclax, which may be relevant to the care of patients with CLL who are often elderly and thus more susceptible to cytopenias and effects of TLS than their younger counterparts (28).

Treatment-emergent adverse events occurring in > 15% of patients included neutropenia, thrombocytopenia, and anemia (hematologic; Table 3), as well as diarrhea, fatigue, nausea, constipation, vomiting, headache, peripheral edema, hypokalemia, and arthralgia (nonhematologic; Table 3). Of 23 patients with CLL/SLL, only 6 (26.1%) had treatment-related neutropenia. The neutrophil count recovered rapidly and was stably maintained without granulocyte colony-stimulating factor (G-CSF) support. In contrast, 36% to 41% of patients (∼75% of patients with grade 3/4 neutropenia) treated with venetoclax may require G-CSF support or dose reductions (16, 29, 30). In addition, neutropenic sequelae, such as fever and infection, were not observed with lisaftoclax, as compared with 72% of venetoclax recipients experiencing infection (29). In contrast, neutropenia was the leading adverse event causing venetoclax dose adjustments in early-phase trials (28). Recent real-world evidence studies offer further support for the health care burden of early, potentially treatment-limiting adverse events with venetoclax (31, 32). These include any grade neutropenia in up to 47% of venetoclax recipients; thrombocytopenia in up to 36%; diarrhea in up to 18%; grade ≥ 3 neutropenic fever in up to 13%; and TLS in up to 13.4% (31, 32).

Our observations on lisaftoclax have been further validated in studies involving larger and more diverse patient populations with longer follow-up periods. Encouraging results in patients with CLL have prompted us to initiate focused clinical trials in which we are evaluating the combination of lisaftoclax with the BTK-inhibitor acalabrutinib or the anti-CD20 mAb rituximab in patients with R/R CLL/SLL (NCT04215809). Multiple ongoing studies are assessing additional efficacy endpoints such as CR rate, PFS and MRD, and safety profiles in other HMs.

In conclusion, BCL-2 inhibitor lisaftoclax is a potentially safe, well tolerated, and efficacious treatment for patients with R/R CLL/SLL and other HMs, supporting its further clinical development.

S. Ailawadhi reports grants and other support from GSK, Sanofi, BMS, Janssen, and Cellectar; other support from Takeda, BeiGene, Regeneron, and Pfizer; and grants from Amgen, Pharmacyclics, Abbvie, and Ascentage outside the submitted work. Z. Chen reports other support from stock options outside the submitted work; in addition, Z. Chen is also an employee of Ascentage. B. Huang reports other support from Ascentage outside the submitted work. A. Paulus reports grants from Ascentage Pharma during the conduct of the study. M.S. Davids reports grants and personal fees from Genentech, AstraZeneca, Merck, MEI Pharma, Novartis, and Ascentage Pharma during the conduct of the study; and grants from Surface Oncology and personal fees from AbbVie, BMS, BeiGene, Genmab, Janssen, TG Therapeutics, Eli Lilly, Adaptive Biosciences, Mingsight, Ono Pharmaceuticals, and Takeda outside the submitted work. C.K. Yannakou reports other support from Ascentage Pharma during the conduct of the study. D. Yang reports grants from Ascentage Pharma Group Corp Ltd (Hong Kong), Major Innovation Team of Soochow (ZXT2018004), International Science & Technology Cooperation Program of Jiangsu Province (BZ2017035), Daniel Foundation of Alabama, Predolin Foundation, Mayo Clinic Cancer Center, and Mayo Clinic Multiple Myeloma Specialized Program of Research Excellence (SPORE P50) during the conduct of the study and personal fees from Ascentage Pharma Group and other support from Ascentage Pharma Group International (HK:6855) outside the submitted work. A. Chanan-Khan reports grants, personal fees, and other support from Ascentage during the conduct of the study; and speaking engagements relevant to Ascentage. Y. Zhai reports grants and personal fees from Ascentage Pharma Group Corp Ltd (Hong Kong); grants from International Science & Technology Cooperation Program of Jiangsu Province (BZ2017035), Major Innovation Team of Soochow (ZXT2018004), Daniel Foundation of Alabama, and Mayo Clinic Multiple Myeloma Specialized Program of Research Excellence (SPORE P50) during the conduct of the study; in addition, Y. Zhai is chief medical officer at Ascentage Pharma Group International, Ascentage Pharma Group Corp Limited, and Ascentage Pharma Group Inc and has stock options in Ascentage Pharma Group International (HK:6855). No disclosures were reported by the other authors.

S. Ailawadhi: Resources, data curation, formal analysis, supervision, funding acquisition, validation, investigation, writing–original draft, collection and assembly of data; provision of study materials, patients, and patient care: provided patient care; data analysis and interpretation; manuscript writing. Z. Chen: Resources, formal analysis, supervision, validation, investigation, writing–original draft, project administration, collection and assembly of data; provision of study materials, patients, and patient care: participated in lisaftoclax phase I clinical trial patient care, data management, and/or the pharmacodynamic study; data analysis and interpretation. B. Huang: Data curation, formal analysis, supervision, methodology, writing–original draft, collection and assembly of data; provision of study materials, patients, and patient care: participated in lisaftoclax phase I clinical trial patient care, data management, and/or the pharmacodynamic study; data analysis and interpretation; manuscript writing. A. Paulus: Data curation, formal analysis, writing–original draft, collection and assembly of data; data analysis and interpretation; manuscript writing. M.C. Collins: Data curation, investigation, methodology, writing–review and editing. L. Fu: Data curation, formal analysis, validation, methodology, writing–review and editing. M. Li: Formal analysis, validation, methodology, writing–review and editing. M. Ahmad: Data curation, formal analysis, investigation, writing–review and editing. L. Men: Formal analysis, validation, methodology, and writing–original draft. H. Wang: Formal analysis, validation, methodology, and writing–original draft. M.S. Davids: Data curation, formal analysis, supervision, investigation, methodology, and writing–original draft. E. Liang: Data curation, supervision, validation, methodology, and writing–original draft. D.J. Mekala: Data curation. Z. He: Supervision, investigation, writing–original draft, and project administration. M. Lasica: Resources, data curation, supervision, investigation, and writing–original draft. C.K. Yannakou: Resources, data curation, supervision, investigation, and writing–original draft. R. Parrondo: Data curation, investigation, writing–review and editing. L. Glass: Investigation, methodology, project administration, writing–review and editing. D. Yang: Conceptualization, resources, supervision, investigation, writing–original draft, and project administration. A. Chanan-Khan: Resources, data curation, formal analysis, supervision, funding acquisition, investigation, methodology, and writing–original draft. Y. Zhai: Conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, investigation, writing–original draft, and project administration. All authors: final approval of manuscript; accountable for all aspects of manuscript.

This study and its report were supported by Ascentage Pharma Group Corp Ltd as well as grants from the Major Innovation Team of Soochow (ZXT2018004) and International Science & Technology Cooperation Program of Jiangsu Province (BZ2017035), China. Experiments and analyses conducted in the Mayo Clinic were supported in part by the Daniel Foundation of Alabama, the Predolin Foundation, the Mayo Clinic Cancer Center, and the Mayo Clinic Multiple Myeloma Specialized Program of Research Excellence (SPORE P50). We wish to thank the patients and families for their participation in this trial. We thank R. Pop for her contributions in acquiring, managing, and analyzing patient data in the Mayo Clinic. We also recognize the Ascentage CMC and Analytic Center for providing lisaftoclax. Ashutosh K. Pathak, MD, PhD, MBA, FRCP (Edin.), Stephen W. Gutkin, Ndiya Ogba, PhD, and Paul O. Fletcher, PhD with Ascentage Pharma as well as Jing Deng, PhD (formerly with Ascentage Pharma), provided further input in manuscript research and preparation.

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