Olutasidenib in post-venetoclax patients with mutant isocitrate dehydrogenase 1 (mIDH1) acute myeloid leukemia (AML)

Abstract

Olutasidenib, a potent, selective, oral, mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, is FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML). Here we report efficacy and safety of olutasidenib in 18 patients with mIDH1 AML who were relapsed (10), refractory (6) or had complete remission with incomplete hematologic recovery (CRi; 2) to a venetoclax combination. Of the 16 patients who were R/R, 4 (25%) achieved complete remission (CR), one (6.3%) achieved CR with partial hematologic recovery (CRh), and 7 (43.8%) achieved a composite complete remission (CRc). Median time to CRc was 1.9 months (range 1–2.8). As of data cutoff (18 June 2021), median duration of CRc was not reached (range, 1.2-NR, ongoing at 30.4+ months). Both patients with CRi at study entry achieved a CR. Safety was consistent with the overall profile of olutasidenib. Olutasidenib offers a valuable treatment option for patients with mIDH1 AML previously treated with venetoclax.

Keywords:

• Olutasidenib
• acute myeloid leukemia
• IDH1 mutation

Introduction

Venetoclax, a BCL-2 inhibitor, in combination with a hypomethylating agent (HMA) is standard treatment for patients ≥60 years old with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy due to age, poor performance status, or comorbidities [1–3]. While composite complete response (CRc) rates with first-line venetoclax-based regimens were 66.4% in the VIALE-A study [4] and 67% in patients with mutated isocitrate dehydrogenase 1 (mIDH1) AML [5], most patients eventually relapse or are refractory (R/R) to treatment, including those with mIDH1 [6,7]. Patients with mIDH1/2 AML who are R/R to a venetoclax-based regimen have a poor prognosis, and few such patients (14%) receive additional systemic therapy, resulting in a median overall survival (OS) of 2.4 months [7,8]. Eight patients with mIDH1 AML who were treated with IDH1 inhibitors (ivosidenib or olutasidenib) after venetoclax-based therapy have been reported in two case series [8,9]; only two patients responded, one complete remission (CR) with ivosidenib and one patient with stable disease (SD) with olutasidenib [8]. Given the efficacy of venetoclax-based therapy, and the potential utility regardless of mutation status, many patients with mIDH AML receive a venetoclax-based regimen as initial therapy. It is thus important to better understand the efficacy of IDH1 inhibitors in patients who relapse after venetoclax-based therapy.

Olutasidenib is a potent, selective, oral, small-molecule inhibitor of mIDH1 [10–14]. Olutasidenib is FDA approved for the treatment of R/R AML based on the registrational cohort (n = 153) of the Phase 2 trial, which demonstrated a rate of CR or CR with partial hematologic recovery (CRh) of 35%, with a median duration of response of 25.9 months [12,13]. In a subset of 12 patients previously treated with venetoclax, the CR + CRh rate was 33% (n = 4), the CR rate was 25% (n = 3), and the overall response rate was 50% (n = 6) [12]. Herein, we elaborate on the efficacy and safety of olutasidenib from the registrational cohort, and 6 additional patients from the Phase 2 trial who had mIDH1 AML and were R/R or had an incomplete response following venetoclax-based therapy.

Methods

This ongoing, Phase 2, open-label, non-randomized, non-blinded, multi-cohort, multicenter study (NCT02719574) of olutasidenib enrolled male and female patients aged ≥18 years harboring mIDH1^R132 with pathologically proven AML [12]. Central confirmation of mutation status was performed using pretreatment peripheral blood and/or bone marrow aspirate samples. Other key inclusion criteria included Eastern Cooperative Oncology Group (ECOG) performance status 0–2, adequate liver and renal function, baseline corrected QT interval by Fridericia (QTcF) of ≤450 msec, negative serum pregnancy test if a woman of childbearing potential, and agreement to use highly effective contraception during the study and for 90 days after the last dose of study drug. Exclusion criteria included symptomatic CNS leukemia, uncontrolled infections or metabolic disorders, clinically significant heart disease or other serious nonmalignant disease (e.g. hydronephrosis, liver failure, or other conditions) that could compromise the study objectives.

This analysis included the subset of adults from four cohorts of the Phase 2 study who were either R/R to a venetoclax-based regimen with a treatment goal of CRc (CR, CRh or CR with incomplete hematologic recovery [CRi]) or had a CRi to a venetoclax-based regimen with a treatment goal of CR or CRh. These patients had been enrolled at 11 clinical sites in 5 countries (Australia, Canada, France, Spain and USA).

Patients received olutasidenib 150 mg BID administered orally in continuous 28-day cycles as monotherapy (n = 16) or in combination with azacitidine (n = 2), which was administered subcutaneously or intravenously daily for 7 days on, 21 days off.

The primary endpoint was a best response of CR or CRh in 3 cohorts (n = 16) and event-free survival (EFS) in the maintenance cohort (n = 2). For this subset analysis, descriptive statistics are provided for modified response criteria of the International Working Group in AML of 2003. The response in patients from the maintenance cohort had to show improvement over their baseline status in order to be counted as a response (e.g. from Cri to CRh or CR). CRh was defined as bone marrow blasts <5% with absolute neutrophil count >0.5 × 10⁹/L and platelet count >50 × 10⁹/L. Secondary endpoints included time to response, duration of response, OS, transfusion independence (TI), and treatment emergent adverse events (TEAE). Duration of Response (DOR) was calculated using Kaplan-Meier (KM) methods from the time of first response until death, relapse, or new anti-cancer therapy; patients without an event were censored at their last response assessment. Patients who discontinued treatment for reasons other than disease progression, disease relapse, or withdrawal of consent were followed for response until progression or relapse occurred. Patients were classified as ‘transfusion dependent’ if platelet and/or red blood cell (RBC) transfusion occurred within 8 weeks prior to baseline and were transfusion independent if no platelet and/or RBC transfusions had occurred for at least 56 days during treatment. TEAEs were recorded from the time of first dose until 28 days after the last dose of study drug. TEAEs were coded using MedDRA version 19.1 and graded via the NCI-CTCAE version 4.03. Data cutoff date was 18 June 2021. This was a subgroup analysis and formal statistical tests were not run; thus, a formal power calculation was not required.

This study was conducted following the Declaration of Helsinki and good clinical practice guidelines. The protocol was approved by the institutional review boards or local ethics committees at participating study sites. Written informed consent was provided by all patients prior to screening and enrollment.

Results

Patients

Eighteen patients who were relapsed (10), refractory (6) or had CRi (2) to a venetoclax-based regimen were included in this analysis. Twelve of these patients were from the pivotal cohort (n = 153) and briefly described in that publication [12], and an additional six patients from the Phase 2 trial were included. At the data cutoff date, five patients (27.8%) continued olutasidenib, and 13 (72.3%) patients discontinued treatment due to progressive disease (PD, 6), adverse events (5), or patient’s decision (2).

The median age was 73 years (range, 65–83) and 77.8% were male. Demographics and disease characteristics are summarized in Table 1. Cytogenetic risk category was intermediate or poor in 88.9% of patients. Disease characteristics, prior therapies, mutations, and response to olutasidenib are shown in an oncoprint in Figure 1. In addition to venetoclax, prior therapies included hypomethylating agents in 14 patients, ivosidenib in 2, and olutasidenib in 2; none of the patients had a prior hematopoietic stem cell transplant (HSCT).

Figure 1. Oncoprint showing disease characteristics, prior therapies and mutations in 18 patients treated with olutasidenib post-venetoclax. Molecular testing was performed at the start of olutasidenib therapy. †Patients 15 and 16 received a combination of olutasidenib plus azacitidine after having received olutasidenib monotherapy as Patients 7 and 10, respectively. AML: acute myeloid leukemia; CR: complete response; CRh: CR with partial hematologic recovery; CRi: complete response with incomplete hematologic recovery; Cytogen: cytogenetics; HMA: hypomethylating agent; Mono/Combo: Monotherapy or Combination; NE, not evaluable; PD, progressive disease; Refract: refractory; relap: relapsed; Sec: secondary; SD, stable disease; Tx: Therapy.

Table 1. Baseline information and demographics (N = 18).

	Post-venetoclax patients (N = 18)
Analysis population, n (%)	18 (100)
Olutasidenib Monotherapy^a	16 (88.9)
Olutasidenib + Azacitidine Combination therapy^b	2 (11.1)
Sex
Men, n (%)	14 (77.8)
Women, n (%)	4 (22.2)
Median age, years (range)	73 (65–83)
AML type, n (%)
Primary (de novo)	8 (44.4)
Secondary	10 (55.6)
Cytogenetics by NCCN or ELN, n (%)
Favorable	1 (5.6)
Intermediate	10 (55.6)
Poor	6 (33.3)
Unknown	1 (5.6)
Median no. of prior regimens (range)	2 (1–6)
Prior venetoclax-based therapy	18 (100)
Induction	15 (83.3)
Consolidation	1 (5.6)
Maintenance or Salvage	2 (11.1)
Prior HMA, n (%)	14 (77.7)
Baseline Status of Disease, n (%)
Refractory	6 (33.3)
Relapsed	10 (55.5)
CRi^c	2 (11.1)
Transfusion dependence, n (%)
RBC	13 (72.2)
Platelet	8 (44.4)

AML: acute myeloid leukemia; CRi: complete response with incomplete hematologic recovery; ELN: European Leukemia Net; NCCN: National Comprehensive Cancer Network; HMA: hypomethylating agent; RBC: red blood cell.

^a 12 patients from the Pivotal Cohort and 4 from other monotherapy cohorts.

^b 2 patients are represented in both the monotherapy and combination therapy rows; baseline characteristics at the start of each treatment regimen are presented in the table.

^c 2 patients with a baseline CRi to prior venetoclax therapy enrolled into a maintenance cohort with olutasidenib monotherapy.

Venetoclax was generally used for induction but was used as consolidation (but not induction) in one patient and continuation (added to azacitidine after initial monotherapy) or salvage therapy in two patients. The median duration of venetoclax treatment was 5.4 months (range 1–34 months). Ten patients (72.2%) had received venetoclax with an HMA (azacitidine in 8, decitabine in 5); three of these patients had received venetoclax in two regimens, one with decitabine and one with azacitidine. Six patients had received venetoclax with cytarabine and two with dinaciclib. Two patients had received ivosidenib monotherapy before or after their venetoclax-based regimen (and prior to olutasidenib). Two other patients had received olutasidenib monotherapy after venetoclax (and prior to olutasidenib combination therapy in this study).

Efficacy

In the 16 R/R patients, the CRc rate was 43.8% following olutasidenib treatment, including CR in 4 (25.0%), CRh in 1 (6.3%) and CRi in 2 (12.5%). In these 16 patients, the median time to CRc was 1.9 months (range, 1–2.8), and median duration of response was not reached (range 1.2-NR, ongoing at 30.4+ months); 3 of these 7 responders had duration of response over 12 months (all ongoing at 18.5+, 22.6+ and 30.4+ months), and one patient had a duration of response ongoing at 9.0+ months (Figure 2). Median OS was 8.3 months (range 0.9–31.3) in the 16 patients and was not reached for those who achieved a CR/CRh.

Figure 2. (A,B) Time course of response to olutasidenib monotherapy or in combination with azacitidine in patients who achieved a CRc and were relapsed or refractory or had a baseline status of CRi to a prior venetoclax regimen. Patient numbers refer to patients shown in Figure 1. †Patients 15 and 16 received a combination of olutasidenib plus azacitidine after having received olutasidenib monotherapy as Patients 7 and 10, respectively. *Patients 17 and 18 were enrolled into a maintenance cohort with a baseline status of CRi; therefore, the duration of response is calculated from the date of achieving CRh. CR: complete remission; CRh: CR with partial hematologic recovery; Cri: CR with incomplete recovery. Reasons for treatment discontinuation: progressive disease in patients 1, 4, 7, 10, 13, and 18; withdrawal by patient in patients 5 and 11; adverse event in patients 3 (Grade 3 differentiation syndrome), 8 (Grade 4 increased liver function tests), 12 (Grade 4 abnormal liver function tests), 14 (Grade 5 enterococcal bacteremia) and 16 (Grade 5 coronavirus disease 2019).

The two patients who entered the study with CRi to venetoclax improved their response to a CRh at 1 and 8.3 months and to a CR at 8.3 and 20.3 months from the start of olutasidenib monotherapy. The durations of CR/CRh in these two patients were 15.3 and 23.1+ (ongoing).

Two of 18 patients received the combination of olutasidenib and azacitidine, and one achieved CR; the other was not evaluated. Of the 16 patients receiving olutasidenib monotherapy, 8 (50%) achieved CRc. Other responses included SD in two patients, PD in three, and not evaluable (NE) in three. None of the patients proceeded to HSCT.

In the 10 patients who had previously received the combination of venetoclax with an HMA, 5 (50%) achieved CRc, including 4 (40%) with CR/CRh [12].

Twelve of the 18 post-venetoclax patients were from the pivotal cohort (and were R/R at baseline) [12]. The median duration of prior venetoclax treatment was 6.7 months (range 2–34 months). In these 12 patients, 6 (50%) achieved a CRc with a median time to response of 1.7 months (range 1–2.8) and a median duration of CRc not reached (range 0–30.4+ months). Four of 12 (33%) achieved a CR/CRh with a median time to response of 2.4 months (range 1–2.8), a median duration of CR/CRh not reached (range 4.8–28.5+ months) [12], and median overall survival of 16.2 months.

Six of the 18 patients (all from the pivotal cohort) had IDH1 variant allele frequency (VAF) data at baseline, which ranged from 3 to 44, and at Cycle 3–4, which ranged from 2 to 49. While there are too few patients to make a comparison between responders (n = 5) and nonresponders (n = 1), the VAF generally increased from Baseline to Cycle 3–4 in the 5 responders and decreased in the 1 nonresponder. Sporadic data in subsequent cycles are available for 4 patients and show a general decline. The initial increase in VAF likely represents differentiation of myeloid cells, thus increasing the number of mIDH1 cells as the normal process of differentiation is restored. mIDH1 inhibitors do not cause apoptosis of mutated cells but rather restore the balance of 2-hydroxyglutarate, allowing differentiation to occur.

Two patients, who had enrolled in an olutasidenib monotherapy cohort following venetoclax-based therapy, subsequently enrolled in a combination therapy cohort that allowed the addition of azacitidine to olutasidenib. One patient had a CRi to olutasidenib monotherapy, progressed, and then achieved a CR with combination therapy. The other had SD on olutasidenib monotherapy, progressed, and then succumbed to COVID-19 nine days after starting combination therapy. The two experiences of these patients are counted separately, including their baseline characteristics, responses, and adverse events. If these experiences were presented as single experiences for each patient, then the CRc rate of the R/R group would be 6 of 14 (42.9%) rather than 7/16 (43.8%).

In the two patients previously treated with ivosidenib (both nonresponders to ivosidenib), one had disease progression with ivosidenib, then SD with 2 venetoclax regimens, and PD with subsequent olutasidenib monotherapy. The other had a CR to a venetoclax regimen, no response to ivosidenib, and was not evaluable in this study due to fatal enterococcal bacteremia on Day 35 of olutasidenib monotherapy.

Transfusion independence (TI)

Of the 16 patients who were R/R at baseline, 12 were dependent on red blood cell (RBC) transfusions and 2 (16.7%) achieved a ≥ 56-day period of RBC TI while receiving olutasidenib. Seven were platelet dependent at baseline, and 2 (28.6%) achieved a platelet TI while on olutasidenib.

Of the two patients who entered the study with CRi, 1 was dependent on both RBC and platelet transfusions; this patient achieved a ≥ 56-day period of RBC and platelet TI while receiving olutasidenib.

Safety

All 18 patients experienced a treatment-emergent adverse event (TEAE). The most commonly reported TEAEs (>20% of patients) included nausea (44.4%), dyspnea (38.9%), fatigue (38.9%), insomnia (33.3%), decreased RBC count (33.3%), abdominal pain (27.8%), back pain (27.8%), peripheral edema (27.8%), confusion (22.2%), epistaxis (22.2%), headache (22.2%), decreased neutrophil count (22.2%), pyrexia (22.2%), and decreased white blood cell count (22.2%). Fifteen (83.3%) patients experienced Grade 3–4 TEAEs, with the most common (>2 patients) being decreased RBC count (33.3%), decreased neutrophil count (22.2%), febrile neutropenia (16.7%), and pneumonia (16.7%). No TEAEs of QTc prolongation were reported.

Differentiation syndrome (DS) occurred in 3 patients—Grade 2 in one patient and Grade 3 in two patients, both of whom discontinued study drug.

Hepatic TEAEs were reported in 6 patients and included increased alanine aminotransferase (ALT) in 5 (Grade 3/4 in 3), aspartate aminotransferase (AST) in 5 (Grade 3 in 2), alkaline phosphatase (ALP) in 5 (Grade 3 in 3), and bilirubin in 2 (none ≥Grade 3), as well as hypoalbuminemia in 3 patients (Grade 3 in 2).

Five patients had an AE resulting in study drug withdrawal including two patients with a CRc: one responder (CR with DOR of 4.8 months) had Grade 4 increased liver function tests [LFTs] (with Grade 3 or 4 increases in ALT, AST and ALP), and one responder (CRi at 1.5 m) had Grade 3 DS; both resolved upon treatment discontinuation. The other 3 patients who withdrew due to a TEAE had Grade 4 increased LFTs, fatal enterococcal bacteremia, and fatal COVID-19.

Discussion

Advances in next generation sequencing have broadened our understanding of the complex genetic landscape of AML and have highlighted many recurrent genes involved in the development of AML [15, 16]. In recent years, the treatment arsenal for AML has expanded beyond the traditional anthracycline and cytarabine-based regimens to include a number of US FDA approved medications and regimens, many of which target specific molecular or cellular subgroups. The small molecule venetoclax in combination with an HMA agent is now standard treatment for AML patients unfit for chemotherapy and has adequate efficacy in mIDH1 AML [4, 5], a mutation that occurs in about 7–14% of patients with AML [17]. At this time, there is no standard of care for therapy following failure of a venetoclax-based regimen in mIDH1 AML, and these patients have a very poor prognosis.

Reported safety events were consistent with the known safety profile of olutasidenib as well as events typically seen with anti-leukemic treatments. Hepatic TEAEs resolved without dose modification in 4/6 patients, and the other 2 patients discontinued study drug. All 6 patients with hepatic events were on concomitant hepatotoxic medications (-azole antifungals, caspofungin, hydrocodone/acetaminophen, ciprofloxacin, ranitidine, flucloxacillin, valacyclovir, amphotericin B), which may have increased their risk of hepatic events. In addition, two of these patients had a recent medical history associated with hepatotoxicity (alcohol abuse and cholestatic LFT derangement). Overall, adverse events were manageable.

In this Phase 2 open-label study, olutasidenib produced durable responses as monotherapy or in combination with azacitidine in patients who were either relapsed, refractory or had a CRi to a prior venetoclax-based regimen. The rates of CRc and overall response for the 16 R/R patients were both 43.8%, which is consistent with the response rates in the pivotal cohort of the Phase 2 trial, in which 66 of 147 (44.9%) R/R patients achieved a CRc and 71 (48.3%) had an overall response [12]. These results appear to be favorable in contrast to the case reports in the literature in which 8 patients in 2 series [8,9] with mIDH1 AML were treated with an IDH1 inhibitor (ivosidenib or olutasidenib) after venetoclax-based therapy. One of 7 (15%) patients on ivosidenib had a CR, and 1 patient received olutasidenib and had SD [8]. The clinical responses seen in this subanalysis of 18 patients are encouraging and support the use of olutasidenib in patients with R/R mIDH1 AML following failure of a venetoclax-based regimen.

Conclusion

Olutasidenib induced durable remissions in patients with mIDH1 AML, who were relapsed, refractory, or had incomplete hematologic recovery to prior treatment with a venetoclax-based regimen. The observed activity is clinically meaningful. Adverse events were consistent with the known safety profile of olutasidenib and those that are anticipated in patients undergoing AML treatment. In light of the limited options and very poor prognosis of patients with AML following failure of venetoclax regimens, olutasidenib represents a valuable therapeutic option for the treatment of this molecularly defined, poor-prognosis patient population.

Acknowledgements

The authors thank the patients and their families for participating in this trial, and the clinical investigators and study staff for implementing the trial. The authors thank Sandra M Aguero, PharmD, BCPS, and Cynthia D. Gioiello, PharmD, for medical writing assistance for early manuscript drafts, which was funded by Rigel Pharmaceuticals, Inc.

Disclosure statement

Dr. J Cortes has received research funding for his current or former institution from, and is a consultant to, Astellas, Amphivena, BMS, Novartis, Pfizer, Takeda, Daiichi, Jazz Pharmaceuticals, Merus, and Forma Therapeutics; and is a consultant to Rigel, BiolineRx, BioPath, Sun Pharma, and Tern. Dr. BA Jonas has received research funding to his institution, is a consultant to, and is a board/advisory committee member for AbbVie, BMS, Daiichi-Sankyo, Genentech/Roche, and Pfizer; has received research funding to his institution, is a consultant to, and is a data monitoring committee member for Gilead; has received research funding to his institution, is a consultant to, and is a protocol steering committee member for GlycoMimetics; is a consultant to and a board/advisory committee member for Kymera, Servier, and Takeda; is a consultant to and has received travel reimbursement from Rigel; has received research funding to his institution from Amgen, AROG, Aptose, Celgene, F. Hoffman-La-Roche, Forma Therapeutics, Forty-Seven, Hanmi, Immune-Onc, Incyte, Jazz Pharmaceuticals, Loxo Oncology, Pharmacyclics, Sigma Tau, and Treadwell. Dr. G Schiller has received research funding, honoraria, is on the speakers’ bureau for, and is a board/advisory committee member for Agios, Gamida, Gilead, and Incyte; has received research funding, honoraria, is on the speakers’ bureau for, holds stock in, and is a board/advisory committee member for Amgen and BMS; has received research funding, honoraria, and is a board/advisory committee member for Novartis, Ono Pharma, and AVM Biotech; has received honoraria, is on the speakers’ bureau for, and is a board/advisory committee member for GlaxoSmithKline (GSK); has received research funding and holds stock in Janssen/Johnson & Johnson; has received research funding and is on the speakers’ bureau for AbbVie, Astellas, Celgene, Karyopharm, and Stemline; has received honoraria and is a board/advisory committee member for AstraZeneca; and has received research funding from Actinium, Actuate, Ambit, Cellectis, Cyclacel, Constellation, Daiichi-Sankyo, Deciphera, DeltaFly, Forma Therapeutics, FujiFilm, Genentech/Roche, Geron, Glycomimetics, Kura Oncology, Mateon, Medimmune, Millennium; Onconova, Pfizer, PrECOG, RegImmune, Sangamo, Samus, Sellas, Tolero, and Trovagene. Dr A Mims has served on advisory boards for BMS, AbbVie, Rigel Pharmaceuticals, Ryvu Therapeutics and has also served on Data Safety and Monitoring Boards for Foghorn Therapeutics, Jazz Pharmaceuticals, and Daiichi Sankyo. Dr. GJ Roboz has served as a consultant for Agios, Amgen, Amphivena, Astex, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Onconova, Pfizer, Roche, and Sunesis; received research funding from AbbVie, BMS, Teva and Karyopharm; is an advisory board member or consultant for Novartis, AbbVie, BeiGene, BerGenBio, Arcellx, Jazz Pharmaceuticals, Syros, BMS, Genentech, ImmunoGen, AstraZeneca, Kura, Ryvu, Magenta, and Qihan Zentalis; has provided research support to Janssen. Dr. AH Wei has received honoraria and research funding from, is a consultant to, is on the speakers’ bureau, and is a board/advisory committee member for Astellas; has received honoraria and research funding from, is on the speakers’ bureau, and is a board/advisory committee member for AbbVie/Genentech, Amgen, Celgene/BMS, and Novartis; has received research funding and honoraria from, is a consultant to, and is a board/advisory committee member for Servier and Syndax; has received honoraria from, is a consultant to, and is a board/advisory committee member for Janssen and Gilead; has received honoraria from and is a board/advisory committee member for MacroGenetics and Pfizer; has received honoraria and research funding from and is a board/advisory committee member for AstraZeneca; has received research funding from Astex; is an employee of the Walter and Eliza Hall Institute; and is eligible for a fraction of the royalty stream related to venetoclax. Dr. P Montesinos has served as a consultant and has received research funding from Servier and Bristol Myers Squibb. Dr. PB Ferrell reports no disclosures. Dr. KWL Yee was a consultant for Bristol Myers Squibb/Celgene, F. Hoffmann-La Roche, GSK, Jazz Pharmaceuticals, Novartis, Pfizer, Shattuck Labs, Taiho Oncology, and Takeda; received research funding from Astex Pharmaceuticals, Forma Therapeutics, F. Hoffmann-La Roche, Forma Therapeutics, Genentech, Geron Corporation, Gilead Sciences, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Novartis, and Treadwell Therapeutics; and received honoraria from AbbVie, TaiHo, and Novartis. Dr. P Fenaux reports no disclosures. Dr. A Schwarer reports no disclosures. Dr. JM Watts has received research funding from and was a board/advisory committee member for Takeda; has received research funding from Immune System Key Ltd; and is a consultant or board/advisory committee member for Genentech, Rafael Pharma, Reven Pharma, Celgene/Bristol-Myers Squib (BMS), Servier, Rigel, Aptose, Astellas, and Daiichi-Sankyo.

Data availability statement

For deidentified data, requests may be sent to [email protected] at least 24 months after clinical trial completion, provided a scientifically valid research proposal is made by qualified, academic researchers for data associated with interventions that have received regulatory approval in the US and Europe.

Additional information

Funding

Funding for this study was provided by Forma Therapeutics and Rigel Pharmaceuticals. Medical writing assistance was funded by Rigel Pharmaceuticals.