Systemic immunoglobulin light-chain amyloidosis is characterized by pathologic deposition of immunoglobulin light chains as amyloid fibrils in vital organs, leading to organ impairment and eventual death. That the process is reversible was evidenced in an in vivo experimental model in which fibril-reactive chimeric monoclonal antibody (mAb) 11-1F4 directly targeted human light-chain amyloid deposits and affected their removal via a phagocyte-mediated response. To determine the tolerability and potential amyloidolytic effect of this agent (now designated mAb CAEL-101), we conducted a phase 1a/b study involving 27 patients, most of whom had manifestations of organ involvement. This was an open-label study in which phase 1a patients received mAb CAEL-101 as a single intravenous infusion with escalating dose levels from 0.5 mg/m2 to 500 mg/m2 to establish the maximum tolerated dose (MTD). In phase 1b, the antibody was administered as a graded series of 4 weekly infusions. For both phases, there were no drug-related serious adverse events or dose-limiting toxicities among recipients, and the MTD was not reached. The majority of patients had deep hematologic responses but persistent organ disease prior to treatment. Fifteen of 24 patients (63%) who manifested cardiac, renal, hepatic, gastrointestinal, or soft tissue involvement had a therapeutic response to mAb CAEL-101 as evidenced by serum biomarkers or objective imaging modalities with a median time to response of 3 weeks. Infusions of mAb CAEL-101 were well tolerated and, for the majority, resulted in improved organ function, notably for those with cardiac impairment. This trial was registered at www.clinicaltrials.gov as #NCT02245867.

We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding antimyeloma idiotype (Id)-keyhole limpet hemocyanin (KLH) vaccine to vaccine-specific costimulated T cells. In this randomized phase 2 trial, patients received either control (KLH only) or Id-KLH vaccine, autologous transplantation, vaccine-specific costimulated T cells expanded ex vivo, and 2 booster doses of assigned vaccine. In 36 patients (KLH, n = 20; Id-KLH, n = 16), no dose-limiting toxicity was seen. At last evaluation, 6 (30%) and 8 patients (50%) had achieved complete remission in KLH-only and Id-KLH arms, respectively (P = .22), and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; P = .32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with patients receiving KLH only, there was a greater change in IR genes in T cells in those receiving Id-KLH relative to baseline. Specifically, upregulation of genes associated with activation, effector function induction, and memory CD8+ T-cell generation after Id-KLH but not after KLH control vaccination was observed. Similarly, in responding patients across both arms, upregulation of genes associated with T-cell activation was seen. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of patients receiving Id-KLH. In conclusion, in this combination immunotherapy approach, we observed significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies. This trial was registered at www.clinicaltrials.gov as #NCT01426828.

CD19-directed chimeric antigen receptor-modified (CAR T) T cells achieve durable remissions in about 30% to 40% of relapsed/refractory large B-cell lymphomas. T-cell exhaustion and/or an immunosuppressive tumor microenvironment may contribute to CAR T-cell failure. Pembrolizumab, an anti-PD1 immune checkpoint inhibitor, may reverse T-cell exhaustion after CAR T-cell therapy. We treated 12 patients with B-cell lymphomas who were either refractory to (n = 9) or relapsed after (n = 3) CD19-directed CAR T-cell (4-1BB-costimulated) therapy with pembrolizumab 200 mg IV every 3 weeks. Median time from CAR T-cell infusion to first pembrolizumab dose was 3.3 months (range, 0.4-42.8 months). Pembrolizumab was well tolerated, and the only grade ≥3 adverse events related to pembrolizumab were neutropenia (n = 3; 25%). Best overall response rate after pembrolizumab was 25% (3 of 12 patients; 1 complete response; 2 partial responses). One (8%) patient had stable disease; thus, 4 of 12 (33%) patients had clinical benefit. After pembrolizumab, 4 patients with clinical benefit had an increase in percentage of CAR T cells by mass cytometry by time of flight (CyTOF); 3 of 4 of these patients also had increases in CAR19 transgene levels by quantitative polymerase chain reaction. Deep immune profiling using CyTOF revealed increased CAR T-cell activation and proliferation and less T-cell exhaustion in clinical responders. Together, PD1 blockade with pembrolizumab after CD19-directed CAR T-cell therapy appears safe and may achieve clinical responses in some patients with B-cell lymphomas refractory to or relapsed after CAR T-cell therapy. This trial was registered at www.clinicaltrials.gove as #NCT02650999.

Inherited predisposition to myeloid malignancies is more common than previously appreciated. We analyzed the whole-exome sequencing data of paired leukemia and skin biopsy samples from 391 adult patients from the Beat AML 1.0 consortium. Using the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation, we curated 1547 unique variants from 228 genes. The pathogenic/likely pathogenic (P/LP) germline variants were identified in 53 acute myeloid leukemia (AML) patients (13.6%) in 34 genes, including 6.39% (25/391) of patients harboring P/LP variants in genes considered clinically actionable (tier 1). 41.5% of the 53 patients with P/LP variants were in genes associated with the DNA damage response. The most frequently mutated genes were CHEK2 (8 patients) and DDX41 (7 patients). Pathogenic germline variants were also found in new candidate genes (DNAH5, DNAH9, DNMT3A, and SUZ12). No strong correlation was found between the germline mutational rate and age of AML onset. Among 49 patients who have a reported history of at least one family member affected with hematological malignancies, 6 patients harbored known P/LP germline variants and the remaining patients had at least one variant of uncertain significance, suggesting a need for further functional validation studies. Using CHEK2 as an example, we show that three-dimensional protein modeling can be one of the effective methodologies to prioritize variants of unknown significance for functional studies. Further, we evaluated an in silico approach that applies ACMG curation in an automated manner using the tool for assessment and (TAPES) prioritization in exome studies, which can minimize manual curation time for variants. Overall, our findings suggest a need to comprehensively understand the predisposition potential of many germline variants in order to enable closer monitoring for disease management and treatment interventions for affected patients and families.

The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (≥1 of neutropenia, thrombocytopenia, anemia) lasting ≥4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected the acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with t-MNs. Single-cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.

Resistance to standard immunochemotherapy remains an unmet challenge in diffuse large B-cell lymphoma (DLBCL), and aberrant DNA methylation may contribute to chemoresistance. Promising early-phase results were reported with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus subcutaneous azacitidine, a hypomethylating agent. In this phase 1 study, we evaluated CC-486 (oral azacitidine) plus 6 cycles of R-CHOP in patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. CC-486 doses of 100, 150, 200, or 300 mg given 7 days before cycle 1 and on days 8-21 of cycles 1-5 were evaluated; additional patients were enrolled in the expansion phase to examine preliminary efficacy. The primary objectives were to determine the safety and the maximum tolerated dose (MTD) of CC-486 in combination with R-CHOP. The most common grade 3/4 toxicities were hematologic, including neutropenia (62.7%) and febrile neutropenia (25.4%); grade 3/4 nonhematologic toxicities were uncommon (<7%). The MTD was not established; 2 patients had dose-limiting toxicities (1 with grade 4 febrile neutropenia; 1 with grade 4 prolonged neutropenia). The recommended phase 2 dose was established as 300 mg. The overall response rate was 94.9%, with 52 patients (88.1%) achieving complete responses. With a median follow-up of 28.9 months, estimated 1- and 2-year progression-free survival rates were 84.1% and 78.6%, respectively. Overall, epigenetic priming with CC-486 before R-CHOP can be delivered with acceptable safety to patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. ClinicalTrials.gov: NCT02343536.

To design a simple and reproducible classifier predicting the overall survival (OS) of patients with acute myeloid leukemia (AML) ≥60 years of age treated with 7 + 3, we sequenced 37 genes in 471 patients from the ALFA1200 (Acute Leukemia French Association) study (median age, 68 years). Mutation patterns and OS differed between the 84 patients with poor-risk cytogenetics and the 387 patients with good (n = 13), intermediate (n = 339), or unmeasured (n = 35) cytogenetic risk. TP53 (hazards ratio [HR], 2.49; P = .0003) and KRAS (HR, 3.60; P = .001) mutations independently worsened the OS of patients with poor-risk cytogenetics. In those without poor-risk cytogenetics, NPM1 (HR, 0.57; P = .0004), FLT3 internal tandem duplications with low (HR, 1.85; P = .0005) or high (HR, 3.51; P < 10-4) allelic ratio, DNMT3A (HR, 1.86; P < 10-4), NRAS (HR, 1.54; P = .019), and ASXL1 (HR, 1.89; P = .0003) mutations independently predicted OS. Combining cytogenetic risk and mutations in these 7 genes, 39.1% of patients could be assigned to a "go-go" tier with a 2-year OS of 66.1%, 7.6% to the "no-go" group (2-year OS 2.8%), and 3.3% of to the "slow-go" group (2-year OS of 39.1%; P < 10-5). Across 3 independent validation cohorts, 31.2% to 37.7% and 11.2% to 13.5% of patients were assigned to the go-go and the no-go tiers, respectively, with significant differences in OS between tiers in all 3 trial cohorts (HDF [Hauts-de-France], n = 141, P = .003; and SAL [Study Alliance Leukemia], n = 46; AMLSG [AML Study Group], n = 223, both P < 10-5). The ALFA decision tool is a simple, robust, and discriminant prognostic model for AML patients ≥60 years of age treated with intensive chemotherapy. This model can instruct the design of trials comparing the 7 + 3 standard of care with less intensive regimens.

E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus 6 cycles of rituximab (IR) to 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (<1 CLL cell per 104 leukocytes) were 29.1%, 30.3%, 23.4%, and 8.6% at 3, 12, 24, and 36 months for FCR, and significantly lower at 7.9%, 4.2%, and 3.7% at 12, 24, and 36 months for IR, respectively. Undetectable MRD at 3, 12, 24, and 36 months was associated with longer progression-free survival (PFS) in the FCR arm, with hazard ratios (MRD detectable/MRD undetectable) of 4.29 (95% confidence interval [CI], 1.89-9.71), 3.91 (95% CI, 1.39-11.03), 14.12 (95% CI, 1.78-111.73), and not estimable (no events among those with undetectable MRD), respectively. In the IR arm, patients with detectable MRD did not have significantly worse PFS compared with those in whom MRD was undetectable; however, PFS was longer in those with MRD levels <10-1 than in those with MRD levels above this threshold. Our observations provide additional support for the use of MRD as a surrogate end point for PFS in patients receiving FCR. In patients on indefinite ibrutinib-based therapy, PFS did not differ significantly by undetectable MRD status, whereas those with MRD <10-1 tended to have longer PFS, although continuation of ibrutinib would very likely be necessary to maintain treatment efficacy.

In PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270.

Patients with chronic myeloid leukemia in chronic phase (CML-CP) resistant/intolerant to ≥2 tyrosine kinase inhibitors (TKIs) are at high risk of experiencing poor outcomes because of disease biology and inadequate efficacy and/or safety of current therapies. Asciminib, a first-in-class BCR-ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP), has the potential to overcome resistance/intolerance to approved TKIs. In this phase 3, open-label study, patients with CML-CP previously treated with ≥2 TKIs were randomized (2:1) to receive asciminib 40 mg twice daily vs bosutinib 500 mg once daily. Randomization was stratified by major cytogenetic response (MCyR) status at baseline. The primary objective was to compare the major molecular response (MMR) rate at week 24 for asciminib vs bosutinib. A total of 233 patients were randomized to asciminib (n = 157) or bosutinib (n = 76). Median follow-up was 14.9 months. The MMR rate at week 24 was 25.5% with asciminib and 13.2% with bosutinib. The difference in MMR rate between treatment arms, after adjusting for MCyR at baseline, was 12.2% (95% confidence interval, 2.19-22.30; 2-sided P = .029). Fewer grade ≥3 adverse events (50.6% vs 60.5%) and adverse events leading to treatment discontinuation (5.8% vs 21.1%) occurred with asciminib than with bosutinib. The study showed a superior efficacy of asciminib compared with that of bosutinib, together with a favorable safety profile. These results support the use of asciminib as a new therapy in patients with CML-CP who are resistant/intolerant to ≥2 prior TKIs. This trial was registered at www.clinicaltrials.gov as #NCT03106779.

Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia (AML). Using an AML composite model (AML-CM) assigning higher scores to older age, increased comorbidity burdens, and adverse cytogenetic risks, we defined 3 distinct prognostic groups and compared outcomes after less-intensive vs intensive induction therapies in a multicenter retrospective cohort (n = 1292) treated at 6 institutions from 2008 to 2012 and a prospective cohort (n = 695) treated at 13 institutions from 2013 to 2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physician perception of cure. In the retrospective cohort, recipients of less-intensive therapies were older and had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks of mortality in AML-CM scores of 4 to 6, 7 to 9, and ≥10. Results were independent of allogeneic transplantation and similar in those age 70 to 79 years. In the prospective cohort, the 2 groups were similar in baseline QOL, geriatric assessment, and patient outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS, and chance of cure, mortality risks and QOL were similar. Less-intensive therapy recipients had shorter length of hospitalization (LOH). Our study questions the survival and QOL benefits (except LOH) of less-intensive therapies in patients with AML, including those age 70 to 79 years or with high comorbidity burdens. A randomized trial in older/medically infirm patients is required to better assess the value of less-intensive and intensive therapies or their combination. This trial was registered at www.clinicaltrials.gov as #NCT01929408.

Myeloid leukemia in children with Down syndrome (ML-DS) is associated with young age and somatic GATA1 mutations. Because of high event-free survival (EFS) and hypersensitivity of the leukemic blasts to chemotherapy, the prior Children's Oncology Group protocol ML-DS protocol (AAML0431) reduced overall treatment intensity but lacking risk stratification, retained the high-dose cytarabine course (HD-AraC), which was highly associated with infectious morbidity. Despite high EFS of ML-DS, survival for those who relapse is rare. AAML1531 introduced therapeutic risk stratification based on the previously identified prognostic factor, measurable residual disease (MRD) at the end of the first induction course. Standard risk (SR) patients were identified by negative MRD using flow cytometry (<0.05%) and did not receive the historically administered HD-AraC course. Interim analysis of 114 SR patients revealed a 2-year EFS of 85.6% (95% confidence interval [CI], 75.7-95.5), which was significantly lower than for MRD- patients treated with HD-AraC on AAML0431 (P = .0002). Overall survival at 2 years was 91.0% (95% CI, 83.8-95.0). Twelve SR patients relapsed, mostly within 1 year from study entry and had a 1-year OS of 16.7% (95% CI, 2.7-41.3). Complex karyotypes were more frequent in SR patients who relapsed compared with those who did not (36% vs 9%; P = .0248). MRD by error-corrected sequencing of GATA1 mutations was piloted in 18 SR patients and detectable in 60% who relapsed vs 23% who did not (P = .2682). Patients with SR ML-DS had worse outcomes without HD-AraC after risk classification based on flow cytometric MRD.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled terminal complement activation and subsequent intravascular hemolysis (IVH). C5 inhibitors prevent membrane attack complex formation, but patients may experience extravascular hemolysis (EVH) and continue to require blood transfusions. Danicopan, an oral proximal complement inhibitor of alternative pathway factor D (FD), is designed to control IVH and EVH. In a phase 2 dose-finding trial, eculizumab-treated transfusion-dependent patients with PNH (n = 12) received danicopan, 100 to 200 mg thrice daily, in addition to their eculizumab regimen for 24 weeks. End points included hemoglobin (Hgb) change vs baseline at week 24 (primary), reduction in blood transfusions, and patient-reported outcomes. Safety, tolerability, and pharmacokinetics/pharmacodynamics were measured. Twelve patients received ≥1 danicopan dose; 1 patients discontinued from a serious adverse event deemed unlikely related to danicopan. Eleven patients completed the 24-week treatment period. Addition of danicopan resulted in a mean Hgb increase of 2.4 g/dL at week 24. In the 24 weeks prior to danicopan, 10 patients received 31 transfusions (50 units) compared with 1 transfusion (2 units) in 1 patient during the 24-week treatment period. Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score increased by 11 points from baseline to week 24. The most common adverse events were headache, cough, and nasopharyngitis. Addition of danicopan, a first-in-class FD inhibitor, led to a meaningful improvement in Hgb and reduced transfusion requirements in patients with PNH who were transfusion-dependent on eculizumab. These benefits were associated with improvement of FACIT-Fatigue. This trial was registered at www.clinicaltrials.gov as #NCT03472885.

Angioimmunoblastic T-cell lymphoma (AITL) is a unique subtype of peripheral T-cell lymphoma (PTCL) with distinct clinicopathologic features and poor prognosis. We performed a subset analysis of 282 patients with AITL enrolled between 2006 and 2018 in the international prospective T-cell Project (NCT01142674). The primary and secondary end points were 5-year overall survival (OS) and progression-free survival (PFS), respectively. We analyzed the prognostic impact of clinical covariates and progression of disease within 24 months (POD24) and developed a novel prognostic score. The median age was 64 years, and 90% of patients had advanced-stage disease. Eighty-one percent received anthracycline-based regimens, and 13% underwent consolidative autologous stem cell transplant (ASCT) in first complete remission (CR1). Five-year OS and PFS estimates were 44% and 32%, respectively, with improved outcomes for patients who underwent ASCT in CR1. In multivariate analysis, age ≥60 years, Eastern Cooperative Oncology Group performance status >2, elevated C-reactive protein, and elevated β2 microglobulin were associated with inferior outcomes. A novel prognostic score (AITL score) combining these factors defined low-, intermediate-, and high-risk subgroups with 5-year OS estimates of 63%, 54%, and 21%, respectively, with greater discriminant power than established prognostic indices. Finally, POD24 was a powerful prognostic factor with 5-year OS of 63% for patients without POD24 compared with only 6% for patients with POD24 (P < .0001). These data will require validation in a prospective cohort of homogeneously treated patients. Optimal treatment of AITL continues to be an unmet need, and novel therapeutic approaches are required.

We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) using data from 4 phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD negativity rates and reduced the risk of disease progression or death by approximately half vs standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response or better (≥CR) with MRD-negative status and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10-5 sensitivity threshold). Patient-level data were pooled from all 4 studies and for patients with TIE NDMM and patients with RRMM who received ≤2 prior lines of therapy (≤2 PL). PFS was evaluated by response and MRD status. Median follow-up (months) was 54.8 for POLLUX, 50.2 for CASTOR, 40.1 for ALCYONE, and 36.4 for MAIA. Patients who achieved ≥CR and MRD negativity had improved PFS vs those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P < .0001; TIE NDMM and RRMM ≤2 PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that ≥CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching ≥CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support ≥CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.clinicaltrials.gov as #NCT02076009, #NCT02136134, #NCT02195479, and #NCT02252172.

MYD88 and CXCR4 mutations are common in Waldenström macroglobulinemia (WM). Mutated CXCR4 (CXCR4Mut) impacts BTK-inhibitor response. We conducted a phase 1 trial of the CXCR4-antagonist ulocuplumab with ibrutinib in this first-ever study to target CXCR4Mut in WM. Ibrutinib was initiated at 420 mg/d with cycle 1 and continued until intolerance or progression; ulocuplumab was given cycles 1 to 6, with a 3 + 3 dose-escalation design. Each cycle was 4 weeks. Thirteen symptomatic patients, of whom 9 were treatment-naive patients were enrolled. Twelve were evaluable for response. At best response, their median serum immunoglobulin M declined from 5574 to 1114 mg/dL; bone marrow disease decreased from 65% to 10%, and hemoglobin increased from 10.1 to 14.2 g/dL (P < .001). The major and VGPR response rates were 100% and 33%, respectively, with VGPRs observed at lower ulocuplumab dose cohorts. Median times to minor and major responses were 0.9 and 1.2 months, respectively. With a median follow-up of 22.4 months, the estimated 2-year progression-free survival was 90%. The most frequent recurring grade ≥2 adverse events included reversible thrombocytopenia, rash, and skin infections. Ulocuplumab dose-escalation did not impact adverse events. The study demonstrates the feasibility of combining a CXCR4-antagonist with ibrutinib and provides support for the development of CXCR4-antagonists for CXCR4Mut WM. This trial was registered at www.clinicaltrials.gov as #NCT03225716.

Asparaginase (ASNase) therapy has been a mainstay of acute lymphoblastic leukemia (ALL) protocols for decades and shows promise in the treatment of a variety of other cancers. To improve the efficacy of ASNase treatment, we used a CRISPR/Cas9-based screen to identify actionable signaling intermediates that improve the response to ASNase. Both genetic inactivation of Bruton's tyrosine kinase (BTK) and pharmacological inhibition by the BTK inhibitor ibrutinib strongly synergize with ASNase by inhibiting the amino acid response pathway, a mechanism involving c-Myc-mediated suppression of GCN2 activity. This synthetic lethal interaction was observed in 90% of patient-derived xenografts, regardless of the genomic subtype. Moreover, ibrutinib substantially improved ASNase treatment response in a murine PDX model. Hence, ibrutinib may be used to enhance the clinical efficacy of ASNase in ALL. This trial was registered at www.clinicaltrials.gov as # NCT02884453.