The characterization and the impact of CSF pleocytosis during blinatumomab therapy for adult acute lymphoblastic leukemia.

Reactive pleocytosis in the CSF has been observed with blinatumomab but has not been well-described. We performed a retrospective study of 88 patients who received intrathecal chemotherapy (IT) while on blinatumomab with CSF analyzed to determine if pleocytosis had an impact efficacy and safety. Blinatumomab was used for relapsed/refractory 62.5%, MRD-positive 31.8%, and consolidation in MRD-negative 5.7%. The incidence of pleocytosis in CSF was 51% and was more frequent after day 15 (55.8% vs. 18.2%, p = 0.025). Pleocytosis did not impact CR, clearance of MRD positivity, PFS and OS rates. Lower incidence of non-CNS extramedullary relapse was seen (3.7% vs. 30.8%, p = 0.011) with pleocytosis in CSF. Analysis of CSF by flow cytometry showed median CD4:CD8 ratio of 1.34. In conclusion, CSF pleocytosis is prevalent with blinatumomab but only demonstrated lower rates of non-CNS extramedullary relapse but no impact on CNS relapse or neurotoxicity.

Comparing transplant outcomes in ALL patients after myeloablative conditioning in mismatch-related or unrelated donor settings.

The optimal myeloablative conditioning regimen for ALL patients undergoing hematopoietic cell transplant (HCT) with an alternative donor is unknown. We analyzed HCT outcomes ALL patients (n = 269) who underwent HCT at our center from 2010 to 2020 in complete remission (CR) after FTBI-etoposide and CNI-based GvHD prophylaxis for matched donor HCT (ETOP-package; n = 196) or FTBI-Fludarabine and post-transplant cyclophosphamide (PTCy)-based prophylaxis for HLA- mismatched (related or unrelated) donors (FLU-package; n = 64). Patients in FLU-package showed a significant delay in engraftment (p < 0.001) and lower cumulative incidence (CI) of any and extensive chronic GVHD (p = 0.009 and 0.001, respectively). At the median follow up of 4.6 years (range 1-12 years); non-relapse mortality, overall or leukemia-free survival and GVHD-free/relapse-free survival were not significantly impacted by the choice of conditioning. However, in patients at CR2 or with measurable residual disease (MRD+), there was a trend towards higher relapse after FLU-package (p = 0.08 and p = 0.07, respectively), while patients at CR1 regardless of MRD status had similar outcomes despite the package/donor type (p = 0.9 and 0.7, respectively). Our data suggests that FLU-package for alternative donors offers comparable outcomes to ETOP-package for matched donor HCT to treat ALL. Disease status and depth of remission at HCT were independent predictors for better outcomes.

Concurrent versus sequential or no triazole anti-fungal therapy in patients undergoing 7 + 3 plus midostaurin induction for FLT-3 acute myelogenous leukemia.

INTRODUCTION: Midostaurin is a multikinase inhibitor approved for the treatment of adult patients with newly diagnosed FMS-like tyrosine kinase 3 mutated (FLT3m) acute myeloid leukemia (AML). Azole antifungal medications are commonly used in AML and are known to interact with anti-cancer drugs such as midostaurin through the CYP3A pathway. However, there are no midostaurin related dose modifications recommended with strong CYP3A inhibitors. METHODS: We retrospectively reviewed 40 patients between 2017-2022 and compared efficacy and safety outcomes in patients who received azole antifungals concurrently to those who did not receive an azole or received it sequentially to midostaurin for treatment of FLT3m AML. RESULTS: Median age of both groups was approximately 55 years and 70% of patients harbored FLT-3 internal tandem duplication mutations. Most patients in the concurrent arm were on either posaconazole (33%) or isavuconazole (50%) for antifungal prophylaxis and micafungin (72%) for the sequential/no azole arm. Overall CR/CRi rate with concurrent versus sequential/no azole were 72% and 77%, and non-hematologic grade 3 toxicities were 22% and 40% (p = 0.21), respectively. Rates of dose reductions (6% vs. 0%, p = 0.26) and held doses (17% vs. 14%, p = 0.79) were not different between concurrent and sequential/no azole. There were no differences in the rates of new fungal infection during induction between the two groups. CONCLUSION: Azoles given concurrently or sequentially with midostaurin were found to be equally safe and effective in the treatment of newly diagnosed FLT3 AML. Additional confirmatory studies are needed due to our limited sample size.

Impact of Antifungal Prophylaxis Continuation or Discontinuation After Allogeneic Hematopoietic Cell Transplant on the Incidence of Invasive Mold Infection.

Background: Continuing antifungal prophylaxis (AFPx) to prevent invasive mold infections (IMIs) in recipients of allogeneic hematopoietic cell transplantation (alloHCT) after primary hospital discharge from alloHCT admission varies among transplant centers despite recommendations to continue prophylaxis through day +75. Characteristics driving AFPx prescribing at hospital discharge and outcomes are unknown. Methods: In this retrospective analysis, we reviewed patients continuing AFPx vs no AFPx at hospital discharge. We included patients with a hospital stay ≥7 days and ≤40 days. We excluded patients with a history of IMI prior to alloHCT, new IMI during admission, or death prior to discharge. Our primary objective was incidence of probable or proven IMI per the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Our secondary objectives were nonrelapse mortality at day +100, overall survival at day +100, and characteristics driving AFPx discontinuation at hospital discharge. Results: Of the 430 patients identified, 387 met inclusion criteria. At discharge, 56% (217/387) continued AFPx, and 44% (170/387) had no AFPx. At day +100, 3 probable IMI cases occurred in the group with continued AFPx vs 1 probable IMI case in the no-AFPx group (no proven IMI). Univariate analysis showed no difference in cumulative incidence of probable IMI (P = .440), nonrelapse mortality (P = .072), and overall survival (P = .855) between groups. Multivariable logistic regression demonstrated that patients were less likely to continue AFPx if they had a diagnosis other than acute myeloid leukemia, a length of stay ≤30 days, acute graft-vs-host disease grade 0 or 1, and corticosteroid use ≤5 days. Conclusions: There was no difference in probable IMI at day +100 after alloHCT based on continuing vs discontinuing AFPx at hospital discharge after alloHCT admission supporting a risk-adapted prophylaxis approach.

Genetic Risk Stratification and Outcomes Among Treatment-Naive Patients With AML Treated With Venetoclax and Azacitidine.

European LeukemiaNet (ELN) acute myeloid leukemia (AML) genetic risk classification systems were based on response to intensive chemotherapy; their ability to discriminate outcomes in older patients treated with venetoclax-azacitidine may be suboptimal. Here, pooled analysis of patients in the phase 3 VIALE-A trial (NCT02993523) and phase 1b study (NCT02203773) examined prognostic stratification according to 2017 and 2022 ELN risk classifications. A bioinformatic algorithm derived new molecular signatures differentiating venetoclax-azacitidine-treated patients based on median overall survival (OS). 279 patients treated with venetoclax-azacitidine and 113 patients treated with placebo-azacitidine were analyzed. When classified by ELN 2017 or 2022 prognostic criteria, most patients had adverse-risk AML (60.2% and 72.8% for venetoclax-azacitidine and 65.5% and 75.2% for placebo-azacitidine, respectively). While outcomes with venetoclax-azacitidine were improved across all ELN risk groups compared with placebo-azacitidine, ELN classification systems poorly discriminated venetoclax-azacitidine outcomes. By applying a bioinformatic algorithm, new molecular signatures were derived differentiating OS outcomes with venetoclax-azacitidine; the mutational status of TP53, FLT3-ITD, NRAS, and KRAS categorized patients into higher-, intermediate-, and lower-benefit groups (52%, 25%, and 23% of patients, respectively), each associated with a distinct median OS (26.5 months [95% CI, 20.2 to 32.7], 12.1 months [95% CI, 7.3 to 15.2], and 5.5 months [95% CI, 2.8 to 7.6], respectively). ELN prognostic classifiers do not provide clinically meaningful risk stratification of OS outcomes for patients with AML treated with venetoclax-azacitidine. TP53, FLT3-ITD, NRAS, and KRAS mutation status allows classification of these patients into three risk groups with distinct differences in median OS.

Consolidation with First and Second Allogeneic Transplants in Adults with Relapsed/Refractory B-ALL Following Response to CD19CAR T Cell Therapy.

CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy has led to unprecedented rates of complete remission (CR) in children and adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL), yet the majority of adults relapse after initial response. One proposed method to extend the durability of remission in adults following response to CAR-T therapy is consolidation with allogeneic hematopoietic cell transplantation (alloHCT). Considering the limited published data for the utility of post CAR-T therapy consolidative alloHCT in r/r B-ALL, especially data related to patients receiving a second alloHCT, we sought to describe outcomes of patients with r/r B-ALL at our institution who received their first or second alloHCT following response to CAR-T therapy. We performed a retrospective analysis of adult patients with r/r B-ALL who responded to either investigational or standard of care (SOC) CD19-targeted CAR-T therapy and underwent consolidation with alloHCT while in CR without interim therapy. We identified 45 patients, of whom 26 (58%) and 19 (42%) received their first and second alloHCT as consolidation post CAR-T therapy, respectively. The median age was 31 years (range: 19-67) and 31 (69%) patients were Hispanic. Ph-like was the most common genetic subtype and comprised over half of cases (53%; n = 24). The median number of prior therapies pre-transplant was 5 (range: 2-7), and disease status at the time of alloHCT was CR1, CR2 or ≥CR3 in 7 (16%), 22 (49%) and 16 (35%) patients, respectively. The median time from CAR-T therapy until alloHCT was 93 (range: 42-262) days. The conditioning regimen was radiation-based myeloablative (MAC) in 22 (49%) patients. With a median follow-up of 2.47 years (range: 0.13-6.93), 2-year overall survival (OS), relapse free survival (RFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 57.3% (95% CI: 0.432-0.760), 56.2% (95% CI: 0.562-0.745), 23.3% (95% CI: 0.13-0.42), and 20.4% (95% CI: 0.109-0.384), respectively. Two-year OS (52% vs. 68%, P = .641), RFS (54% vs. 59%, P = .820), CIR (33.5% vs. 8.5%, P = .104), and NRM (12.5% vs. 32.2%, P = .120) were not significantly different between patients who underwent their first vs. second transplant, respectively. In univariate analysis, only Ph-like genotype was associated with inferior RFS (P = .03). AlloHCT post CAR-T response is associated with a relatively low early mortality rate and encouraging survival results in high-risk adults with r/r B-ALL, extending to the second alloHCT for fit and eligible patients.

Intensive Induction Chemotherapy versus Hypomethylating Agents in Combination with Venetoclax in NPM1-mutant AML.

While intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), data from older patients shows that hypomethylating agents + venetoclax (HMA/VEN) can lead to durable remissions among patients with NPM1 mutations. Whether IC or HMA/VEN is superior in patients ≥60 years-old with NPM1-mutant AML is unknown. To compare IC and HMA/VEN, we performed an international, multicenter retrospective cohort study of patients with newly diagnosed, NPM1-mutant AML.We included 221 patients (147 IC, 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR; defined as CR + CR with incomplete count recovery [CRi]) rate was similar for IC and HMA/VEN (cCR: 85% vs. 74%; p=0.067). While OS was favorable with IC in unselected patients compared to HMA/VEN (24-month OS 59% [95% CI: 52-69%] vs. 38% [95% CI 27-55%]; p=0.013), it was not statistically different among patients 60-75 years-old (60% [95% CI 52-70%] vs. 44% [95% CI 29-66%]; p=0.069) and patients who received an allogeneic stem cell transplant (70% [95% CI: 58-85%] vs. 66% [95% CI: 44-100%]; p=0.56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS with IC 65% [95% 56-74%] vs. 40% [95% CI: 26-60%] with HMA/VEN; p=0.009) and without FLT3-ITD mutations might benefit from IC compared with HMA/VEN (24-month OS: 68% [95% CI: 59-79%] vs. 43% [95% CI: 29-63%]; p=0.008). In multivariable analysis, OS was not statistically different for patients treated with IC and HMA/VEN (hazard ratio for death HMA/VEN vs. IC: 0.71; 95% CI: 0.40-1.27; p=0.25).

Outcomes following allogeneic hematopoietic cell transplantation relapse in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Improved first progression-free survival following allogeneic hematopoietic cell transplantation relapse with the use of immunotherapy.

Toxicities associated with tyrosine kinase inhibitor maintenance following allogeneic hematopoietic cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Allogeneic hematopoietic cell transplantation (HCT) offers a potential cure in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL); nonetheless, relapses are common and the major cause of mortality. One strategy to prevent relapse is tyrosine kinase inhibitor (TKI) maintenance post-HCT, but published clinical experience is primarily with the first-generation TKI imatinib while data with newer generation TKIs are limited. We conducted a retrospective analysis of 185 Ph+ ALL patients who underwent HCT followed by TKI maintenance from 2003 to 2021 at City of Hope. Initially, 50 (27.0%) received imatinib, 118 (63.8%) received a second-generation TKI (2G-TKI), and 17 (9.2%) received ponatinib. A total of 77 patients (41.6%) required a dose reduction of their initial TKI due to toxicity. Sixty-six patients (35.7%) did not complete maintenance due to toxicity; 69 patients (37.3%) discontinued 1 TKI, and 11 (5.9%) discontinued 2 TKIs due to toxicity. Initial imatinib versus 2G-TKI versus ponatinib maintenance was discontinued in 19 (38.0%) versus 68 (57.6%) versus 3 (17.6%) patients due to toxicity (p = .003), respectively. Patients on ponatinib as their initial TKI had a longer duration of TKI maintenance versus 2G-TKI: 576.0 days (range, 72-921) versus 254.5 days (range, 3-2740; p = .02). The most common reasons for initial TKI discontinuation include gastrointestinal (GI) intolerance (15.1%), cytopenia (8.6%), and fluid retention (3.8%). The 5-year overall survival and progression-free survival for the total population were 78% and 71%, respectively. Our findings demonstrate the challenges of delivering post-HCT TKI maintenance in a large real-world cohort as toxicities leading to TKI interruptions, discontinuation, and dose reduction were common.

Therapy-related acute lymphoblastic leukaemia in women with antecedent breast cancer.

Therapy-related acute lymphoblastic leukaemia (tr-ALL) is a disease entity attributed to previous exposure to chemotherapy and/or radiation for antecedent malignancy. There is observed female predominance for tr-ALL, likely due to high prevalence and excellent curable rate for non-metastatic breast cancer as well as the frequent use of carcinogenic agents as part of adjuvant therapy. Here, we reviewed 37 women with diagnosis of ALL following breast cancer treatment with focus on cytogenetic categorization. Philadelphia chromosome positivity (Ph+), KMT2A alterations and other cytogenetic change groups were observed in 32%, 22% and 46% of patients respectively. Median overall survival (OS) and relapse-free survival (RFS) were 19.4 and 12.9 months, overall while both OS and RFS were superior in tr-ALL with Ph+ disease compared to KMT2Ar and other cytogenetics respectively. Seventeen (45.9%) patients underwent consolidative allogeneic haematopoietic cell transplantation (alloHCT) in CR1 out of which 4 (24%) relapsed following transplant. Both OS and RFS were superior in the KMT2Ar cytogenetics group following alloHCT. Ph chromosome represents the largest genetic entity of tr-ALL following breast cancer therapy, and it may be associated with superior survival outcomes while KMT2Ar may be associated with poorer outcomes that can perhaps be mitigated by alloHSCT.

Flotetuzumab as a salvage immunotherapy in advanced CD123-positive hematological malignancies, a phase 1 pilot study.

CD123 "expression" is common in hematological malignancies, including acute lymphoblastic leukemia (ALL). Flotetuzumab is a novel, investigational CD3/CD123 DART®. We conducted a phase 1 study evaluating safety and efficacy of flotetuzumab in relapsed/refractory ALL (Cohort A) and other advanced CD123-positive hematological malignancies (excluding myeloid malignancies) (cohort B). Thirteen patients (9 in Cohort A and 4 in Cohort B) were treated at dose level 1 (500 ng/kg/day) before early closure due to discontinuation of drug development by sponsor. Two dose limiting toxicities (Grade 4 thrombocytopenia and neutropenia) occurred in one patient in Cohort B. Cytokine release syndrome occurred in most patients (85%), all being grade ≤2. Responses only occurred in Cohort B, with a partial response in one patient with Hodgkin's lymphoma and morphological complete remission in the bone marrow in one patient with blastic plasmacytoid dendritic cell neoplasm. In conclusion, flotetuzumab had a manageable safety profile in advanced CD123-positive hematological malignancies.

Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).

Long-term follow-up of VIALE-A: Venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia.

Venetoclax-azacitidine is approved for treatment of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy based on the interim overall survival (OS) analysis of the VIALE-A study (NCT02993523). Here, long-term follow-up is presented to address survival benefit and long-term outcomes with venetoclax-azacitidine. Patients with newly diagnosed AML who were ineligible for intensive chemotherapy were randomized 2:1 to receive venetoclax-azacitidine or placebo-azacitidine. OS was the primary endpoint; complete remission with/without blood count recovery (CR/CRi) was a key secondary endpoint. This final analysis was conducted when 100% of the predefined 360 OS events occurred. In VIALE-A, 431 patients were enrolled to venetoclax-azacitidine (n = 286) or placebo-azacitidine (n = 145). At 43.2 months median follow-up, median OS was 14.7 months (95% confidence interval [CI], 12.1-18.7) with venetoclax-azacitidine, and 9.6 months (95% CI, 7.4-12.7) with placebo-azacitidine (hazard ratio, 0.58 [95% CI, 0.47-0.72], p < .001); the estimated 24-month OS rate was 37.5% and 16.9%, respectively. Median OS for patients with IDH1/2 mutations and those with measurable residual disease responses was reached in this final analysis. CR/CRi rate was similar to interim analysis. Any-grade hematologic and gastrointestinal adverse events were most common in venetoclax-azacitidine and placebo-azacitidine arms, including thrombocytopenia (47% and 42%) and neutropenia (43% and 29%). No new safety signals were identified. Long-term efficacy and safety confirm venetoclax-azacitidine is an improvement in standard-of-care for patients with AML who are not eligible for intensive chemotherapy because of advanced age or comorbidities.

Treatment of relapsed or refractory FLT-3 acute myelogenous leukemia with a triplet regimen of hypomethylating agent, venetoclax, and gilteritinib.

Relapsed or refractory (R/R) acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) mutations remains a difficult and hard to treat entity. Gilteritinib is a potent oral FLT-3 inhibitor that improves overall survival in R/R AML, but studies are limited in combining gilteritinib with a hypomethylating agent and venetoclax treatment backbone (HMA-VEN-GILT). Here we report our experience with HMA-VEN-GILT for 22 R/R FLT3 AML patients. HMA-VEN-GILT yielded an ORR of 77.3% (17/22), CR 4.5% (1/22), CRi 13.6% (3/22), MLFS 59.1% (13/22). Median follow-up was 10.4 months with a relapse rate of 29.4% (5/17), median time to relapse of 69 days (range 35-298 days), 6-month overall survival of 84%, and median OS of 10.1 months. Additionally, 36.4% (8/22) of patients proceeded to hematopoietic stem cell transplant. In conclusion, HMA-VEN-GILT for the treatment of R/R FLT3 AML is feasible and can be used as a bridge to allogeneic transplantation.

Patterns of interventions for central venous catheter-associated deep vein thrombosis and outcomes in cancer patients.

PURPOSE: This letter evaluated the impact of different management strategies, specifically the presence or absence of therapeutic anticoagulation, on clinical outcomes for central venous catheter (CVC)-associated deep vein thrombosis (DVT) in cancer patients. METHODS: One-hundred ninety-eight adult cancer patients with a confirmed CVC-associated DVT diagnosis from February 2013 and February 2021 were included. RESULTS: Incidence of symptomatic recurrent venous thromboembolism (VTE) was similar between patients who received therapeutic anticoagulation and those who did not (14% vs 16%, p = 0.807). In addition, therapeutic anticoagulation did not significantly alter the incidence of grade 3 and above bleeding events despite most patients having hematologic malignancies (9% vs 8%, p = 0.826). CONCLUSION AND RELEVANCE: Therapeutic anticoagulation was not associated with a reduction in the incidence of recurrent VTE or increase the incidence of bleeding in adult cancer patients following a CVC-associated DVT diagnosis.

A phase 1 trial of 8-chloro-adenosine in relapsed/refractory acute myeloid leukemia: An evaluation of safety and pharmacokinetics.

BACKGROUND: This study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 8-chloro-adenosine (8-Cl-Ado) in patients with relapsed/refractory acute myeloid leukemia (AML). METHODS: 8-Cl-Ado was administered daily for 5 days; the starting dose was 100 mg/m2 , the highest dose tested was 800 mg/m2 . The end points were toxicity, disease response, and PK/PD measurements. RESULTS: The predominant nonhematologic toxicity was cardiac with grade ≥3 toxicity. Plasma PK in all patients suggested heterogeneity among patients, yet, some dose-dependency for the accumulation of 8-Cl-Ado. Two 8-Cl-Ado metabolites accumulated at similar levels to 8-Cl-Ado. Cellular PK in eight patients indicated accumulation of 8-Cl-ATP, which was associated with AML blast cytoreduction in peripheral blood. The authors determined the RP2D of 8-Cl-Ado to be 400 mg/m2 . CONCLUSIONS: Given the cardiac adverse events observed, patients require monitoring for arrhythmias and QT interval during infusion. Although peripheral blood cytoreduction was observed, responses were transient, suggesting combination strategies will be required.