Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults.

BACKGROUND: Many older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)-negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission. METHODS: In a phase 3 trial, we randomly assigned patients 30 to 70 years of age with BCR::ABL1-negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.01% leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary end point was overall survival, and relapse-free survival was a secondary end point. RESULTS: The data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81%). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to overall survival (at 3 years: 85% vs. 68%; hazard ratio for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P = 0.002), and the 3-year relapse-free survival was 80% with blinatumomab and 64% with chemotherapy alone (hazard ratio for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatric events was reported in the blinatumomab group than in the chemotherapy-only group. CONCLUSIONS: The addition of blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival. (Funded by the National Institutes of Health and others; E1910 ClinicalTrials.gov number, NCT02003222.).

Dose-escalation of second-line and first-line asciminib in chronic myeloid leukemia in chronic phase: the ASC2ESCALATE Phase II trial.

Up to 40% of newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP) discontinue treatment by 5 years, primarily due to resistance or intolerance. Rates of resistance to second-line (2L) treatment are also high. Some patients with resistance respond with dose escalation of tyrosine kinase inhibitors (TKIs). Asciminib demonstrated safety and efficacy across a broad dosage range. ASC2ESCALATE is an ongoing, Phase II, multicenter, single-arm, dose-escalation study of asciminib in 2L and first-line treatment of CML-CP. The primary end point is major molecular response at 12 months in 2L. Secondary end points include molecular responses at and by scheduled time points, survival, and safety. ASC2ESCALATE is the first study investigating asciminib in CML-CP following failure of one prior TKI.Clinical Trial Registration: NCT05384587 (ClinicalTrials.gov).

ASC2ESCALATE is an ongoing, Phase II, multicenter, single-arm, #dose-escalation study of oral asciminib in first-line and second-line treatment for patients with #CML in chronic phase.

Implementation and evaluation of high-dose methotrexate administration guidelines.

BACKGROUND: High-dose methotrexate is used to treat a variety of malignancies. Methotrexate-associated supportive care and the threshold methotrexate level for the discontinuation of supportive care are not consistent among studies. We evaluated the implementation of high-dose methotrexate administration guidelines, which raised the standard threshold methotrexate level for the discontinuation of supportive care from <0.05 to <0.1 µmol. METHODS: A single-center, observational analysis of patients receiving high-dose methotrexate from 1 January 2015 to 31 May 2017 was conducted. The primary endpoint was time from the start of the methotrexate infusion until the discontinuation of the sodium bicarbonate infusion, before and after guideline implementation. RESULTS: Fifty-two patients met the inclusion criteria, which comprised of a total of 136 individual methotrexate doses and were included in the retrospective analysis. Twenty-four patients were included in the prospective analysis, which comprised a total of 46 individual methotrexate doses. The primary endpoint, time until discontinuation of the sodium bicarbonate infusion, was a median of 97.7 h in the retrospective group versus 73.2 h in the prospective group (p = 0.098). Secondary endpoints also favored patients in the prospective group, including hours of hospitalization, number of methotrexate levels checked, weight gained during admission, and adherence to the guideline. CONCLUSION: Among patients who received high-dose methotrexate, implementation of a guideline using a methotrexate threshold of <0.1 µmol was able to significantly decrease the time to discontinuation of supportive care and subsequently may lead to early hospital discharge given that we did not show a statistical significance.

Real-World Evaluation of Treatment Patterns and Clinical Outcomes among Patients With Chronic Myeloid Leukemia in Chronic Phase Treated With Asciminib in Clinical Practice in the United States: Real-world asciminib treatment outcomes in CML-CP.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are the mainstay treatment for chronic myeloid leukemia in chronic phase (CML-CP). Asciminib, an ABL/BCR::ABL1 inhibitor which binds to the myristoyl pocket, was recently approved in the US for patients with CML-CP previously treated with ≥2 TKIs or with the T315I mutation. This study described treatment patterns and real-world clinical outcomes among patients with CML-CP treated with asciminib in US clinical practice. METHODS: Electronic health record data from adult patients with CML-CP who initiated asciminib after ≥2 prior TKIs, without the T315I mutation, were obtained from the Flatiron Health database. Time-to-treatment discontinuation and molecular response (MR; time-to-BCR::ABL ≤0.1% and time-to-BCR::ABL1 ≤1%, separately) were evaluated from asciminib initiation (index date) using Kaplan-Meier analyses. RESULTS: Overall, 97 patients initiated asciminib (median age: 63 years, 50.5% female, 64.9% White) after either 2 (47.4%) or 3 (24.7%), or ≥4 (27.8%) prior TKIs. In total, 85.7% and 78.1% of patients remained on asciminib by 12- and 24-weeks postindex, respectively. Among patients with ≥1 MR assessment postindex, 31.3% (95% confidence interval [CI]: 21.6%, 43.9%) and 49.7% (95% CI: 38.1%, 62.6%) achieved or maintained BCR::ABL1 ≤0.1%, while 51.3% (95% CI: 40.1%, 63.6%) and 64.2% (95% CI: 52.6%, 75.6%) achieved or maintained BCR::ABL1 ≤1%, by 12- and 24-weeks, respectively. CONCLUSIONS: Results of this real-world study describing clinical outcomes among patients with CML-CP treated with asciminib after ≥2 prior TKIs in the US demonstrated that asciminib was well-tolerated and effective. These findings were consistent with results from the ASCEMBL trial.

A phase 1 trial of venetoclax in combination with liposomal vincristine in patients with relapsed or refractory B-cell or T-cell acute lymphoblastic leukemia: Results from the ECOG-ACRIN EA9152 protocol.

Introduction: Relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) remains a therapeutic challenge. Preclinical data in both B- and T-ALL suggests synergy of venetoclax (VEN) with vincristine (VCR). We designed a phase I/II trial (EA9152) of the combination of L-VCR and VEN for patients with r/r B-or T-cell ALL or LL. Here, we report the safety and efficacy outcomes of the phase I portion of this trial (NCT03504644). Methods: In a 3+3 dose escalation design, r/r ALL subjects were given single-agent VEN doses reaching 400, 600, or 800 mg for the three respective dose levels. Weekly L-VCR at 2.25 mg/m2 IV was started on D15 of cycle 1. The primary phase I objective was to determine the maximum tolerated dose (MTD) of the combination. Results: Among the 18 patients in phase I, grade ≥ 3 treatment-related adverse events were reported in 89% of treated patients. Two patients (two of three) at dose level 3 experienced dose-limiting toxicities. Therefore, the MTD of the combination was determined to be dose level 2 (VEN 600 mg). Twenty-two percent of evaluable patients (N = 4) achieved a complete response, with two of them showing no evidence of measurable residual disease (MRD). Conclusion: The combination of VEN and L-VCR was found to be safe for patients with r/r ALL and encouraging preliminary efficacy, including MRD negative responses. With the removal of L-VCR from the US market, the phase 2 portion of this trial is actively enrolling with vincristine sulfate.

Clarifying the use of ruxolitinib in patients with myelofibrosis.

Myelofibrosis (MF) is a hematopoietic stem cell malignancy classified as a myeloproliferative neoplasm (MPN). The clinical course of individuals with MF is heterogeneous and characterized by constitutional symptoms, bone marrow myeloproliferation and fibrosis, progressive cytopenias, and symptomatic splenomegaly. Historically, patients with this debilitating disease have had limited treatment options, and disease-modifying agents were not available. Hematopoietic stem cell transplantation is the only potentially curative therapy, but it is only an option for select patients. The discovery of an activating point mutation in the Janus kinase 2 gene (JAK2V617F) in a significant portion of patients with MPNs led to improved understanding of the pathobiology of these disorders and prompted rapid development of JAK inhibitors. Ruxolitinib (Jakafi) is the first-in-class and only JAK inhibitor currently approved by the US Food and Drug Administration (FDA) for the treatment of patients with MF; approval was based on the results of the COMFORT (COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment) I and II studies. While not a curative option, ruxolitinib offers great palliative potential and results in significant reduction in splenomegaly and improvement in constitutional symptoms in the majority of treated patients, thus improving their quality of life and performance status. Additionally, ruxolitinib is the only agent that has demonstrated a survival benefit in patients with MF. The optimal use of ruxolitinib for MF patients is challenging and complex. In this article, we provide updated data on ruxolitinib therapy for patients with MF and offer expert opinion on the appropriate use of this agent in the community practice.

Real-world Management of CML: Outcomes and Treatment Patterns.

PURPOSE OF REVIEW: Chronic myeloid leukemia (CML) is a disease that previously signified a poor prognosis, but treatment options and outcomes have improved over the last several decades. Despite this, challenges remain in optimal management in clinical practice, as the characteristics in trial populations differ from patients who are treated in a real-world setting. This review describes recent updates in real-world treatment patterns and outcomes in patients with CML. RECENT FINDINGS: Several analyses describing real-world practice patterns show that tyrosine kinase inhibitors (TKIs) are the most commonly prescribed agents in multiple lines of therapy. First-generation (1G) and second-generation (2G) TKIs are the most commonly prescribed, even in the third line and beyond. Third-generation (3G) TKIs are typically utilized in patients with resistant disease who are younger with fewer comorbidities. Hematopoietic stem cell transplant (HSCT) is utilized significantly less, given other treatment options available. The goals of treatment with CML have shifted to quality of life, cost savings, and treatment-free response (TFR). Despite clear guidelines for attempting TFR, discontinuation practice patterns remain inconsistent. TKIs are the mainstay of CML treatment, including those in later lines of therapy. In real-world practice, several challenges still remain with regard to optimal management. Specifically, ideal sequencing of treatments, side effect profiles of tyrosine kinase inhibitors (TKIs), current role and timing of transplant, and adherence to recommendations for attempting to achieve a treatment-free response (TFR). A national registry could characterize these practice patterns in order to find ways to optimize care for CML patients.

Dasatinib/prednisone induction followed by blinatumomab/dasatinib in Ph+ acute lymphoblastic leukemia.

Novel treatment strategies are needed for the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in older patients. This trial evaluated the feasibility and outcomes with the anti-CD19 bispecific T-cell-engaging antibody, blinatumomab, in combination with dasatinib and steroids. Patients 65 years of age or older with Ph+ or Ph-like ALL (with dasatinib-sensitive fusions/mutations) were eligible and could be newly diagnosed or relapsed/refractory. Induction therapy consisted of dasatinib/prednisone. Patients not achieving response by day 56 proceeded to blinatumomab reinduction therapy. Patients achieving response with induction or reinduction therapy proceeded to blinatumomab/dasatinib postremission therapy for 3 cycles followed by dasatinib/prednisone maintenance. All patients received central nervous system prophylaxis with intrathecal methotrexate for a total of 8 doses. Response was assessed at days 28, 56, and 84 and at additional time points based on response parameters. Measurable residual disease was assessed centrally by 8-color flow cytometry at day 28. A total of 24 eligible patients with newly diagnosed Ph+ ALL were enrolled with a median age of 73 years (range, 65-87 years). This combination was safe and feasible. With a median of 2.7 years of follow-up, 3-year overall survival and disease-free survival were 87% (95% confidence interval [CI], 64-96) and 77% (95% CI, 54-90), respectively. Although longer follow-up is needed, these results are encouraging, and future trials are building on this backbone regimen. This trial was registered at www.clinicaltrials.gov as #NCT02143414.

Management of Myeloproliferative Neoplasms in the Molecular Era: From Research to Practice.

The 1960 discovery of the Philadelphia chromosome in chronic myeloid leukemia (CML) marked the beginning of the modern genomic era of oncology. In the following years, the molecular underpinnings of CML were unraveled, culminating in the development of the first molecularly targeted therapy: imatinib. Imatinib revolutionized CML management, inducing deep molecular responses for most patients and aligning survival curves with those of age-matched control participants. Five additional tyrosine kinase inhibitors are now approved for CML: dasatinib, nilotinib, bosutinib, ponatinib, and asciminib (approved October 2021). The 2005 discovery of JAK2 mutations in myelofibrosis (MF) sparked enthusiasm that molecularly targeted therapies could have a similar impact in that disease. Three JAK inhibitors are now available for MF: ruxolitinib, fedratinib, and pacritinib (approved February 2022). JAK inhibitors are helpful for improving symptoms and splenomegaly but still only scratch the surface of MF pathophysiology. Clinical research testing novel agents, next-generation JAK inhibitors, and combinations of JAK inhibitors plus novel agents is moving at a tremendous pace in the hope that outcomes for patients with MF may mirror those with CML one day. This review provides an update on the status of clinical care and research for MF and addresses ongoing issues related to CML management.

Chronic Myeloid Leukemia: Part II-Cost of Care Among Patients in Advanced Phases or Later Lines of Therapy in Chronic Phase in the United States from a Commercial Perspective.

Background: Tyrosine kinase inhibitors (TKIs) are the standard-of-care treatment for chronic myeloid leukemia in chronic phase (CML-CP). Despite advances in therapy, there remains a proportion of patients with CML-CP that are refractory/intolerant to TKIs, and these patients cycle through multiple lines of therapy. Moreover, even with TKIs, some patients progress to accelerated phase/blast crisis (AP/BC), which is associated with particularly poor clinical outcomes. Objectives: To describe real-world treatment patterns, healthcare resource utilization (HRU), and costs of patients with CML-CP reaching later lines of therapy or progressing to AP/BC in the United States. Methods: Adult CML patients from administrative claims data (January 1, 2000-June 30, 2019) were classified by health state: on third-line (CML-CP On Treatment), on fourth or later lines (CML-CP Post-Discontinuation), or progressed to AP/BC (CML-AP/BC). Outcomes were assessed by health state. Results: There were 296 (4620 patient-months), 83 (1644 patient-months), and 949 (25 593 patient-months) patients classified in the CML-CP On Treatment, CML-CP Post-Discontinuation, and CML-AP/BC cohorts, respectively. Second-generation TKIs (nilotinib, dasatinib, and bosutinib) were most commonly used in the CML-CP On Treatment (69.1% of patient-months) and CML-CP Post-Discontinuation cohorts (59.1% of patient-months). Three-month outpatient incidence rates (IRs) were 7.6, 8.3, and 7.0 visits in the CML-CP On Treatment, CML-CP Post-Discontinuation, and CML-AP/BC cohort, respectively, with mean costs of $597 per service. Three-month inpatient IRs were 0.6, 0.7, and 1.4 days in the CML-CP On Treatment, CML-CP Post-Discontinuation, and CML-AP/BC cohort, respectively, with mean costs of $5892 per day. Mean hematopoietic stem cell transplantation cost was $352 333; mean 3-month terminal care cost was $107 013. Discussion: Cost of CML care is substantial among patients with CML reaching third-line, fourth or later lines, or progressing to AP/BC, suggesting that the disease is associated with a significant economic and clinical burden. From third-line to fourth or later lines, HRU was observed to increase, and the incidence of inpatient days was particularly high for those who progressed to AP/BC. Conclusion: In this study, patients with CML cycling through TKIs in later lines of therapy or progressing to AP/BC experienced substantial HRU and costs, suggesting unmet treatment needs.

Chronic Myeloid Leukemia: Part I-Real-World Treatment Patterns, Healthcare Resource Utilization, and Associated Costs in Later Lines of Therapy in the United States.

Background: Despite advances in tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia in chronic phase (CML-CP), a sizeable proportion of patients with CML-CP remains refractory or intolerant to these agents. Objectives: Treatment patterns, healthcare resource utilization (HRU), and costs were evaluated among patients with CML who received third or later lines of therapy (3L+), a clinical population that has not been previously well-studied, with unmet treatment needs as TKI therapy has repeatedly failed. Methods: Adult patients with CML who received 3L+ were identified in the IBM® MarketScan® Databases (January 1, 2001-June 30, 2019) and the SEER-Medicare-linked database (January 1, 2006-December 31, 2016). Treatment patterns were observed from CML diagnosis. HRU and direct healthcare costs (payer's perspective, 2019 USD) were measured in a 3L+ setting. Results: Among 296 commercially insured patients with 3L+ (median age, 58.5 years; female, 49.7%), the median duration of first-line (1L), second-line (2L), and 3L therapy was 8.5, 4.2, and 8.3 months, respectively. The annual incidence rate during 3L+ was 3.4 for inpatient days, 30.8 for days with outpatient services, and 1.2 for emergency department visits. Mean per-patient-per-month (PPPM) total healthcare costs (pharmacy + medical costs) were $18 784 in 3L+, $15 206 in 3L, and $19 546 in 4L, with inpatient costs driving most of the difference between 3L and 4L (mean [3L] = $2528 PPPM, mean [4L] = $6847 PPPM). Among 53 Medicare-insured patients with 3L+ (median age, 72.0 years; female, 39.6%), the median duration of 1L, 2L, and 3L therapy was 9.7, 5.0, and 7.0 months, respectively. During 3L+, the annual incidence rate was 10.3 for inpatient days, 61.9 for days with outpatient services, and 1.5 for emergency department visits. Mean PPPM total healthcare costs were $14 311 in 3L+, $15 100 in 3L, and $16 062 in 4L. Discussion: Patients with CML receiving 3L+ rapidly cycled through multiple lines. Costs increased from 3L to 4L; in commercially insured patients, inpatient costs were responsible for most of the cost increase between 3L and 4L, underlying these patients' continued need for care. Conclusions: These findings support the need for better treatment options in patients with CML undergoing later lines of therapy.

Why isn't there a one-size-fits-all approach for relapsed/refractory acute myeloid leukemia? Insights into different variables for decision-making.

Relapsed refractory acute myeloid leukemia (R/R AML) has a poor prognosis. While the heterogeneity and diversity of R/R AML pose hurdles towards defining a standard of care, there have been various advances over the years. These, however, have added to the complexity of decision-making for R/R AML. This review has summarized evidence that will provide insights into factors that influence treatment choices in R/R AML and determine whether ongoing clinical trials can aid in identifying a standard approach for different sub-groups of patients.

Tyrosine kinase inhibitor therapy discontinuation in patients with chronic myeloid leukemia in chronic phase in the United States after clinical practice guideline updates.

A physician survey (July 2019-August 2019) and a retrospective patient medical chart review (November 2019-December 2019) were conducted to assess TKI therapy discontinuation practice in patients with Ph + CML-CP in the US after the publication of practice guidelines updated with recommendations for TKI discontinuation. After guideline updates, 90% of physicians from the survey reported attempting TKI discontinuation and 24% of their patients discontinued TKI after achieving an adequate response. Although TKI therapy discontinuation practice is increasing, particularly in community-based practice, a little more than half of physicians were aware of these updated guidelines resulting in TKI discontinuation attempted under suboptimal conditions, mainly limited to first-line TKI therapy, with more than half of physicians without access to at least MR4.5 sensitivity level of detection monitoring. Stricter response criteria per guideline recommendations were observed to relate to lower relapse rates following TKI discontinuation, emphasizing the importance of communicating these recommendations and access to adequate monitoring tools.

Comparison of salvage chemotherapy regimens and prognostic significance of minimal residual disease in relapsed/refractory acute myeloid leukemia.

We compared the outcomes of salvage chemotherapy in 146 patients with relapsed (57.5%) or refractory (42.5%) AML who received CLAG-M (51%), MEC (39%) or CLAG (10%). Minimal residual disease (MRD) was assessed by flow cytometry. Bivariate, Kaplan-Meier, and Cox regression analyses were conducted. Complete remission (CR) rate of 46% (CLAG-M 54% versus MEC/CLAG 40%, p = .045) was observed with MRD-negative CR of 33% (CLAG-M 39% versus MEC/CLAG 22%, p = .042). Median overall survival (OS) was 9.7 months; the longest OS occurred with CLAG-M (13.3, 95%CI 2.4-24.3) versus MEC (6.9, 95%CI 2.9-10.9) or CLAG (6.2, 95%CI 2.4-12.6) (p = .025). When adjusted for age, gender, relapsed/refractory AML, poor risk AML, MRD, chemotherapy and transplant, CLAG-M (HR 0.63, 95% CI 0.40-0.98, p = .042), MRD-negativity (HR 0.15, 95% CI 0.07-0.30, p < .001) and transplant (HR 0.22, 95% CI 0.13-0.39, p < .001) were associated with higher OS. Our findings confirm that CLAG-M is a reasonable salvage regimen for RR-AML followed by transplant.

Tyrosine kinase inhibitor therapy treatment and discontinuation in patients with chronic myeloid leukemia in chronic phase in the United States: a clinical practice perspective.

Tyrosine kinase inhibitor (TKI) therapy discontinuation practice in patients with chronic myeloid leukemia chronic phase (CML-CP) was assessed in real-world practice prior to the release of recommendations on discontinuation. Data were collected from US oncologists/hematologists (through web-based physician survey and patient chart review) on TKI therapy discontinuation practice including monitoring, adequate response for discontinuation, relapse, and symptoms following discontinuation. From the physician survey, 34% of oncologists/hematologists attempted discontinuation, with two-thirds doing so outside of a trial. From the chart review, TKI therapy was discontinued in 3.4% of patients after they achieved an adequate response with the intention to remain CML-therapy-free until disease relapse. Among these patients, 21% relapsed and 17% had symptoms following discontinuation. There was a lack of consensus on the definition of adequate response suggesting that discontinuation was attempted without clear guidelines and under suboptimal conditions underscoring the need for physician education regarding guidelines for TKI therapy discontinuation.

Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial.

PURPOSE: The clinical relevance of targeting the RAS/RAF/MEK/ERK pathway, activated in 70% to 80% of patients with acute myelogenous leukemia (AML), is unknown. EXPERIMENTAL DESIGN: Selumetinib is an oral small-molecule inhibitor of MAP-ERK kinase (MEK)-1/2. Forty-seven patients with relapsed/refractory AML or 60 years old or more with untreated AML were enrolled on a phase II study. Patients were stratified by FLT3 ITD mutation status. The primary endpoint was response rate (complete, partial, and minor). Leukemia cells were analyzed for extracellular signal-regulated kinase (ERK) and mTOR phosphorylation. RESULTS: Common drug-related toxicities were grade 1-2 diarrhea, fatigue, nausea, vomiting, and skin rash. In the FLT3 wild-type cohort, six of 36 (17%) patients had a response [one partial response, three minor responses, two unconfirmed minor responses (uMR)]. No patient with FLT3 ITD responded. NRAS and KRAS mutations were detected in 7% and 2% of patients, respectively. The sole patient with KRAS mutation had uMR with hematologic improvement in platelets. Baseline p-ERK activation was observed in 85% of patients analyzed but did not correlate with a response. A single-nucleotide polymorphism (SNP) rs3733542 in exon 18 of the KIT gene was detected in significantly higher number of patients with response/stable disease compared with nonresponders (60% vs. 23%; P = 0.027). CONCLUSIONS: Selumetinib is associated with modest single-agent antileukemic activity in advanced AML. However, given its favorable toxicity profile, combination with drugs that target other signaling pathways in AML should be considered. The potential association of SNP rs3733542 in exon 18 of the KIT gene with antileukemic activity of selumetinib is intriguing, but will require validation in larger trials.