Modified Delphi Panel Consensus Recommendations for Management of Severe Aplastic Anemia.

Severe aplastic anemia (SAA) is a rare hematologic condition for which there is no clear management algorithm. A panel of 11 adult and pediatric experts on aplastic anemia was assembled and, using the RAND/UCLA modified Delphi panel method, evaluated >600 varying patient care scenarios to develop clinical recommendations for the initial and subsequent management of patients of all ages with SAA. Here we present the panel's recommendations to rule out inherited bone marrow failure (IBMF) syndromes, on supportive care prior to and during first-line therapy, and on first-line (initial management) and second-line (subsequent management) therapy of acquired SAA, focusing on when transplant versus medical therapy is most appropriate. These recommendations represent the consensus of 11 experts informed by published literature and experience. They are intended only as general guidance for experienced clinicians who treat patients with SAA and are in no way intended to supersede individual physician and patient decision-making. Current and future research should validate this consensus using clinical data. Once validated, we hope these expert panel recommendations will improve outcomes for patients with SAA.

Impact of academic medical center access on outcomes in multiple myeloma.

Treatment at academic cancer centers (ACs) is associated with improved survival across hematologic malignancies, though the benefit in multiple myeloma (MM) has not been examined. This study aims to evaluate survival outcomes at Commission on Cancer accredited ACs compared to non-academic centers (NACs) for patients receiving MM-directed therapy. The National Cancer Database (NCDB) was used to identify demographics and overall survival (OS) of MM patients diagnosed from 2004 to 2017 and to compare outcomes by facility type. Survival analysis was repeated in a propensity score matched cohort, with NACs matched 1:1 to ACs by age, race, comorbidity score, insurance, year of diagnosis, distance traveled, and income. Of 163 375 MM patients, 44.5% were treated at ACs. Patients at ACs were more likely to receive MM-directed therapy compared to NACs (81% vs. 73%, p < .001). For patients receiving treatment, median OS at ACs was 71.3 months versus 41.2 months at NACs (p < .001). When adjusted for baseline demographics, patients treated at ACs had reduced mortality; hazard ratio (HR) 0.79 (95% CI 0.78-0.81, p < .001). The propensity score matched cohort maintained this survival benefit with a median OS of 59.9 months at ACs versus 37.0 months at NACs (p < .001), HR of 0.66 (95% CI 0.64-0.67, p < .001). ACs treated younger patients with fewer comorbidities and were more likely to treat racial minorities and patients with Medicaid or private insurance, and the uninsured. In this analysis, MM patients treated at ACs have significantly improved survival. While potentially related to access to specialized care, socioeconomic factors that drive facility selection may also contribute.

Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study.

BACKGROUND: Primary analyses of cohort 1a of the REFINE trial showed that addition of navitoclax to ruxolitinib induced a 35% or greater reduction in spleen volume (SVR35) and reduced symptoms in patients with myelofibrosis no longer benefiting from ruxolitinib. Here, we report the exploratory post-hoc biomarker analyses from cohort 1a. METHODS: REFINE is a phase 2, multicentre, open-label trial designed to assess the activity and safety of navitoclax alone or in combination with ruxolitinib in patients with primary or secondary (post-polycythaemia vera or post-essential thrombocythaemia) myelofibrosis. Cohort 1a of the study included patients who had disease progression or suboptimal response on stable ruxolitinib monotherapy. Patients in cohort 1a, who had previously received ruxolitinib for 12 weeks or more, continued their current stable dose, and navitoclax was orally administered at 50 mg per day and escalated weekly to a maximum of 300 mg per day, based on tolerability. The primary activity endpoint was SVR35 at week 24 from baseline. Secondary endpoints were a 50% or greater reduction in total symptom score (TSS50) at week 24 from baseline as measured by the Myelofibrosis Symptom Assessment Form (version 4.0), anaemia response assessed according to International Working Group-Myeloproliferative Neoplasms Research and European LeukemiaNet criteria, and change in grade of bone marrow fibrosis according to the European consensus grading system; and exploratory endpoints included overall survival and changes in inflammatory cytokines. Exploratory analyses investigated potential prognostic biomarkers of the benefit of navitoclax-based combination treatment, including bone marrow fibrosis and variant allele frequency, in patients with a suboptimal response to ruxolitinib. This study is registered with ClinicalTrials.gov (NCT03222609) and is ongoing. FINDINGS: Between Nov 14, 2017, and April 10, 2019, 34 patients in cohort 1a received at least one dose of navitoclax plus ruxolitinib. 23 (68%) patients were male, with 32 (94%) being White. At data cutoff (May 6, 2021), the median follow-up for survivors was 26·2 months (IQR 21·9-32·3). 33 patients were evaluable for biomarker analyses; 19 (58%) had high molecular risk mutations. Five (31%) of 16 patients had SVR35 at week 24 in the high molecular risk group, as did four (31%) of 13 in the non-high molecular risk group. Four (36%) of 11 patients in the high molecular risk group had TSS50 at week 24 compared with two (25%) of eight in the non-high molecular risk group; seven (39%) of 18 in the high molecular risk group had an improvement in fibrosis by at least one grade compared with five (36%) of 14 in the non-high molecular risk group; and four (28%) of 14 had reductions in variant allele frequency of 20% or greater in the high molecular risk group compared with two (17%) of 12 in the non-high molecular risk group. Patients with improvements in fibrosis of one grade or more and a reduction of 20% of more in variant allele frequency had improved overall survival (median overall survival not reached) compared with those who did not achieve fibrosis improvement or a reduction in variant allele frequency (median overall survival 28·5 months [95% CI 19·6-not estimable] for both), suggesting potential disease modification. Additionally, changes in concentrations of ß-2-microglobulin (week 12: r=0·57; week 24: r=0·57), TIMP metallopeptidase inhibitor 1 (week 12: r=0·47; week 24: r=0·54), TNF receptor type II (r=0·55; week 24: r=0·40), and vascular cell adhesion molecule-1 (r=0·58; week 24: r=0·50) were positively associated with changes in spleen volume. INTERPRETATION: These biomarker analyses reveal clinically meaningful splenic responses independent of high molecular risk mutation status in patients treated with navitoclax plus ruxolitinib who were not benefiting from ruxolitinib monotherapy. Furthermore, the overall survival benefit observed in those with an improvement in fibrosis or a reduction in variant allele frequency is suggestive of disease modification, implying the therapeutic potential of adding navitoclax to ruxolitinib for patients with myelofibrosis who had disease progression or suboptimal response to ruxolitinib monotherapy. FUNDING: AbbVie.

Addition of Navitoclax to Ongoing Ruxolitinib Therapy for Patients With Myelofibrosis With Progression or Suboptimal Response: Phase II Safety and Efficacy.

PURPOSE: Targeting the BCL-XL pathway has demonstrated the ability to overcome Janus kinase inhibitor resistance in preclinical models. This phase II trial investigated the efficacy and safety of adding BCL-XL/BCL-2 inhibitor navitoclax to ruxolitinib therapy in patients with myelofibrosis with progression or suboptimal response to ruxolitinib monotherapy (ClinicalTrials.gov identifier: NCT03222609). METHODS: Thirty-four adult patients with intermediate-/high-risk myelofibrosis who had progression or suboptimal response on stable ruxolitinib dose (≥ 10 mg twice daily) were administered navitoclax at 50 mg once daily starting dose, followed by escalation to a maximum of 300 mg once daily in once in weekly increments (if platelets were ≥ 75 × 109/L). The primary end point was ≥ 35% spleen volume reduction (SVR35) from baseline at week 24. Secondary end points included ≥ 50% reduction in total symptom score (TSS50) from baseline at week 24, hemoglobin improvement, change in bone marrow fibrosis (BMF) grade, and safety. RESULTS: High molecular risk mutations were identified in 58% of patients, and 52% harbored ≥ 3 mutations. SVR35 was achieved by 26.5% of patients at week 24, and by 41%, at any time on study, with an estimated median duration of SVR35 of 13.8 months. TSS50 was achieved by 30% (6 of 20) of patients at week 24, and BMF improved by 1-2 grades in 33% (11 of 33) of evaluable patients. Anemia response was achieved by 64% (7 of 11), including one patient with baseline transfusion dependence. Median overall survival was not reached with a median follow-up of 21.6 months. The most common adverse event was reversible thrombocytopenia without clinically significant bleeding (88%). CONCLUSION: The addition of navitoclax to ruxolitinib in patients with persistent or progressive myelofibrosis resulted in durable SVR35, improved TSS, hemoglobin response, and BMF. Further investigation is underway to qualify the potential for disease modification.

A clinical, histopathological, and molecular study of two cases of VEXAS syndrome without a definitive myeloid neoplasm.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is caused by somatic mutations in UBA1 and is identified by a genotype-driven method. This condition affects unrelated men with adultonset inflammatory syndromes in association with hematologic manifestations of peripheral cytopenia and bone marrow myeloid dysplasia. Although bone marrow vacuolization restricted to myeloid and erythroid precursors has been identified in patients with VEXAS, the detailed clinical and histopathological features of peripheral blood and bone marrows remain unclear. The current case report describes the characteristic hematologic findings in patients with VEXAS, including macrocytic anemia, thrombocytopenia, marked hypercellular bone marrow with granulocytic hyperplasia, megaloblastic changes in erythroid precursors, and the absence of hematogones in addition to prominent vacuoles in myeloid and erythroid precursor cells. Characterizing the clinical and hematologic features helps to raise awareness and improve diagnosis of this novel, rare, but potentially underrecognized disease. Prompt diagnosis expands the general knowledgeable and understanding of this disease, and optimal management may prevent patients from developing complications related to this refractory inflammatory syndrome and improve the overall clinical outcome.

Histiocytic Neoplasms, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

Histiocytic neoplasms are rare hematologic disorders accounting for less than 1% of cancers of the soft tissue and lymph nodes. Clinical presentation and prognosis of these disorders can be highly variable, leading to challenges for diagnosis and optimal management of these patients. Treatment often consists of systemic therapy, and recent studies support use of targeted therapies for patients with these disorders. Observation ("watch and wait") may be sufficient for select patients with mild disease. These NCCN Guidelines for Histiocytic Neoplasms include recommendations for diagnosis and treatment of adults with the most common histiocytic disorders: Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease.

Dasatinib overcomes stroma-based resistance to the FLT3 inhibitor quizartinib using multiple mechanisms.

FLT3-ITD mutations occur in 20-30% of AML patients and are associated with aggressive disease. Patients with relapsed FLT3-mutated disease respond well to 2nd generation FLT3 TKIs but inevitably relapse within a short timeframe. In this setting, until overt relapse occurs, the bone marrow microenvironment facilitates leukemia cell survival despite continued on-target inhibition. We demonstrate that human bone marrow derived conditioned medium (CM) protects FLT3-ITD+ AML cells from the 2nd generation FLT3 TKI quizartinib and activates STAT3 and STAT5 in leukemia cells. Extrinsic activation of STAT5 by CM is the primary mediator of leukemia cell resistance to FLT3 inhibition. Combination treatment with quizartinib and dasatinib abolishes STAT5 activation and significantly reduces the IC50 of quizartinib in FLT3-ITD+ AML cells cultured in CM. We demonstrate that CM protects FLT3-ITD+ AML cells from the inhibitory effects of quizartinib on glycolysis and that this is partially reversed by treating cells with the combination of quizartinib and dasatinib. Using a doxycycline-inducible STAT5 knockdown in the FLT3-ITD+ MOLM-13 cell line, we show that dasatinib-mediated suppression of leukemia cell glycolytic activity is STAT5-independent and provide a preclinical rationale for combination treatment with quizartinib and dasatinib in FLT3-ITD+ AML.

The transcriptome of CMML monocytes is highly inflammatory and reflects leukemia-specific and age-related alterations.

Chronic myelomonocytic leukemia (CMML) is an aggressive myeloid neoplasm of older individuals characterized by persistent monocytosis. Somatic mutations in CMML are heterogeneous and only partially explain the variability in clinical outcomes. Recent data suggest that cardiovascular morbidity is increased in CMML and contributes to reduced survival. Clonal hematopoiesis of indeterminate potential (CHIP), the presence of mutated blood cells in hematologically normal individuals, is a precursor of age-related myeloid neoplasms and associated with increased cardiovascular risk. To isolate CMML-specific alterations from those related to aging, we performed RNA sequencing and DNA methylation profiling on purified monocytes from CMML patients and from age-matched (old) and young healthy controls. We found that the transcriptional signature of CMML monocytes is highly proinflammatory, with upregulation of multiple inflammatory pathways, including tumor necrosis factor and interleukin (IL)-6 and -17 signaling, whereas age per se does not significantly contribute to this pattern. We observed no consistent correlations between aberrant gene expression and CpG island methylation, suggesting that proinflammatory signaling in CMML monocytes is governed by multiple and complex regulatory mechanisms. We propose that proinflammatory monocytes contribute to cardiovascular morbidity in CMML patients and promote progression by selection of mutated cell clones. Our data raise questions of whether asymptomatic patients with CMML benefit from monocyte-depleting or anti-inflammatory therapies.

Effect of treatment dose reductions in the setting of hand-foot syndrome on survival outcomes in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor receptor inhibitors.

Purpose Hand-foot syndrome is a common dose limiting toxicity of vascular endothelial growth factor receptor tyrosine kinase inhibitors used for treatment of patients with metastatic renal cell carcinoma. The effect of treatment dose reductions, in the context of hand-foot syndrome, on survival outcomes is reported. Methods This was a retrospective case series of patients receiving vascular endothelial growth factor receptor tyrosine kinase inhibitors from 1 January 2004 to 31 October 2013. The main outcomes were progression-free and overall survival in these patients experiencing hand-foot syndrome and undergoing treatment dose reductions. Univariate and multivariate analyses were conducted utilizing Kaplan-Meier method and COX Proportional Hazard model with landmark analyses at 2 months. Results Of the 120 patients evaluated, treatment dose reductions for any reason were required in 68 (56.7%) patients. The most common reasons for treatment dose reductions were mucositis, hand-foot syndrome, and fatigue. The median progression-free survival and overall survival were significantly longer in patients with hand-foot syndrome with or without treatment dose reductions as compared to those without hand-foot syndrome. Conclusions An improvement in survival outcomes was observed in metastatic renal cell carcinoma patients with treatment-associated hand-foot syndrome despite treatment dose reductions. These data need validation in a larger cohort to confirm the hypothesis that treatment dose reductions in the setting of hand-foot syndrome do not negatively impatient survival.

Minimal Residual Disease Eradication in CML: Does It Really Matter?

BCR-ABL1 tyrosine kinase inhibitors (TKIs) have improved the prognosis of chronic phase chronic myeloid leukemia (CP-CML) to an extent that survival is largely determined by non-CML mortality. Monitoring for minimal residual disease by measuring BCR-ABL1 messenger RNA is a key component of CML management. CP-CML patients who achieve a stable deep molecular response may discontinue (TKIs) with an ~ 50% chance of entering treatment-free remission (TFR). So far discontinuation of TKIs has largely been limited to clinical trials, but is on the verge of becoming a part of wider clinical practice. Careful patient selection, dense molecular monitoring, and prompt reinstitution of treatment in the event of relapse are all vital to reproduce the same level of success. Much effort has been dedicated to identifying therapeutic strategies to eliminate CML stem cells and enable to TFR in more patients. Unfortunately, despite promising preclinical data, as yet, none of the various approaches have entered clinical practice.

Everolimus Versus Temsirolimus in Metastatic Renal Cell Carcinoma After Progression With Previous Systemic Therapies.

BACKGROUND: Everolimus is an approved agent for use after disease progression with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) in patients with metastatic renal cell carcinoma. With recently published trials showing efficacy of nivolumab and cabozantinib in the second-line therapy setting, the use of everolimus will likely move to the third- or fourth-line therapy setting. Temsirolimus has occasionally been used instead of everolimus for many reasons, including financial considerations, assurance of patient compliance given its intravenous administration, its toxicity profile, patient performance status, and patient or physician preference. However, efficacy of everolimus and temsirolimus in this setting have not been compared in a randomized trial. The results from retrospective studies have been inconsistent. MATERIALS AND METHODS: We identified patients treated with a first-line VEGFR-TKI for metastatic renal cell carcinoma and then treated with either everolimus or temsirolimus on progression from the databases of 2 large academic cancer centers. Progression-free survival (PFS) and overall survival (OS) were assessed from the initiation of second-line treatment using the Kaplan-Meier method. RESULTS: A total of 90 patients received either everolimus (n = 59; 66%) or temsirolimus (n = 31; 34%) after progression during first-line VEGFR-TKI therapy. The patient and disease characteristics were similar in both groups. The median PFS was not different, but OS was superior with everolimus compared with temsirolimus (24.2 months vs. 12.1 months; hazard ratio, 0.58; P = .047). CONCLUSION: Our results bolster existing guidelines supporting everolimus over temsirolimus as salvage therapy after previous systemic therapies.

Incidence of Severe Nephrotoxicity With Cisplatin Based on Renal Function Eligibility Criteria: Indirect Comparison Meta-analysis.

BACKGROUND: The objective of this meta-analysis was to indirectly compare incidence of nephrotoxicity in trials using cisplatin (CIS) for treatment of solid tumors when renal function was assessed using serum creatinine (SCr) or creatinine clearance (CrCl) for eligibility criteria. METHODS: Randomized trials comparing CIS-containing with non-CIS-containing chemotherapy regimens were identified in PubMed. Included studies were performed from 1990 to 2010, used SCr or CrCl as an eligibility criterion, and reported incidence of grade ≥3 nephrotoxicity for both treatment arms using World Health Organization (WHO) or National Cancer Institute (NCI) toxicity criteria. The relative risk (RR) of grade ≥3 nephrotoxicity associated with CIS versus non-CIS regimens was examined. Subgroup analyses, adjusted indirect comparison, and metaregression were used to compare SCr and CrCl. RESULTS: The literature search identified 2359 studies, 42 studies met all the inclusion criteria (N=9521 patients). SCr was used as an eligibility criterion in 20 studies (N=4704), CrCl was used in 9 studies (N=1650), and either was used in 13 studies (N=3167). The overall RR for developing nephrotoxicity with CIS versus non-CIS treatment was 1.75 (P=0.005). Subgroup analyses showed an increased risk when SCr was used (RR=2.60, P=0.005) but not when CrCl was used (RR=1.50, P=0.19). Both the adjusted indirect comparison and metaregression showed a nonsignificantly reduced risk of nephrotoxicity when CrCl was used. CONCLUSIONS: CIS-based therapy was associated with a significant increase in severe nephrotoxicity. The risk of severe nephrotoxicity appears to be lower when CrCl was used to determine whether people should be treated with CIS.

Survival Outcomes and Tumor IMP3 Expression in Patients with Sarcomatoid Metastatic Renal Cell Carcinoma.

Metastatic renal cell carcinoma with sarcomatoid histology (SmRCC) is associated with poor survival. No data is available from randomized trials on the efficacy of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors in SmRCC. We identified SmRCC patients from a single institutional database. To identify predictive and prognostic biomarkers, immunohistochemistry (IHC) analysis was performed on the tumor samples for downstream targets of VEGF and mTOR pathways. Survival outcomes were stratified by IHC analysis, extent of sarcomatoid component, Memorial Sloan-Kettering Cancer Center (MSKCC), and Heng risk criteria. Twenty-seven patients with SmRCC were included. First line therapy included targeted therapy (n = 19), immunotherapy (n = 4), cytotoxic chemotherapy (n = 1), and no treatment (n = 3). Median OS was 8.2 months (95% CI 3.8-14.2 months). Median survival in months, based on MSKCC and Heng risk groups, was favorable 89.3 versus 84.5, intermediate 9.5 versus 12.7, and poor 3.9 versus 5.1. None of the IHC markers predicted outcomes of treatment with VEGF or mTOR inhibitors. Only tumor IMP3 expression was associated with inferior OS, although not statistically significant (IMP3 negative 14.2 versus IMP3 positive 4.9 months; HR 0.46, 95% CI 0.16-1.21; P = 0.12). The study was limited by small sample size.

shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance.

The mechanisms underlying tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML) patients lacking explanatory BCR-ABL1 kinase domain mutations are incompletely understood. To identify mechanisms of TKI resistance that are independent of BCR-ABL1 kinase activity, we introduced a lentiviral short hairpin RNA (shRNA) library targeting ∼5000 cell signaling genes into K562(R), a CML cell line with BCR-ABL1 kinase-independent TKI resistance expressing exclusively native BCR-ABL1. A customized algorithm identified genes whose shRNA-mediated knockdown markedly impaired growth of K562(R) cells compared with TKI-sensitive controls. Among the top candidates were 2 components of the nucleocytoplasmic transport complex, RAN and XPO1 (CRM1). shRNA-mediated RAN inhibition or treatment of cells with the XPO1 inhibitor, KPT-330 (Selinexor), increased the imatinib sensitivity of CML cell lines with kinase-independent TKI resistance. Inhibition of either RAN or XPO1 impaired colony formation of CD34(+) cells from newly diagnosed and TKI-resistant CML patients in the presence of imatinib, without effects on CD34(+) cells from normal cord blood or from a patient harboring the BCR-ABL1(T315I) mutant. These data implicate RAN in BCR-ABL1 kinase-independent imatinib resistance and show that shRNA library screens are useful to identify alternative pathways critical to drug resistance in CML.

Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia.

Mutations in the BCR-ABL1 kinase domain are an established mechanism of tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive leukemia, but fail to explain many cases of clinical TKI failure. In contrast, it is largely unknown why some patients fail TKI therapy despite continued suppression of BCR-ABL1 kinase activity, a situation termed BCR-ABL1 kinase-independent TKI resistance. Here, we identified activation of signal transducer and activator of transcription 3 (STAT3) by extrinsic or intrinsic mechanisms as an essential feature of BCR-ABL1 kinase-independent TKI resistance. By combining synthetic chemistry, in vitro reporter assays, and molecular dynamics-guided rational inhibitor design and high-throughput screening, we discovered BP-5-087, a potent and selective STAT3 SH2 domain inhibitor that reduces STAT3 phosphorylation and nuclear transactivation. Computational simulations, fluorescence polarization assays and hydrogen-deuterium exchange assays establish direct engagement of STAT3 by BP-5-087 and provide a high-resolution view of the STAT3 SH2 domain/BP-5-087 interface. In primary cells from chronic myeloid leukemia (CML) patients with BCR-ABL1 kinase-independent TKI resistance, BP-5-087 (1.0 µM) restored TKI sensitivity to therapy-resistant CML progenitor cells, including leukemic stem cells. Our findings implicate STAT3 as a critical signaling node in BCR-ABL1 kinase-independent TKI resistance, and suggest that BP-5-087 has clinical utility for treating malignancies characterized by STAT3 activation.

Correlation of degree of hypothyroidism with survival outcomes in patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor receptor tyrosine kinase inhibitors.

BACKGROUND: Hypothyroidism is a common adverse effect of vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy in patients with metastatic renal cell carcinoma (mRCC). Some studies have shown an association with improved survival. However, hypothyroidism severity has not been correlated with survival outcomes. We report the incidence and severity of VEGFR-TKI therapy-associated hypothyroidism in correlation with the survival outcomes of patients with mRCC. PATIENTS AND METHODS: A retrospective analysis of patients with mRCC who received VEGFR-TKIs (2004 through 2013) was conducted from a single institutional database. Hypothyroidism, progression-free survival (PFS), and overall survival (OS) were assessed. Univariate and multivariate analyses were performed using the Kaplan-Meier method and Cox proportional hazard models. RESULTS: Of 125 patients with mRCC, 65 were eligible. Their median age was 59 years (range, 45-79 years), and 46 (70.8%) were male. Hypothyroidism occurred in 25 patients (38.5%), of whom 13 had a peak thyroid-stimulating hormone (TSH) level > 10 mIU/L during treatment. The median OS was significantly longer in patients with a peak TSH > 10 mIU/L than in patients with a peak TSH of ≤ 10 mIU/L (not reached vs. 21.4 months, P = .005). On multivariate analysis, risk criteria, number of previous therapies, and severe hypothyroidism (TSH > 10 mIU/L) during VEGFR-TKI therapy remained significant for improvements in PFS and OS. CONCLUSION: The severity of VEGFR-TKI therapy-associated hypothyroidism (TSH > 10 mIU/L) was associated with improved survival outcomes in patients with mRCC and should not necessitate a dose reduction or therapy discontinuation.