Lenalidomide-Epoetin Alfa Versus Lenalidomide Monotherapy in Myelodysplastic Syndromes Refractory to Recombinant Erythropoietin

Abstract

PURPOSE

Impaired response to erythropoietin underlies ineffective erythropoiesis and anemia in myelodysplastic syndromes (MDS). We investigated whether treatment with lenalidomide (LEN), which augments erythropoietin receptor signaling in vitro, can restore and improve hemoglobin response to epoetin (EPO) alfa in patients with lower-risk, non-del(5q) MDS who have anemia that is refractory to or have low probability of benefit from treatment with recombinant erythropoietin.

METHODS

In a phase III, US intergroup trial, we randomly assigned patients to receive either LEN and EPO alfa or LEN alone following stratification by serum erythropoietin concentration and prior erythropoietin treatment.

RESULTS

A total of 195 evaluable patients were randomly assigned: 99 patients to the LEN-EPO alfa cohort and 96 to LEN alone. After four cycles of treatment, the primary end point of major erythroid response (MER) was significantly higher (28.3%) with the combination compared with LEN alone (11.5%) (P = .004). Among 136 patients who completed 16 weeks of study treatment, 38.9% and 15.6% achieved MER, respectively (P = .004). Additionally, minor erythroid response was achieved in 18.2% and 20.8% of patients, for an overall erythroid response rate of 46.5% versus 32.3%. Among LEN nonresponders, 38 crossed over to the addition of EPO alfa with 10 patients (26.3%) achieving a MER. Responses to the combined treatment were highly durable with a median MER duration of 23.8 months compared with 13 months with LEN alone.

CONCLUSION

LEN restores sensitivity to recombinant erythropoietin in growth factor–insensitive, lower-risk, non-del(5q) MDS, to yield a significantly higher rate and duration of MER compared with LEN alone (funded by the National Cancer Institute; E2905 ClinicalTrials.gov identifier: NCT02048813).

INTRODUCTION

Symptomatic anemia is the most common indication for the treatment of patients with lower-risk myelodysplastic syndromes (MDSs). Treatment with recombinant erythropoietin has been the long-standing standard of care; however, only a small subset of patients experience a sustained, meaningful improvement in hemoglobin.^1,2 Ineffective erythropoiesis in MDS arises in part from deficient lipid raft integrity that impairs erythropoietin receptor signal fidelity, thereby limiting growth factor responsiveness.^3,4 The thalidomide analogue lenalidomide (LEN) promotes erythropoiesis in vitro and enables the expansion of primitive erythroid precursors.⁵ We showed that LEN relieves repression of erythropoietin receptor signaling in MDS progenitors by inducing the assembly of membrane lipid raft microdomains that are enriched in signaling competent, Janus kinase-2/erythropoietin receptor complexes.^3,6 In contrast, in MDS with chromosome 5q deletion (del(5q)), LEN is selectively cytotoxic to the MDS clone by virtue of synthetically lethal degradation of the haplodeficient casein kinase 1A1 encoded within the commonly deleted region.^7,8 In two prior clinical studies in patients with transfusion-dependent, lower-risk, non-del(5q) MDS whose anemia was resistant to recombinant erythropoietins, LEN displayed modest single agent effectiveness, giving rise to RBC transfusion independence in 26% of patients that lasted a median of 10 and 7 months.^9,10 In a proof of principle, small two-stage pilot study in patients with erythropoietin-refractory, lower-risk, non-del(5q) MDS, the addition of epoetin (EPO) alfa to LEN treatment yielded erythroid responses in 26% of patients who were unresponsive to LEN alone, suggesting that LEN may overcome clinical growth factor resistance to augment response to recombinant erythropoietin.¹¹ Recently, a randomized trial involving 131 patients with lower-risk, transfusion-dependent MDS demonstrated that the combination of LEN and EPO beta was superior to LEN alone, further supporting our hypothesis.¹² Based on these data, we performed a randomized phase III trial comparing treatment with LEN and EPO alfa with LEN alone in patients with lower-risk, non-del(5q) MDS who had anemia that was refractory to or were not candidates for treatment with recombinant erythropoietin.

CONTEXT

• Key Objective

• Using a phase III randomized trial, we investigated whether treatment with LEN can restore and improve hemoglobin response to EPO alfa in patients with lower-risk, non-del(5q) myelodysplastic syndromes who have anemia that is refractory to or have low probability of benefit from treatment with recombinant erythropoietin.

• Knowledge Generated

• Major erythroid response was significantly higher (28.3%) with the combination of LEN and erythropoietin when compared with LEN alone (11.5%) (P = .004). Responses to the combined treatment were highly durable with a median major erythroid response duration of 23.8 months compared with 13 months with LEN alone.

• Relevance

• Patients with lower-risk, non-del(5q) myelodysplastic syndromes with anemia insensitive to growth factors may derive benefit from combination of LEN and erythropoietin.

METHODS

Eligible patients were aged ≥ 18 years with a diagnosis of MDS or nonproliferative chronic myelomonocytic leukemia (WBC < 12,000/μL) other than MDS with deletion (5q) of at least 3-month duration according to WHO criteria^13,14 and International Prognostic Scoring System categories of low- or intermediate-1-risk disease¹⁵ and had symptomatic anemia either untransfused with hemoglobin < 9.5 g/dL in the 8 weeks prior to random assignment or with RBC transfusion dependence (ie, ≥ 2 units/mo) confirmed 8 weeks before random assignment. Informed consent was obtained from all study participants. Patients must have failed to respond or lost response to treatment with recombinant erythropoietin (defined in the Data Supplement, online only) or had low probability of response (erythropoietin-naïve patients receiving ≥ 2 U RBC/mo for a minimum of 8 weeks and serum erythropoietin > 500 mU/mL in the 8 weeks prior to random assignment for a hemoglobin < 9.5 g/dL).¹⁶ Patients with therapy-related MDS were excluded. Patients with MDS with deletion (5q) were enrolled but assigned to receive LEN alone and excluded from this analysis. Additional inclusion or exclusion criteria are provided in the Data Supplement. The primary end point was major erythroid response (MER) at week 16 that was defined according to transfusion status at baseline: (1) achievement of RBC transfusion independence for ≥ 8 consecutive weeks accompanied by a sustained ≥ 1 g/dL hemoglobin rise compared with mean pretransfusion baseline value in transfusion-dependent patients (≥ 4 U RBC/8 wk) or (2) a > 2 g/dL rise in hemoglobin without transfusion for ≥ 8 consecutive weeks in nontransfusion-dependent patients (< 4 U RBC/8 wk).

A total trial enrollment of 252 patients was planned to have 212 patients with non-del(5q) MDS randomly assigned for the primary analysis. Using the statistical package EaSt (Cytel Software Corporation, 1993, Cambridge, MA) to account for multiple interim looks in a sequential design for binomial distribution with continuity correction, a sample size of 212 randomly assigned patients was estimated to provide approximately 80% power to detect an improvement of 20% in MER rate in the combination arm with an overall one-sided type I error rate of 0.025, assuming 30% of MER rate in the LEN-alone arm.

Details about trial oversight, study design, response and safety assessment, statistical analysis, and targeted sequencing are provided in the Data Supplement.

RESULTS

Patients

From January 2009 through May 2016, the trial enrolled a total of 247 patients. Among those enrolled, 38 had Del(5q) MDS and were not randomly assigned. Of the 209 eligible patients randomly assigned, 14 (seven receiving LEN alone and seven receiving the combination) were excluded from the primary analysis because of a 4-month interruption in drug supply. Among the 195 evaluable patients, 99 were assigned to LEN and EPO alfa treatment and 96 to LEN alone (CONSORT diagram, Fig 1). Baseline characteristics were overall well-balanced between arms with 85% of patients transfusion-dependent, receiving a median of 4 units/8 wk (Table 1). Only 15 (15.2%) patients assigned to combined treatment and 15 (15.6%) assigned to LEN alone were untransfused at baseline. Bone marrow pathology was centrally reviewed by J.M.B. for assignment of WHO MDS category. A total of 47.2% of patients had MDS with ring sideroblasts (MDS-RS). The median age was 74 years (range, 47-92 years), 71.3% of patients were male, and the median interval from diagnosis was 1.6 years (range, 0-18 years). Overall, 93% of patients received prior treatment with recombinant erythropoietin and 18% received prior treatment with an azanucleoside. More patients randomly assigned to the treatment with LEN-alone received prior treatment with an azanucleoside than patients randomly assigned to the treatment with LEN alone (P = .04). The median serum erythropoietin level was 156 mU/mL (range, 11-3,264 mU/mL).

FIG 1.

CONSORT diagram. ^aThree patients crossed over to LEN and EPO alfa before finishing four cycles of treatment with LEN alone. EPO, epoetin; LEN, lenalidomide; MDS, myelodysplastic syndromes.

TABLE 1.

Baseline Patient Demographic and Disease Characteristics

Efficacy

Of the 195 evaluable patients, 157 (81%) were assigned to treatment with LEN at a dose of 10 mg once daily (81 LEN and EPO v 76 LEN alone), whereas 38 (19%) were administered LEN 5 mg once daily (18 LEN and EPO v 20 LEN alone). In an intent-to-treat analysis, the proportion of patients who achieved a MER was significantly higher in the combined treatment group (28 of 99 patients, 28.3%) than in those patients assigned to LEN alone (11 of 96, 11.5%; P = .004). Patients who did not have response evaluation were included in the calculation of response rates as nonresponders. Among the 136 patients who completed 16 weeks of study treatment, 28 of 72 (38.9%) and 10 of 64 (15.6%) achieved a MER (P = .004). Additionally, among the 65 nonresponders to LEN monotherapy, 38 patients crossed over to receive the addition of EPO alfa with 10 patients (26.3%) achieving a MER. The maximum hemoglobin concentration in all major erythroid responders reached a median of 12.4 g/dL (range, 10.2-15.5 g/dL), with a corresponding median rise of 4.1 g/dL (range, 1.6-8.0 g/dL), compared with the baseline mean pretransfusion value. The corresponding improvement in hemoglobin by the treatment arm was similar, with a median rise in hemoglobin of 4.0 g/dL (range, 1.6-7.3 g/dL) and 4.1 g/dL (range, 2.0-8.0 g/dL) in the combination and LEN treatment arms, respectively (P = .79). The median interval from initiation of treatment to achievement of MER was comparable between treatment arms (LEN, 3.6 months v LEN and EPO alfa, 3.7 months; range, 2.1-5.5 months v 1.0-10.6 months). The median duration of treatment with EPO alfa in major erythroid responders was 14.9 months (range, 0.7-82.3 months), whereas the median duration of treatment with LEN in MER responders receiving the combination was 17.4 months (range, 3.4-81.8 months). The median duration of MER was 23.8 months among the 39 responders in the combined therapy cohort compared with 13 months in the LEN cohort (log rank test, P = .24, Fig 2). Overall, 15 of 46 (32.6%) patients receiving < 4 units/8 wk and 13 of 53 (24.5%) patients averaging > 4 units/8 wk receiving the combined treatment experienced a MER, compared with 4 of 41 (9.8%) and 7 of 55 (12.7%) of patients receiving LEN monotherapy (P = .75).

FIG 2.

Kaplan-Meier estimate of duration of major erythroid response in responders. LEN, lenalidomide; LEN + EPO, lenalidomide plus epoetin.

Multivariable logistic regression modeling was performed to examine the potential impact of covariates on MER by adjusting for the number of years from diagnosis > 2, WHO disease type, International Prognostic Scoring System risk score, prior treatment with an azanucleoside or recombinant erythropoietin, baseline serum erythropoietin level, bone marrow blast percentage, baseline total leukocyte count, baseline transfusion burden (< 4 units/8 wk v ≥ 4 units/8 wk), and assigned treatment. After adjusting for covariates, only treatment with the combination remained significant (P = .01). There was no significant difference in MER by treatment arm according to baseline transfusion burden.

There was no difference in the frequency of minor erythroid response between the treatment arms. Eighteen (18.2%) patients receiving the combined treatment achieved a minor erythroid response compared with 20 (20.8%) receiving LEN alone. Overall erythroid response rate, that is, major and minor erythroid response, was marginally higher with treatment with LEN-EPO alfa (n = 46, 46.5%) compared with treatment with LEN alone (n = 31, 32.3%), respectively (P = .057).

A total of 127 patients had sufficient baseline DNA from bone marrow or peripheral blood for targeted deep gene sequencing. Among the 195 patients included in the primary analyses, 103 had informative sequencing data that included 76 non-MER and 27 MER patients. Of the 170 myeloid and bone marrow failure genes sequenced, mutations were detected in 85 genes (Data Supplement). Nine genes were mutated in more than 5% of patients, including SF3B1 (37.9%), TET2 (31.1%), ASXL1 (11.7%), EZH2 (8.7%), DNMT3A (6.8%), KDM6B (6.8%), PCLO (6.8%), NOTCH1 (5.8%), and BRCA2 (5.8%). There were no significant differences in the distribution of gene mutations by response. Analysis of the distribution of gene mutations by functional class (ie, ribosomes and translation, transcription factors, kinase and signaling, epigenetic modifiers, DNA repair, cohesin complex, mRNA splicing, and other classes) identified no significant differences in the mutation frequency by response in univariate analysis (Data Supplement). In multivariate analysis, only the distribution of kinase and signaling gene mutations approached significance with a lower mutation rate in MER patients than in non-MER patients (n = 22, 28.9%; v n = 4, 14.8%; P = .08). Of interest, comparison of response according to the number of gene mutations (Data Supplement) showed that nonresponders had a significantly higher proportion of patients without mutation or with a lower number of mutations versus MER patients in univariate analysis (n = 16, 21.1%; v n = 1, 3.7%; P = .031); however, this was not confirmed in multivariate analysis. There were no significant differences in the duration of MER according to the total number of gene mutations or mutation functional class with the exception of DNA repair gene mutations (Data Supplement) in which the median duration of MER approached significance (unmutated, 8.5 months v mutated, not reached with 95% confidence lower limit 4.1 months; P = .054 log rank test).

Safety

There was no statistically significant difference in the frequency of grade 3 or greater, nonhematologic adverse events between the treatment arms (Table 2). The most frequently reported grade 3 or greater nonhematologic adverse events were fatigue (n = 11, 5.6%), maculopapular rash (n = 7, 3.6%), febrile neutropenia (n = 6, 3.1%), and diarrhea (n = 5, 2.6%). Grade 3 or greater hematologic adverse events were consistent with those previously reported in non-del(5q) MDS clinical trials.^9,10 Grade 3 or greater neutropenia was reported in 125 (64%) patients and thrombocytopenia in 58 (29.7%). There were no reported cases of venous thrombosis or thromboembolic events. Two patients progressed to acute lymphatic leukemia while on treatment, both in the LEN-only treatment cohort. Four patients developed acute myelogenous leukemia after study completion while on follow-up. There were four treatment-related deaths on study, two in the monotherapy cohort and two who were assigned the combination.

TABLE 2.

Grade 3 or Greater Adverse Events by Study Treatment

The frequency of treatment discontinuation because of adverse events was comparable between treatment arms. Overall, treatment was reported to be discontinued for adverse events in 36 (18.5%) participants, including 20 receiving the combination therapy (20.2%) and 16 (16.7%) in the LEN-only cohort.

DISCUSSION

LEN stabilizes the erythropoietin receptor in vitro by inhibiting the E3 ubiquitin ligase RNF41, thereby promoting plasma membrane accumulation of signaling competent, Janus kinase-2 and erythropoietin receptor complexes to enhance response to erythropoietin.⁶ In this randomized trial involving patients with lower-risk, non-del(5q) MDS who were previously unresponsive to or unlikely to benefit from treatment with recombinant erythropoietin, LEN-EPO alfa was superior to treatment with LEN alone, yielding significantly higher rates of both major and overall erythroid responses in this predominantly transfusion-dependent patient population. Modulation of erythropoietin responsiveness by LEN also yielded MERs in 26.3% of LEN monotherapy nonresponders who crossed over to the combination and led to a longer clinically meaningful duration of response that approached a median of 2 years compared with 13 months in patients receiving LEN. Of interest, although the addition of EPO alfa was necessary to capture or restore response to erythropoietin, in many instances, it was not necessary to maintain response. The median duration of EPO alfa treatment in major erythroid responders was 14.9 months, whereas the median duration of MER was 23.8 months, indicating that after achieving MER, responses were sustained in many patients by treatment with LEN alone. Importantly, although the response rate to treatment with recombinant erythropoietin is highly affected by the need for and frequency of red cell transfusions, we found no significant difference in the frequency of MER between heavily transfused and low transfusion burden patients (≥ 4 units v < 4 units/8 wk), reflecting the distinctly different mechanism of action of LEN.¹ Moreover, there was no difference in the frequency of thromboembolic events or leukemia progression, and the proportion of patients experiencing an adverse event of grade 3 or greater was similar in the two groups. Neither the specific gene nor functional class of mutation significantly influenced response to treatment with LEN-EPO; however, patients achieving a MER had a significantly lower proportion without mutation (3.7% v 21.1%; P = .031). Similarly, neither the total number of gene mutations nor mutation functional class influenced the duration of MER with the sole exception of DNA repair gene mutations, which favorably affected duration of response (unmutated, median 8.5 months v mutated, not reached; P = .054 log rank test).

In another randomized trial involving 131 patients with lower-risk, transfusion-dependent MDS, the combination of LEN and EPO beta was also superior to LEN alone.¹² The trial design and eligibility in both trials were similar; however, erythroid response was assessed using less-stringent International Working Group criteria and crossover from monotherapy to the combination was not permitted.¹⁷ The proportion of patients who achieved transfusion independence in this heavily transfusion-dependent patient population (median, 6 units/8 wk) was comparable with the proportion of patients who achieved a MER in the current study, that is, 24.2% and 13.8% in the combination and LEN arms, respectively, with corresponding median response durations of 18.1 and 15.1 months (P = .47). These response rates observed by others and us were both less than our pretrial assumptions of 50% efficacy with the LEN and erythropoietin combinations and reflect the real-world efficacy rates in patients with transfusion-dependent and pretreated MDS. Although a low serum erythropoietin level was an independent covariate associated with response in that study, we found no relationship in the current study. Given the longer duration of response in our less heavily transfused patient population, initiation of treatment with LEN and erythropoietin upon emergence of resistance to recombinant erythropoietin may yield more durable erythroid responses to the combination.

One possible limitation of this trial is the consequence of halting accrual following the detection of benefit at the fifth and final planned interim analysis. Given the late time point of analysis, this resulted in only an 8% (n = 17 patients) reduction in sample size compared with the prespecified estimate, which is unlikely to overestimate the observed rate of erythroid response. In support of this, a prior randomized placebo-controlled study of LEN in patients with transfusion-dependent, non-del(5q), lower-risk MDS who had failed erythropoietin treatment reported a transfusion independence frequency of 26.9%, which closely aligns with the overall erythroid response rate to LEN alone in the current study.¹⁰ Moreover, the median follow-up of 10.4 months is sufficient to provide confidence in the durability of response to the combination.

Patients with MDS commonly present with anemia, and transfusion dependence leads to significant patient morbidity including complications from iron overload and economic and social hardships associated with RBC transfusions. Historical data from clinical trials of recombinant erythropoietin in MDS that preceded initiation of the E2905 trial showed that responses to EPO occurred generally within 6-8 weeks of treatment.¹ The standard of care at that time was administration of a minimum of 6-8 weeks of therapy before assessment of benefit, and thus, we chose 8 weeks of EPO unresponsiveness as an inclusion criterion, although the majority of patients in the E2905 trial received much longer treatment trials. A 16-week window of study treatment before response assessment of the LEN and EPO combination was based on the results of the MDS-002 multicenter study of LEN in patients with non-Del5q MDS.⁹ In that study, more than 90% of responses occurred between weeks 8 and 16, thereby permitting nonresponders in the E2905 trial to discontinue therapy or crossover to the combination without subjecting nonresponders to LEN monotherapy to extended ineffective treatment. Luspatercept is an agent recently approved by the Food and Drug Administration for the treatment of anemia in patients with MDS-RS. Luspatercept is an antagonist of transforming growth factor-beta superfamily members that relieves late-stage erythroid maturation impairment in MDS erythroid precursors.¹⁸ In a phase III trial comparing luspatercept with placebo in patients with transfusion-dependent, lower-risk MDS with RS who had anemia refractory to recombinant erythropoietin treatment, 37.9% of luspatercept-treated patients achieved transfusion independence lasting a median of 30.6 weeks accompanied by a median rise in hemoglobin of 2.55 g/dL. Patients with a diagnosis of MDS-RS accounted for nearly half of the patients participating in this study. In this specific disease subset, the major and overall erythroid response rates to LEN-EPO alfa were 34.6% and 51.9%, respectively, with a median response duration of 16.3 months and a median peak hemoglobin improvement of 4.1 g/dL, which compares favorably with the results in the luspatercept study. Moreover, like recombinant erythropoietin, response to luspatercept is inversely related to transfusion burden, which did not affect response to LEN-EPO alfa.

In conclusion, among patients with lower-risk, non-del(5q) MDS who do not benefit from treatment with recombinant erythropoietin, the addition of LEN to EPO alfa offers a superior probability of clinically meaningful and highly durable erythroid response without significant added toxicity compared with treatment with LEN alone.

AUTHOR CONTRIBUTIONS

Conception and design: Alan F. List, Zhuoxin Sun, Amit Verma, Rami S. Komrokji, Selina M. Luger, Charles A. Schiffer, Mark R. Litzow, Martin S. Tallman

Provision of study materials or patients: Alan F. List, Rami S. Komrokji, Jaroslaw Maciejewski, Puneet S. Cheema, David F. Claxton, Andrew S. Artz, Mark R. Litzow

Collection and assembly of data: Zhuoxin Sun, John M. Bennett, Rami S. Komrokji, Kathy McGraw, Jaroslaw Maciejewski, Jessica K. Altman, Puneet S. Cheema, Timothy R. Wassenaar, Andrew S. Artz, Mark R. Litzow

Data analysis and interpretation: Alan F. List, Zhuoxin Sun, Amit Verma, Rami S. Komrokji, Kathy McGraw, David F. Claxton, Selina M. Luger, Ryan J. Mattison, Andrew S. Artz, Charles A. Schiffer, Mark R. Litzow, Martin S. Tallman

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Lenalidomide-Epoetin Alfa Versus Lenalidomide Monotherapy in Myelodysplastic Syndromes Refractory to Recombinant Erythropoietin

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Alan List

Honoraria: Celgene, Aileron Therapeutics, Cellular Biomedicine Group

Consulting or Advisory Role: Celgene, Cellular Biomedicine Group, Aileron Therapeutics, Acceleron Pharma, International Personalized Cancer Center, Precision Biosciences, CTI BioPharma Corp, Prelude Therapeutics

Research Funding: Celgene

Travel, Accommodations, Expenses: Celgene, Cellular Biomedicine Group

Other Relationship: Thousand Talents Award

Amit Verma

Stock and Other Ownership Interests: Stelexis Therapeutics, Throws Exception

Honoraria: Stelexis Therapeutics, Celgene, Acceleron Pharma

Consulting or Advisory Role: Janssen, Novartis

Research Funding: Janssen Oncology, Bristol-Myers Squibb

Rami S. Komrokji

Stock and Other Ownership Interests: Abbvie

Consulting or Advisory Role: Novartis, Incyte, Bristol-Myers Squibb, Jazz Pharmaceuticals, Abbvie, Geron, Acceleron Pharma

Speakers' Bureau: Jazz Pharmaceuticals, Bristol-Myers Squibb, Agios

Travel, Accommodations, Expenses: Incyte, Jazz Pharmaceuticals, Bristol-Myers Squibb, Agios

Kathy McGraw

Research Funding: Genentech, Celgene

Jaroslaw Maciejewski

Consulting or Advisory Role: Celgene, Novartis

Jessica K. Altman

Consulting or Advisory Role: GlycoMimetics, Theradex, Agios, Kura Oncology, Abbvie, Astellas Pharma

Research Funding: Astellas Pharma, Pfizer, Ambit BioSciences, Agios, Bristol-Myers Squibb, Spectrum Pharmaceuticals, BioLineRx, ARIAD, MethylGene, Cyclacel, Celgene, Boehringer Ingelheim, Biosight, Kura Oncology, Abbvie, Amgen, Aprea AB, Amphivena, Fujifilm, Kartos Therapeutics, Astex Pharmaceuticals

Travel, Accommodations, Expenses: Biosight, Astellas Pharma, Daiichi Sankyo

Selina M. Luger

Honoraria: Agios, Bristol-Myers Squibb, Daiichi Sankyo, Loxo, Abbvie/Genentech

Research Funding: Onconova Therapeutics, Biosight, Roche/Genentech, Kura Oncology, Celgene

Travel, Accommodations, Expenses: Biosight

Andrew S. Artz

Employment: Radiology Partners

Stock and Other Ownership Interests: Radiology Partners

Consulting or Advisory Role: Biogen

Charles A. Schiffer

Consulting or Advisory Role: Celgene, Juno Therapeutics, Astellas Pharma, Innate Pharma, Molecular Templates

Research Funding: Bristol-Myers Squibb, Celgene, ARIAD, Novartis, Micromedic

Mark R. Litzow

Consulting or Advisory Role: Sanofi, Newlink Genetics

Research Funding: Amgen, Astellas Pharma, Actinium Pharmaceuticals, Pluristem Therapeutics, Abbvie/Genentech, Tolero Pharmaceuticals, Abbvie

Martin S. Tallman

Honoraria: Jazz Pharmaceuticals, Roche, Novartis

Consulting or Advisory Role: Abbvie, Daiichi Sankyo, Orsenix, Delta-Fly Pharma, Tetraphase Pharma, Jazz Pharmaceuticals, Roche, Novartis

Research Funding: Abbvie, Orsenix, Biosight, GlycoMimetics, Rafael Pharmaceuticals, Amgen

Patents, Royalties, Other Intellectual Property: UpToDate updates

No other potential conflicts of interest were reported.