Novel Therapeutics in Acute Myeloid Leukemia
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- Sweet, K. & Lancet, J.E. Curr Hematol Malig Rep (2014) 9: 109. doi:10.1007/s11899-014-0199-0
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Acute myeloid leukemia (AML) is a heterogenous disease, and the standard treatment with cytotoxic chemotherapy has remained largely unchanged for over four decades. As more is being learned about AML and the potential molecular targets found within the leukemia cells, an abundance of targeted therapies are becoming available for study in the treatment of this challenging disease. This review serves to provide a brief overview of some of several agents currently being studied and developed in AML.
KeywordsAcute myeloid leukemiaCytotoxic chemotherapyNovel therapeuticsPharmacokinetically advantageous broad cytotoxicsHeterogeneity
Summary of Trials with Novel Agents
Mechanism of Action
Small-molecule inhibitor of Raf, c-kit, RET, FLT3, VEGF, PDGFR and FGFR
MTD 300–400 mg PO BID
Safe in combination with conventional chemotherapy
Improved CR/CRi when used in frontline
Short duration of response
Active when combined with azacitidine
Small-molecule inhibitor of protein kinase C, VEGFR-2, PDGFR-α, PDGFR-β, c-kit and FLT3
Single agent MTD 75 mg PO TID
MTD when combined with conventional chemotherapy 50–100 mg PO BID
Single agent: blast reduction in 70 % of patients
With cytotoxic chemo: 92 % CR rate in young patients
33 % ORR in FLT3-ITD + AML
Bis-aryl urea inhibitor of FLT3, KIT, PDGFR-α, PDGFR-β, RET and CSF1R
MTD 200 mg/day continuous dosing
Single agent: 44 % CRc in FLT3-ITD + patients
53 % CRc rate in FLT3-ITD + patients >70y/o
Quinolone derivative which inhibits topoisomerase II
No superior schedule with weekly versus twice weekly dosing
Single agent: age >60, 72 mg/m2 days 1 & 4; 34 % ORR, median OS 7.7 months
VALOR: placebo controlled; combination with IDAC in R/R patients. Closed to accrual, results pending.
Nucleoside analog which inhibits DNA polymerase
Single agent: MTD 2000 mg/m2/day CIVI days 1–5
In combination with Idarubicin: MTD 1000 mg/m2/day CIVI; 40 % CR/CRp
Single agent: 18 % CR/CRp, 43 % OS at 6 months
Combination with idarubicin: 45 % CR/CRi
CLAVELA: Median OS 3.5 months vs. 3.3 months in controls – failed to meet primary endpoint
Cytosine nucleoside analogue which leads to DNA strand breaks and apoptosis
MTD 325 mg PO BID x 7 days or 425 mg PO BID x 3 days
28 % objective responses
Patients >70 y/o: Most effective dose 400 mg PO BID x 3 days/week for 2 weeks; 45 % ORR, 30 % CR/CRi, 10 % 30-day mortality
LI1: Randomized sapacitabine vs. low-dose cytarabine in elderly AML; ongoing
Synthetic flavone derivative which inhibits multiple serine-threonine cyclin-dependent kinases
MTD 50 mg/m2/day days 1-3, with Ara-c and mitoxantrone; 23 % CR in R/R AML
75 % CR in newly diagnosed patients; 15 % CR in primary refractory patients, Median OS 8 months overall, and 18 months in newly diagnosed patients
67 % CR and median OS 7.4 months in FLT3ITD + patients
Randomized Phase II FLAM vs. 7 + 3 CR 68 vs. 48 %; final results pending
Polo-like kinase inhibitor which leads to cell cycle arrest and apoptosis
MTD in combination with LDAC 350 mg IV days 1 and 15; 22 % CR/CRi in R/R AML
Randomized combination volasertib + LDAC vs. LDAC; CR/CRi 31 % vs. 11.1 %
Liposomal cytarabine and daunorubicin
Recommended phase II dose 101 units/m2; 23 % CR/CRp
Randomized CPX-351 vs. 7 + 3 in patients >60 y/o; CR/CRi 57.6 % vs. 31.6 %. OS benefit with CPX-351 in sAML subset
Humanized anti-CD33 monoclonal antibody conjugated with calicheamicin
In 2000, accelerated FDA approval based on 26 % ORR in patients >60 y/o in first relapse
SWOG S0106: GO vs. 7 + 3 in young patients; No difference in CR, PFS or OS, but increased death rate with GO (5.5 % vs. 1.4 %); Led to voluntary withdrawal of GO from market
AML16, ALFA-0701: Improved OS and EFS with GO, no increase toxicity or death rate with GO
Humanized monoclonal antibody against CD33
Limited toxicity; When given over long periods of time, very tolerable – most common AE was injection site reactions; 41 % ORR
Randomized LDAC vs. LDAC + lintuzumab in elderly patients with untreated AML; No OS benefit with lintuzumab
Combined with MEC in R/R setting; no improvement in CR rate
Monoclonal CD33 antibody-drug conjugate with pyrrolobenzodiazepine which causes DNA crosslinking and cell death
Despite the abundance of research, long-term survival in AML remains poor, and the search continues for more effective treatments with less toxicity. Genetic profiling is increasingly being used for prognostic purposes and treatment decisions . In the therapeutic arena, while targeting of genetic alterations with specific therapies could conceivably improve outcomes, the presence of multiple genetic “drivers” in AML makes it unlikely that targeting a single molecular anomaly will translate into clinical success .
Trials investigating targeted treatments often involve large groups of patients who have been selected without regard to the presence or absence of a particular anomaly. The molecular heterogeneity of AML may limit the efficacy of these treatments, which are directed at one particular target, thereby resulting in low response rates and subsequent lack of new drug approval . Although a subset of patients may benefit from some of these new treatments, this beneficial effect will be obscured when the drug is tested in such a diverse group of subjects. By selectively choosing study patients who are known to have the targeted aberration, we may begin to see the desired response rates . This review will discuss some of the novel agents currently being studied in AML and will provide insight into what may become available in the near future (Table 1).
Small Molecule Inhibitors
The FMS-like tyrosine kinase 3 (FLT3) gene found on chromosome 13 plays a role in early hematopoiesis and development of myeloid precursors [12, 13]. Upregulation of the FLT3 ligand and receptor occurs in most leukemia cell lines. In the presence of the FLT3 internal tandem duplication (ITD) mutation – which occurs in nearly 25 % of patients with AML – hyperactivity of the FLT3 tyrosine kinase occurs, resulting in constitutive activity of FLT3 and dysregulation of cellular proliferation [12, 14, 15]. FLT3-ITD mutations commonly occur in conjunction with leukocytosis and diploid cytogenetics, resulting in higher relapse rates when compared with patients who have wild-type FLT3 [10, 12, 16-18].
Given the frequency of this mutation as well as its adverse prognostic effects, targeting FLT3 is a reasonable therapeutic strategy. However, the heterogeneity of AML implies that the targeting of FLT3-ITD alone will not be sufficient to result in durable remissions. FLT3 mutations are not considered founding mutations, but rather driver mutations, bringing into question their role in the pathogenesis of AML [10, 19]. Furthermore, the appropriate timing of FLT3 inhibitors during treatment is not entirely clear . Nonetheless, a number of FLT3 inhibitors have been studied in AML, both as single agents and in combination. Many of the earlier-generation drugs were less selective and potent than the newer-generation drugs . Three of the most advanced FLT3 inhibitors include Sorafenib, Midostaurin, and Quizartinib (formerly known as AC220).
Sorafenib is a small-molecule inhibitor of Raf kinase that is approved for treatment of advanced renal cell carcinoma and hepatocellular carcinoma. It has additional activity against c-kit and RET proteins, FLT3, vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR) [21, 22]. Preclinical studies have indicated that even at very low concentrations, sorafenib inhibits growth and proliferation of FLT3-ITD-mutated AML cells in both mice and humans, in addition to inducing apoptosis by dephosphorylating MEK1/2 and ERK [21, 23]. Early studies in AML reported tolerable doses of sorafenib ranging from 300 mg to 400 mg PO BID [24, 25]. When it was used as a single agent in the relapsed setting, Man et al. found that 12 of 13 patients treated with sorafenib achieved complete response (CR), complete response with incomplete count recovery (Cri), or near-CRi (defined as focal prominence of blasts in the bone marrow that could not be enumerated), and four patients were able to go on to allogeneic stem cell transplant .
There is known to be synergy between sorafenib and conventional chemotherapy, which has prompted further trials studying combinations with cytarabine, anthracyclines, or hypomethylating agents [24, 27-33]. Some studies have found improved CR and Cri rates in the upfront setting using sorafenib in combination with other agents, and subset analyses show superior efficacy in the FLT3-ITD-mutated patients. The responses tend to be short-lived, however, with most patients developing resistance within a year of beginning treatment [24, 30-32]. Ravandi et al. found that using sorafenib with azacitidine prevented the significant increase in FLT3 ligand that is seen when sorafenib is used with high-intensity chemotherapy, thereby improving its efficacy . On the other hand, trials with patients >60 years of age failed to show a benefit with sorafenib in combination with standard induction regimens, and noted increased toxicity in patients receiving sorafenib compared with placebo [27, 29].
Midostaurin (PKC312) is a small-molecule inhibitor of protein kinase C, VEGFR-2, PDGFR-α, PDGFR-β, c-kit, and FLT3. The tolerable single-agent dose in AML is 75 mg PO TID . Trials combining midostaurin with other chemotherapeutic or hypomethylating agents reported a tolerable dose of 50–100 mg PO BID [35-38]. As a single agent, midostaurin resulted in significant blast reductions in the peripheral blood and bone marrow in nearly 70 % of patients with relapsed FLT3-ITD-mutated AML, although without bona fide remissions. In patients with wild-type (WT) FLT3 genotype, the results were less striking [34, 35]. Mild-to-moderate gastrointestinal toxicity (nausea/vomiting) was common.
When midostaurin (at a dose of 50 mg PO BID for 14 days) was combined with cytotoxic chemotherapy, younger patients with newly diagnosed FLT3-ITD-mutated AML achieved a CR rate of 92 %, and the combination was generally well-tolerated . In combination with decitabine, severe pulmonary toxicity occurred with concurrent administration but not with sequential dosing. While over half of all patients achieved at least stable disease, only 13 % had FLT3-ITD mutations . A recent study of midostaurin and azacitidine in relapsed/refractory AML or myelodysplastic syndrome found the combination to be well-tolerated, with overall response rates of 21 % in all patients and 33 % in patients with FLT3-ITD mutations, indicating potential clinical benefit in heavily pretreated patients . A definitive phase III U.S. intergroup study of induction chemotherapy plus or minus midostaurin in AML has completed accrual, with results expected to be reported in the near future.
Quizartinib (AC220) is a high-potency bis-aryl urea FLT3 inhibitor that was uniquely designed with high selectivity against other kinases. Whereas previous FLT3 inhibitors resulted in limited response duration in AML, the pharmacokinetic properties of quizartinib lead to a sustained inhibition of FLT3. While it has a significantly higher affinity for FLT3, Quizartinib also inhibits Kit, PDGFRα, PDGFRβ, RET, and CSF1R.
As a single agent, quizartinib appears to be the most clinically active of the FLT3 inhibitors. Most clinical trials with single-agent quizartinib have been conducted in the relapsed/refractory setting. Composite complete response (CRc) rates (CR + CRi + CRp) in adult patients following failure of second-line chemotherapy were 44 % in the FLT3-mutated group and 34 % in the FLT3 WT patients [40•]. In elderly patients, CRc rates were 57 % in those with FLT3-ITD mutations and 36 % in FLT3-WT patients . A subset analysis of this study looking at outcomes in patients over 70 years of age found a 53 % CRc rate in those with a FLT3-ITD mutation and 43 % in those without, indicating efficacy in a patient population that has proven to be very difficult to treat in the past . Trials with quizartinib in combination with conventional chemotherapy are ongoing.
Volasertib is a first-in-class inhibitor of the Polo-like kinase (Plk) family of proteins, which induce cell cycle arrest and apoptosis [43-45]. The first-in-man phase I study with volasertib involved patients with solid tumors, and the vast majority of DLTs were related to myelosuppression . When Bug and colleagues designed a phase I study in patients with relapsed/refractory AML, they found the combination of volasertib and low-dose ara-c (LDAC) to be well-tolerated. Most of the adverse events were related to myelosuppression, and a combination of volasertib (350 mg IV on days 1 and 15) and LDAC (20 mg SC BID on days 1–10 of a 28-day cycle) led to a CR/CRi rate of 22 % in a heavily pretreated population .
The phase II component of the above-mentioned trial randomized patients with newly diagnosed AML who were ineligible for intensive chemotherapy to receive either volasertib with LDAC or LDAC alone. Forty-two patients received combination treatment and 45 patients received single agent LDAC. The CR/CRi rate in the combination cohort was significantly higher than that of the LDAC cohort (31 % vs 11.1 %, p = 0.0277), with a trend towards improved event-free survival in the combination group. A larger phase III trial using volasertib with LDAC is now underway .
Cell Cycle Inhibitors
Flavopiridol is a synthetic flavone derivative that inhibits multiple serine-threonine cyclin-dependent kinases that result in apoptosis in hematopoietic cell lines, including those from AML. In vitro data indicate that flavopiridol has direct cytotoxic effects, but when it is administered sequentially with ara-C and mitoxantrone – both of which are most efficacious when cells are in S phase – it sensitizes the remaining leukemic cells to these drugs as they reenter the cell cycle .
A phase I study was conducted that utilized a regimen of flavopiridol (MTD was 50 mg/m2/d) as a 1-hour infusion on days 1–3, followed by ara-C 2 g/m2/72 h beginning on day 6, followed by a bolus of mitoxantrone 40 mg/m2 on day 9 (FLAM). The study was carried out in 34 patients with relapsed/refractory AML or acute lymphoblastic leukemia (ALL), and CR rates were 23 % and 12.5 %, respectively. The most common toxicities were tumor lysis and mucositis .
A phase II trial with FLAM studied 62 AML patients with either relapsed/refractory disease or newly diagnosed secondary AML, as well as those with adverse cytogenetics. Of the 15 patients with newly diagnosed AML, 75 % achieved CR, compared with only 15 % (2/13) in the primary refractory cohort. Overall, 32 patients (52 %) achieved CR, 12 of whom subsequently underwent allogeneic stem cell transplant. Median OS was 8 months for all 62 patients, and 18 months in the newly diagnosed patients .
A second phase II trial enrolled 45 newly diagnosed poor-risk patients, including nine with FLT3-ITD mutations. The CR rate was an impressive 67 %, and with a median follow-up of 22 months, the median OS was 7.4 months. Age was an independent risk factor for poor overall survival, with patients >60 year of age faring worse than the younger patients. FLAM showed excellent clinical benefit in the presence of FLT3-ITD mutations, with 8/9 patients achieving CR [48•].
A more recent a randomized phase II trial compared FLAM with standard “7 + 3” with daunorubicin 90 mg/m2 and ara-C in newly diagnosed high-risk AML. The trial has concluded, and results are pending. An interim analysis was presented at the 2012 American Society of Hematology annual meeting. The primary endpoint of this study was CR rate after cycle 1 of therapy, and 62 patients were evaluable for this endpoint at the time of presentation. Tumor lysis was more common in the FLAM arm, but the CR rate was also higher in the FLAM cohort (68 % vs. 48 %). Although the difference had not reached statistical significance at the time of this preliminary analysis, it may indicate promise for the use of flavopiridol in treatment of high-risk AML .
Novel Chemotherapeutic Agents
Vosaroxin (formerly voreloxin, SNS-595) is a first-in-class quinolone derivative known to inhibit topoisomerase II by DNA intercalation, causing site-selective DNA double-strand breaks, G2 arrest, and apoptosis [50-52]. The mechanism of action bears similarities to anthracyclines. However, the volume of distribution of vosaroxin is markedly lower compared to anthracyclines, suggesting the likelihood that off-target organ toxicity is lower. Furthermore, unlike anthracycline drugs, vosaroxin is not a P-gp substrate, and it has shown activity in anthracycline-resistant models .
Phase I and II clinical trials have been reported in which vosaroxin was used both as a single agent and in combination with cytarabine, which was proven to be a safe combination. [52, 53]. A phase Ib open-label dose-escalation study looked at weekly versus twice-weekly dosing of vosaroxin alone. Although a superior dosing schedule was not established, the trial did result in bone marrow blast clearance in over 20 % of patients, with five patients achieving CR or CRp. A phase II study of single-agent vosaroxin in patients >60 years of age led to a 34 % ORR. The optimal dosing schedule of 72 mg/m2 on days 1 and 4 produced a 35 % CR/CRp rate and a median OS of 7.7 months . Finally, a phase 1b/II trial of vosaroxin + cytarabine established the safety of this combination, with combined CR + CRi rates in first relapsed and primary refractory disease of 36 % and 21 %, respectively . These promising results prompted a phase III double-blind randomized placebo-controlled trial (VALOR) to establish the efficacy of vosaroxin in combination with intermediate-dose ara-C (IDAC) compared with IDAC alone in first relapsed/primary refractory AML. The trial has completed accrual, with results still pending .
Elacytarabine is the lipophilic 5’-elaidic acid ester of cytarabine (ara-C). Ara-C is a nucleoside analog that incorporates into DNA, thereby inhibiting the activity of DNA polymerase and ultimately resulting in apoptosis. Ara-C serves as the backbone for nearly all treatment regimens in AML, utilizing the human equilibrative nucleoside transporter (hENT1) to enter cells. A large proportion of AML patients, however, have hENT1 deficiency which results in ara-C resistance. Elacytarabine was designed to enter cells independent of hENT1 [57-60]. Preclinical data indicate activity of elacytarabine in AML cell lines with known resistance to cytarabine [61, 62].
The first phase I clinical trials determined safe dosage as both single agent and in combination with standard-dose idarubicin, resulting in a 40 % CR/CRp rate [57, 58]. Phase II trials conducted in the relapsed setting resulted in a CR/CRp rate of 18 %, with a 6-month OS of 43 % when used as a single agent and 45 % CR/CRi when used in combination with idarubicin . Correlative studies found approximately 50 % of patients had deficient hENT1 expression, which likely contributed to their resistance to prior ara-C based regimens .
A phase III trial of elacytarabine versus investigator’s choice in patients with advanced AML (CLAVELA) was conducted at 76 centers worldwide. Unfortunately, the study failed to meet its primary endpoint of improved OS with elacytarabine (median OS 3.5 months with elacytarabine vs. 3.3 months in controls), and all studies with this drug are currently suspended .
Sapacitabine is a rationally designed oral cytosine nucleoside analog that incorporates into DNA, leading to strand breaks and apoptosis after subsequent rounds of DNA replication [64-66]. The recommended dose from a phase I trial is either 325 mg PO BID x 7 days or 425 mg PO BID x 3 days weekly for two weeks. Sapacitabine was well-tolerated, and 28 % of patients had objective responses . In light of the oral administration and relatively mild side effect profile, further trials have been carried out with sapacitabine in the elderly population, where palliation and quality of life become significant factors.
A randomized phase II study of AML patients over 70 years of age with either untreated or relapsed AML was conducted with three distinct dosing schedules. Sapacitabine 400 mg PO BID for 3 days weekly for two weeks was the most effective dose schedule, with a 45 % ORR in the 20 patients randomly assigned to this schedule. CR or CRi was attained in 30 %, and 30-day mortality was only 10 % [65••]. A separate randomized study (LI1 trial) evaluating sapacitibine versus low-dose cytarabine in elderly AML patients is underway, and the results are eagerly anticipated .
The tolerability and limited side-effect profile of sapacitabine make it an ideal combination with other low-intensity AML treatments. A phase I/II trial is now underway utilizing sapacitabine alternating with decitabine in elderly patients. Preliminary results did not reveal any dose-limiting toxicities, and objective responses were seen in 6 of the 21 patients enrolled . This study may provide better insight into the utility of sapacitabine in the elderly AML population.
CPX-351 is a liposomal encapsulation of cytarabine and daunorubicin at a 5:1 molar concentration ratio. Building upon the concept that drug combinations may act synergistically, additively, or antagonistically, preclinical studies revealed that a liposomally encapsulated combination of cytarabine and daunorubicin produced the best synergy at the 5:1 molar ratio in AML cells, maintaining this ratio in vivo for over 24 hours [68, 69]. In the first-in-human phase I study with CPX-351 in patients with primarily advanced AML, the compound was well tolerated, with very infrequent grade 3/4 toxicities that included mucositis, maculopapular rash, decreased ejection fraction, and increased liver enzymes, with a recommended phase II dose of 101 units/m2. Amongst the 43 AML patients treated in this study, an overall response rate of 23 % (CR + CRi) and median remission duration of 6.9 months were observed . Importantly, pharmacokinetic studies confirmed that the 5:1 molar ratio was maintained for up to 24 hours on both days 1 and 5, while the half-lives of the cytarabine and daunorubicin were observed to be much longer than with free drugs [69, 70].
As a result of the favorable tolerability, pharmacokinetic profile, and efficacy reported in this phase I trial, multiple phase IIb studies have been developed to analyze the efficacy in specific subpopulations of AML patients. A trial of relapsed AML patients under the age of 65 years showed improved CR/CRi rates with CPX-351 compared with investigator’s choice . In another trial in untreated older (>60 y/o) adults with AML, patients were randomized to CPX-351 or 7 + 3. Response rates in this study trended higher with CPX-351 (66.7 % vs. 51.2 %), with a significant survival advantage observed in CPX-351-treated patients with secondary AML [72•]. A large multicenter phase 3 trial comparing CPX-351 with conventional induction (“7 + 3”) is underway to confirm these findings in secondary AML.
Immune/Monoclonal Antibody Therapies
Gemtuzumab ozogamicin (GO) is an antibody-drug conjugate (ADC) – an anti-CD33 monoclonal antibody conjugated to the antitumor antibiotic calicheamicin [73, 74] – that received accelerated approval by the U.S. FDA in 2000 after a phase II study demonstrated efficacy when used as a single agent in patients > 60 years in first relapse .
From 2004 to 2009, a large intergroup trial designed by the Southwest Oncology Group (SWOG) evaluated the benefit of adding GO (6 mg/m2 on day 4) to standard induction and consolidation therapy, demonstrating no difference in CR rate, PFS, or OS, but with a higher induction death rate in the GO arm compared with the control arm (5 % vs. 1 %, respectively). The results of this interim analysis led to early discontinuation of the trial and the voluntary withdraw of GO from the market in June 2010 .
Since then, two large randomized studies of induction chemotherapy +/- GO were published, the results of which seem to contradict the findings of the SWOG trial, demonstrating modestly improved overall survival in the GO arms, without excess early mortality. Both of these trials (MRC AML-16 and ALFA-0701) focused on patients aged > 50 years and utilized GO at lower or fractionated doses [76, 77].
Taken together, these data indicate clinical benefit of low-dose or fractionated GO combined with chemotherapy, leading many to believe that this compound will eventually become reapproved for use in the United States. In further support, a recently presented meta-analysis of the five randomized trials combining GO with chemotherapy demonstrated overall survival benefit attributable to GO .
Other Novel Anti-CD33 Therapeutics
The attractiveness of CD33 as a biologically important and accessible therapeutic target has led to continued pursuit of novel anti-CD33 strategies in the clinic. One such example is lintuzumab (SGN-33; HuM195), a humanized monoclonal antibody directed against CD33 with effector function through multiple mechanisms. This agent recently underwent testing in a large randomized trial against low-dose cytarabine as initial therapy for elderly patients with CD33-positive AML, but conferred no overall survival advantage .
Perhaps more promising is the compound SGN33a, which is currently in phase I testing. This agent is an ADC consisting of an anti-CD33 monoclonal antibody conjugated to a novel synthetic pyrrolobenzodiazepine dimer, leading to DNA crosslinking and cell death. In preclinical studies, this compound demonstrated greater cytotoxic potency against AML cell lines and primary cells than gemtuzumab ozogamicin, including in AML cells demonstrating multidrug resistance phenotype . In light of the above-stated recent evidence of the efficacy of gemtuzumab ozogamicin, the appeal of second-generation ADCs appears justified.
The heterogeneity of AML makes it a difficult disease to treat successfully. While treatment has remained relatively unchanged for nearly four decades, the future appears brighter with the advent of novel targeted therapeutics along with more potent and pharmacokinetically advantageous broad cytotoxics. As more information becomes available with regard to the genetic alterations driving this disease, along with a better understanding of the multiple regulatory pathways involved in the pathogenesis of AML, more targets for potential treatments will be developed. The availability of new agents for clinical trials, combined with the ability to target more specific patient populations harboring specific molecular abnormalities, will ultimately lead to the improved outcomes so desperately needed in AML.
Compliance with Ethics Guidelines
Conflict of Interest
Dr. Kendra Sweet declares no potential conflict of interest relevant to this article.
Dr. Jeffrey E. Lancet is a consultant for Boehringer Ingelheim, Celator, and Seattle Genetics.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.