Impact of cumulative dose of brentuximab vedotin on outcomes of frontline therapy for advanced-stage Hodgkin lymphoma

In the pivotal phase 3 study, ECHELON-1, brentuximab vedotin (BV), doxorubicin, vinblastine, and dacarbazine (A + AVD) demonstrated a survival advantage among patients aged ≥18 years with stage III or IV classic Hodgkin lymphoma (cHL), compared with those who received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).^1-3 Consequently, A + AVD is one of the standards of care for all patients with advanced-stage cHL. BV is a monoclonal antibody drug conjugated with a protease-cleavable linker to the microtubule-disrupting agent monomethyl auristatin E, which targets CD30 on the Hodgkin lymphoma Reed-Steenberg cell.⁴ 

The ECHELON-1 trial showed that adding BV and eliminating bleomycin from frontline therapy in the A + AVD regimen lowered the incidence of pulmonary toxicity compared with the ABVD regimen. However, A + AVD showed higher rates of neutropenia and febrile neutropenia, which led to the recommendation of primary prophylaxis with granulocyte colony-stimulating factor (G-CSF).⁵ Moreover, peripheral neuropathy (PN) occurred more frequently in patients receiving A + AVD than in those receiving ABVD, which led to BV discontinuation in 10% of the A + AVD group in the ECHELON-1 trial.

In a single-center retrospective study of patients with advanced-stage cHL treated in a real-world setting with A + AVD, 22% of patients required at least 1 dose reduction of BV, and 46% had at least 1 dose omission of BV because of various toxicities.⁶ It is unknown whether the cumulative dose reduction of BV because of toxicities affects the efficacy and safety of frontline therapy. We evaluated the safety and outcomes of patients with stage III-IV cHL treated with standard-of-care A + AVD in a large real-world analysis across 9 academic US institutions.

The study cohort consisted of 179 adult patients (aged ≥18 years) with Ann Arbor stage III or IV cHL treated with frontline A + AVD unrelated to any trial, as described in the ECHELON-1 trial.^1,2 The A + AVD regimen consisted of 1.2 mg of BV per kilogram of body weight (mg/kg; maximum dose, 120 mg), 25 mg of doxorubicin per square meter of body surface area, 6 mg of vinblastine per square meter of body surface area, and 375 mg of dacarbazine per square meter of body surface area IV on days 1 and 15 of each 28-day cycle for up to 6 cycles. Primary prophylaxis with G-CSF was provided at physician’s discretion. Patients were treated between January 2010 and April 2022 at 9 US institutions described in supplemental Table 1 in the supplemental Appendix. Patients were stratified into 3 cohorts according to the cumulative dose of BV (CDB): 1 cohort without dose reduction/omission (12 administrations of BV at 1.2 mg/kg, ie, 14.4 mg/kg) and 2 cohorts of near equal size with dose reduction/omission of BV: moderately reduced CDB ranging from 10.5 to 14.1 mg/kg (ie, 73%-98% of the intended CDB) and severely reduced CDB ranging from 2.4 to 9.6 mg/kg (ie, 17%-67% of the intended CDB).

The study excluded patients treated with BV in 21-day cycles (rather than the standard 28 days) or an intended dose of BV above or below 1.2 mg/kg because of potential differences in safety and efficacy. The study did not include patients who received BV monotherapy before AVD because of the different pharmacokinetics and patient populations. The Eastern Cooperative Oncology Group performance status was used to describe performance status at baseline, and the International Prognostic Score (IPS) was used to divide patients into prognostic groups.^7-9 B symptoms are defined as the presence of weight loss (>10% of body weight over the past 6 months), drenching night sweats, and/or fever. Common Terminology Criteria for Adverse Events version 5.0 was used to grade adverse events.¹⁰ Events were documented according to electronic health records. Follow-up data were collected through August 2022. The study was approved by the institutional review board at each participating institution and conducted in accordance with institutional guidelines and the principles of the Declaration of Helsinki. The institutional review board approved the request of waiver of informed consent and a waiver of authorizations because the study does not involve diagnostic or therapeutic intervention or any type of direct patient contact.

Descriptive statistics are provided, including mean, standard deviation, median, and range for continuous variables, and frequency counts and percentages for categorical variables. The association between categorical variables was evaluated using the χ² or Fisher exact test, and the difference in a continuous variable between patient groups was evaluated using the Mann-Whitney test. The primary end point was progression-free survival (PFS), and the secondary end points were adverse events and overall survival (OS).

PFS time was calculated from the date of initiation of frontline therapy to relapse or progression of the disease, death, or last follow-up. OS time was defined as the time from the start of frontline therapy to death or last follow-up. Data of patients who were alive during follow-up were censored at the last follow-up date. The Kaplan-Meier method was used to estimate PFS and OS, and the difference in PFS/OS was evaluated using the log-rank test. The median follow-up time was calculated using the reverse Kaplan-Meier method.¹¹ Univariable Cox proportional hazards model was fitted for PFS on continuous covariates. Statistical software SAS 9.4 (SAS, Cary, NC), S-Plus 8.2 (TIBCO Software Inc, Palo Alto, CA), and SPSS 21 (IBM Corp, Armonk, NY) were used for all the analyses.

From January 2010 to April 2022, 179 patients at 9 academic sites in the United States were treated with A + AVD. Overall, 56% of the patients were men, 73% had stage IV disease, 66% had B symptoms, 44% had an IPS of 4 to 7, and the median age was 37 years (21% of patients were aged ≥60 years). Baseline characteristics are shown in Table 1.

Overall, 91% of patients received 6 cycles of chemotherapy AVD (range, 2-6 cycles), 41% had at least 1 dose omission of BV, and 30% had at least 1 dose reduction of BV. Considering the number of events with dose reduction and omission of BV, 28% of patients received a severely reduced CDB between 2.4 and 9.6 mg/kg, 27% received a moderately reduced CDB between 10.5 and 14.1 mg/kg, and 45% received the intended CDB of 14.4 mg/kg, with a median CDB of 13.2 mg/kg for all the patients. There were statistically significant (P = .0029) differences in the median age across CDB groups (median age of 52 years [range, 18-79 years] in the group with CDB between 2.4 and 9.6 mg/kg, 43 years [range, 21-74 years] in the group with CDB between 10.5 and 14.1 mg/kg, and 29 years [range, 18-76 years] in the group with CDB of 14.4 mg/kg). Overall, only 4 patients received consolidative radiotherapy in the first remission.

In addition, 96% of patients received prophylactic G-CSF, with a median number of cumulative administrations of pegfilgrastim of 12 (range, 1-12).

Further patient characteristics and details regarding CDB are described in supplemental Table 1 in the supplemental Appendix.

The safety profiles are summarized in Table 2 and supplemental Table 2. Overall, any-grade neutropenia was reported in 60%, and febrile neutropenia was reported in 18% of patients. For the patients who presented with at least 1 episode of febrile neutropenia, the median age was 48 years (range, 18-73 years), and 88% had received G-CSF in the 15 days before the event.

All-grade PN occurred in 75% of patients, including grade ≥3 PN (ie, at least severe symptoms, limiting self-care activities of daily living) in 12% of patients. The median age of the patients who experienced grade 3 neuropathy was higher than those without grade 3 neuropathy (50 vs 36 years; P value = .026).

Higher CDB did not show statistically significant association with grade ≥3 neuropathy. The proportion of patients with grade ≥3 neuropathy was 4% in the CDB 14.4 mg/kg group, 17% in the CDB 10.5 to 14.1 mg/kg group, and 22% in the group of CDB 2.4 to 9.6 mg/kg group (P = .007). At the last follow-up, 35% of patients had complete resolution of their PN, and 34% had partial improvement.

Neuropathy and hematotoxicity/febrile neutropenia were the reasons for dose reduction of BV in 72% and 11% of cases, respectively, and for dose omission of BV in 60% and 10% of cases, respectively.

During therapy, 49% had at least 1 emergency department visit (median, 1 visit [range, 1-9]), and 41% were hospitalized at least once (median duration of hospital stay of 7.5 days [range, 1-79 days]). Furthermore, 4 patients presented with grade ≥3 elevation of lipase, 6 with grade ≥3 elevation of alanine aminotransferase, 7% with deep vein thrombosis, and 4% with pulmonary embolism.

After 2 to 3 cycles of A + AVD, interim positron emission tomography/computed tomography (PET/CT) demonstrated that 73% of patients had a Deauville score¹² ranging from 1 to 3, 17% had a score of 4, 6% had a score of 5, and 4% of patients did not have an interim PET/CT. At the completion of therapy, the Deauville scores were 1 to 3 in 75% of patients, 4 in 4%, 5 in 11%, and not available in 9%. Among the 50 patients who received a severely reduced CDB of 2.4 to 9.6 mg/kg, 70% had a Deauville score of 1 to 3 at the interim PET/CT; among them, only 1 patient had a disease relapse later. There was no statistically significant correlation between CDB and end-of-therapy Deauville score (P = .45). A further summary of responses, CDB, and relapses is described in Table 3.

Overall, disease progression occurred in 22 patients; 82% had stage IV and a median IPS of 3.5 (range, 0-6; with a median age of 32.5 years [range, 18-75 years]). These patients received a median CDB of 14.4 mg/kg (range, 3.6-14.4 mg/kg) and had additional therapy. Among them, 45% had a Deauville score of 1 to 3 at the interim PET/CT after 2 to 3 cycles of therapy, and 27% had a score of 1 to 3 at the end-of-therapy PET/CT.

The median PFS was not reached, and the 12-month PFS was 90.3% (95% confidence interval [CI], 85.9-95.0). The median follow-up time was 27.4 months (95% CI, 24.8-29). The impact of CDB on the PFS was not significant (P value = .15) when this variable was analyzed as a categorical or continuous variable (Figure 1A).

Alternatively, when comparing patients with full intended dose of BV with those with any dose reduction of BV, the latter had better PFS rates, and this difference in PFS was marginally significant (P value = .06; supplemental Figure 1 in the supplemental Appendix). Other analyses comparing different dose groups, such as a third of intended CDB compared with more than a third of intended CDB, did not show statistically significant inferior PFS (supplemental Figures 1-4; supplemental Table 3 in the supplemental Appendix).

In a subgroup analysis, patients aged <60 years did not show statistically significant improved PFS compared with patients aged ≥60 years (12-month PFS was 89% [95% CI, 83-94] for patients aged <60 years vs 97% [95% CI, 91-100] for patients aged ≥60 years) (Figure 1B-C; supplemental Table 4 in the supplemental Appendix). In a univariate analysis, age at diagnosis did not show a statistically significant association with PFS (P = .58) or CDB (P = .66).

The 24-month OS was 98.5% (95% CI, 96.5-100). Overall, 4 patients died, 1 of stroke and retroperitoneal bleeding (aged 73 years at time of death; CDB of 9.6 mg/kg), 1 of acute myeloid leukemia (aged 69 years at time of death; CDB of 7.5 mg/kg), 1 of sepsis (aged 67 years at the time of death; CDB of 10.8 mg/kg; death possibly related to complication of a procedure and not associated with treatment or in the setting of febrile neutropenia), and 1 of unknown cause (aged 48 years at time of death; CDB of 6 mg/kg).

This study presents an overview of the impact of CDB on the safety and efficacy of the A + AVD regimen in a real-world setting based on combined data from 9 US academic institutions. Our results show that reduced CDB neither compromises the efficacy of the A + AVD regimen nor affects its safety based on a lack of statistically significant differences in the survival and adverse events rates between the study groups.

The 6-year follow-up data of the pivotal ECHELON-1 trial showed a survival advantage in patients treated with A + AVD over those who received ABVD (6-year OS, 93.9% in the A + AVD group vs 89.4% in the ABVD group).¹ The regimen A + AVD will possibly replace ABVD as the standard-of-care therapy in the treatment of advanced-stage cHL at many institutions. However, the impact of CDB on safety and efficacy was not presented for patients in the ECHELON-1 trial, which is needed to guide clinical decisions.

In the ECHELON-1 trial, among the 662 patients treated with A + AVD, the median number of doses of BV received was 12 (range, 1-12 doses), and 26% of patients received a dose reduction of BV.² Similarly, in our real-world setting study, the median number of doses of BV was 12 (range, 1-12 doses), and 30% of patients had at least 1 dose reduction of BV.

In our real-world study, 76% of patients who had an interim PET/CT had a Deauville score of 1 to 3, which increased to 83% at the completion of therapy. Compared with patients treated with A + AVD in the ECHELON-1 trial, 89% had Deauville score of 1 to 3 at the interim PET/CT, and 86% had this score at the completion of therapy.² The lower complete metabolic response rate in our study at the end of therapy could be due to the higher proportion of adults aged ≥60 years. Nevertheless, the patients in our study presented a 12-month PFS of 90.3% (95% CI, 85.9-95.0), which is comparable with the estimated 12-month PFS of 86% for the patients treated with A + AVD in the ECHELON-1 trial. The CDB did not show a statistically significant impact on PFS (P value = .15), even for patients with severe CDB reduction. More studies are needed to evaluate how to avoid overtreatment and identify which patients could benefit from a higher CDB.

In the pivotal phase 2 study by Younes et al, with BV for patients with relapsed or refractory cHL, the median time to objective response was 5.7 weeks, and the median time to complete response was 12 weeks, suggesting that BV works rapidly and that extended BV may not be as critical.¹³ cHL has a bimodal age distribution, peaking first in adolescence or early adulthood and again in older adults, usually >60 years of age.¹¹ Outcomes in adults aged ≥60 years with cHL have traditionally been poor, partly related to poor tolerance to standard chemotherapy. In the ECHELON-1 trial, 13% of patients treated with A + AVD were aged ≥60 years (median age was 35 years [range, 18-82 years]), which was lower than that in our study (21% of patients aged ≥60 years; median age, 37 years [range, 18-79 years]).

In a detailed analysis of an older patient (aged ≥60 years) subset of the ECHELON-1 study conducted by Evens et al, after a median follow-up of 60.9 months, the 5-year PFS was 67.1% with A + AVD vs 61.6% with ABVD (P = .443).¹⁴ Overall, A + AVD showed similar efficacy to that of ABVD, with survival rates in both arms comparing favorably with those of prior series in older patients with advanced-stage cHL in the later study.¹⁴ Compared with ABVD, A + AVD was associated with higher rates of neuropathy and neutropenia but lower rates of pulmonary-related toxicity.¹⁴ Yet, in our study, patients aged ≥60 years did not show inferior PFS compared with younger patients.

Alternatively, sequential BV-AVD was studied for patients with cHL aged ≥60 years with an intended CDB of 10.8 mg/kg. Based on the intent to treat, the 2-year PFS and OS rates were 84%, and 93%, respectively.¹⁵ 

Neuropathy is a cumulative expected class effect of microtubule-binding drugs, such as the microtubule-disrupting agent monomethyl auristatin E covalently linked to the immunoglobulin G1 antibody–directed against CD30.

Increased risks of PN are possibly due to overlapping toxicity between BV and vinblastine.¹⁶ Emerging data of BV plus adriamycin and dacarbazine without vinblastine suggest that this regimen may be efficacious in the frontline early-stage Hodgkin lymphoma with less hematotoxicity and neurotoxicity.¹⁶ In an in vitro study, auristatin E was 52-fold more potent than vinblastine.¹⁷ In addition, the single-center retrospective analysis by Mistry et al suggests that reduction or omission of vinca alkaloids from initial chemotherapy does not deleteriously affect outcomes in patients with lymphoma.¹⁸ Consequently, vinblastine is unlikely to add to therapeutic effectiveness, although it seems to be additive for toxicity. Studies are underway, investigating the substitution of vinca alkaloids with novel targeted agents.¹⁹ 

PN of any grade induced by BV occurred in 75% of the patients in our study and was the most common reason for dose modification or discontinuation of BV. In comparison, PN occurred in 67% of patients in the ECHELON-1 trial.² 

In our study, 21% of patients aged ≥60 experienced grade ≥3 neuropathy (compared with 12% of all patients) despite decreased CDB. Similarly, in the study by Evens et al, grade ≥3 neuropathy occurred in 18% of patients.¹⁴ In contrast, in the phase 2 trial with sequential administration of BV-AVD and an intended CDB of 10.8 mg/kg for older patients, only 4% of patients experienced grade ≥3 neuropathy.¹⁵ 

The inverse correlation of grade ≥3 neuropathy and CDB (P = .007) is possibly due to the limited tolerance of some patients who experienced severe early neuropathy requiring early dose reduction or omission of BV. Inversely, patients who did not have severe BV-induced neuropathy could tolerate high CDB. Moreover, some patients possibly had preexisting neuropathy, which worsened with BV and limited the CDB. Finally, severe neuropathy was more common in older patients, possibly because of more preexisting or risk factors for neuropathy.

The primary mitigation strategy for neurotoxicity consists of dose adjustments and treatment discontinuation. In standard-of-care and clinical trials, neurological symptoms related to BV are mainly self-reported by patients and not evaluated by electromyography. Moreover, some clinicians may not adjust doses or discontinue BV despite PN. Our study showed a dosing variation between the different institutions, as reported in supplemental Table 1 in the supplemental Appendix.

Moreover, 18% of our study patients presented at least 1 episode of febrile neutropenia despite the common use of pegfilgrastim prophylaxis. In particular, 29% of patients aged ≥60 years presented at least 1 episode of febrile neutropenia of any grade despite decreased CDB. In the study by Evens et al, any-grade febrile neutropenia occurred in 37% of patients aged ≥60 years treated with A + AVD.¹⁴ 

BV combinations have been studied for different cHL populations, including untreated patients with early stages^16,20,21 and pediatric patients,²² as salvage therapy,^23,24 and consolidation therapy after autologous stem cell transplantation.²⁵ More studies are necessary to evaluate how to avoid overtreatment and to which extent our findings can be generalized to other therapeutic regimens that include BV. As a matter of fact, the retrospective study by Wagner et al showed that patients with relapsed/refractory cHL treated with BV maintenance after autologous stem cell transplantation, similar to the AETHERA²⁵ trial, did not show a statistically significant impact of CDB on PFS.²⁶ 

In the Response Adapted Therapy in Advanced Hodgkin Lymphoma trial, the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects but not significantly lower efficacy than with continued ABVD.²⁷ A similar PET/CT-directed study²⁸ with BV instead of bleomycin could potentially allow for a dose reduction or omission of BV for early responders. In our study, 76% of patients who had an interim PET/CT scan presented a Deauville score of 1 to 3 (Table 2). Among the latter, 7.6% had a relapse after receiving a median CDB of 14.4 mg/kg (range, 4.8-14.2 mg/kg), and no deaths occurred. In comparison, 84% of patients in the Response Adapted Therapy in Advanced Hodgkin Lymphoma study presented a Deauville score of 1 to 3 at the interim PET/CT. Alternatively, in the ECHELON-1 trial, the 5-year PFS of patients with a Deauville score of 4 to 5 at the interim PET/CT was 60.6%.³ Large prospective studies are needed.

Considering that neuropathy and hematotoxicity can be dose-limiting toxicities of BV, this study is the first, to our knowledge, to evaluate the impact of full vs reduced CDB because of dose reduction and/or dose omission on the efficacy and safety of A + AVD. The strengths of our study include the novelty of analyzing the CDB and its impact on the efficacy and safety of patients with cHL treated with A + AVD, the inclusion of patients from various centers, and the availability of granular data. We acknowledge some major limitations of this study, including its relatively small population size, with low power to detect the difference in PFS between the reduced CDB group and the full CDB group because of the limited number of events observed, short follow-up time, lack of central radiology review, and retrospective nature. Moreover, we could not fit the multivariate model because of the limited number of events. In addition, some clinicians might have omitted BV if the patients reached complete metabolic response at the interim PET/CT, creating a bias toward patients with lower CDB and good PFS.

Considering the increased frequency of neurotoxicity and hematotoxicity of A + AVD, our study provides insight into the impact of dose reduction/omission of BV on efficacy and safety. In this real-world experience, A + AVD was a highly effective treatment strategy for patients with advanced-stage cHL, even with dose reduction/omission of BV. Further studies are needed to refine the optimal dose of BV in the frontline setting to check whether toxicity can be reduced without compromising efficacy.

The authors acknowledge Brian Kabat and Shaun Riska from the Mayo Clinic for data management.

This work was supported by Lymphoma Specialized Programs of Research Excellence grant P50 CA97274.

Contribution: R.E.S. and H.J.L. designed the research; R.E.S. performed the research; R.E.S., S.R.H., A.K., T.M.H., N.E., K.A., P.B.A., K.B., D.P., J.P.A., I.S.L., K.D., A.M.E., K.P., S.M.B., M.K., S.B.A., P.T., R.L., S.S., and M.N. collected the data; R.E.S., L.F., and H.J.L. analyzed and interpreted the data; L.F. performed statistical analysis; and R.E.S., N.E., J.P.A., I.S.L., A.M.E., S.M.B., P.T., R.L., S.S., L.F., S.A., R.N., F.V., S.W., P.F., C.C.P., J.R.G., B.S.D., and H.J.L. wrote the manuscript.

Conflict-of-interest disclosure: R.E.S. has received research funding from Seagen, Bristol Myers Squibb (BMS), GlaxoSmithKline, and Rafael Pharmaceuticals. T.M.H. is a member of the data monitoring committee at Seagen, Tess Therapeutics, and Eli Lilly and Company; is a member of the scientific advisory board of MorpohSys, Incyte, BeiGene, and Loxo Oncology; and receives research support to the Lymphoma Epidemiology of Outcomes grant from Genentech, Sorrento, and BMS. N.E. has received research funding from BeiGene; is a member of the speaker’s bureau for Incyte and BeiGene; and receives honoraria from, consults for, and serves on the advisory boards of Merck, ADC Therapeutics, Lilly, and Novartis. J.P.A. is a member of the advisory boards of ADC Therapeutics and Genentech, and has received research support from ADC Therapeutics. I.S.L. participated in the advisory board of Adaptive Biotechnology and provided lecture at Kyowa Kirin Pharmaceutical Development Inc. A.M.E. is a member of the advisory board (research-related) for Seattle Genetics, Hutchmed, Incyte, Daiichi Sankyo, and Epizyme, and is a consultant (a member of the data and safety monitoring board) for Novartis, AbbVie, and Pharmacyclics. M.K. has received research support/funding from Novartis; provided consultancy for AbbVie, AstraZeneca, Celgene/BMS, Adaptive Biotechnologies, ADC Therapeutics, BeiGene, Genentech, ImpactBio, and Syncopation; served on the speaker’s bureau of Seagen; and was part of the data management committee at Celgene and Genentech. P.T. has received consultancy fees from TG Therapeutics, ADC Therapeutics, Genentech, Kura Oncology, Seagen, Eli Lilly and Company, and Genmab. R.L. has received research funding from TG Therapeutics, Incyte, Bayer, Cyteir, Genentech, Seagen, and Rapt, and provided consultancy for Cancer Study Group, Seagen, and Foresight Diagnostics. S.S. has received research funding from ADC Therapeutics, AstraZeneca, Ayala (spouse), Bayer, BeiGene, BMS (spouse), De Novo Biopharma, Enterome, Genentech, Ignyta (spouse), Incyte Corporation, Kymera Therapeutics, Merck Sharp and Dohme Corp, MorphoSys, Nanjing Pharmaceuticals Co, Ltd, Portola Pharmaceuticals, and Viracta Therapeutics, and provided consultancy for or was a member of the advisory board of ADC Therapeutics, AstraZeneca, BeiGene, Epizyme, Karyopharm, Kite Pharma, Incyte, Numab Therapeutics AG, AbbVie, Coherus Biosciences advisory board (spouse), and Genentech. S.A. has received research support to institution for clinical trials from Seattle Genetics, Merck, Xencor, Chimagen, and Tessa Therapeutics; has membership on Tessa Therapeutics and Chimagen scientific advisory committee; serves on the data safety monitoring board for Myeloid Therapeutics; and is a consultant for ADC Therapeutics, and KiteE/Gilead. R.N. is consultant for AbbVie and had speaker/preceptorship disclosure from Incyte. F.V. received research funding from CRISP Therapeutics, Allogene, and Geron Corporation, and received in the past 3 years, honoraria from i3Health, Elsevier, America Registry of Pathology, Congressionally Directed Medical Research Program, Society of Hematology Oncology, and the National Research Foundation of Singapore. C.C.P. has received research support from Merck. B.S.D. has received research funding from Seagen. H.J.L. has received research funding from Seagen, BMS, Takeda, Oncternal Therapeutics, and Celgene; receives travel, accommodation, and expenses from Oncternal Therapeutics; receives honoraria from Aptitude Health, Cancer Experts Now, Curio Science, and Century Therapeutics; and reports consulting for or an advisory role at BMS and Guidepoint Global. The remaining authors declare no competing financial interests.

Correspondence: Raphael E. Steiner, Department of Lymphoma and Myeloma, the University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429, Houston, TX 77030; email: resteiner1@mdanderson.org.