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. Author manuscript; available in PMC: 2018 Sep 15.
Published in final edited form as: Cancer. 2017 May 11;123(18):3602–3608. doi: 10.1002/cncr.30762

Palmar-Plantar Erythrodysesthesia Syndrome Following Treatment with High-Dose Methotrexate or High-Dose Cytarabine

Seth E Karol 1,2, Wenjian Yang 3, Colton Smith 3, Cheng Cheng 4, Clinton F Stewart 3, Sharyn D Baker 5, John T Sandlund 2, Jeffrey E Rubnitz 2, Michael W Bishop 2, Alberto S Pappo 2, Sima Jeha 2, Ching-Hon Pui 1,2, Mary V Relling 3
PMCID: PMC5589497  NIHMSID: NIHMS870286  PMID: 28493546

Abstract

Background

Palmar-plantar erythrodysesthesia syndrome (PPES) is an uncommon side effect of high-dose cytarabine or methotrexate. Prior case reports of PPES have been limited, and the predisposing factors for the development of PPES remain unknown.

Methods

We reviewed our databases and identified 22 (1.3%) patients who developed 39 episodes of PPES among 1720 patients following treatment with high-dose cytarabine or methotrexate.

Results

Symptoms lasted a mean of 6.4 days. Hands and feet were both involved in 68% of initial episodes. Parenteral opioids were required for pain control in 27% of patients. In comparison to 1,698 children treated with similar therapy, children who developed PPES were older (mean age at diagnosis 14.3 vs. 7.7 years, P=9.4×10-8). The frequency of PPES was less common in patients receiving methotrexate alone (7/946; 0.7%) when compared to cytarabine (7/205; 3.4%, P=0.004) but was not different in those receiving both high-dose methotrexate and cytarabine (8/569; 1.4%, P=0.21). Prolonged infusions of methotrexate were associated with less frequent PPES (P=1.5×10-5) compared to rapid infusions, as was co-administration of dexamethasone with cytarabine (P=2.5×10-6). Self-described race and gender were not associated with PPES. In multivariate analysis, older age and high-dose cytarabine administration without dexamethasone remained associated with PPES (P=1.1×10-4 and 0.038, respectively). A genome-wide association study did not identify any associations with PPES meeting the genome-wide significance threshold, but top variants were enriched for skin eQTLs, including rs11764092 in AUTS2 (P=6.45×10-5).

Conclusions

Our data provide new insight into the incidence of PPES as well as its risk factors.

Keywords: palmar-plantar erythrodysesthesia syndrome, methotrexate, cytarabine, pediatric oncology, chemotherapy, susceptibility

Introduction

Survival following the diagnosis of childhood cancer has steadily increased over the last 30 years, partly due to improvements in supportive care that have allowed the administration of higher doses of chemotherapy.1 Among toxicities that have accompanied these higher doses of therapy, there is palmar-plantar erythrodysesthesia syndrome (PPES), also called hand-foot syndrome or chemotherapy-induced acral erythema,2 a dermatologic toxicity typically affecting the palmar aspects of the hands and plantar aspects of the feet.3 Patients who experience PPES suffer redness, swelling, pain, and sometimes desquamation of the affected skin.4

PPES is rare in pediatrics. Although the largest pediatric case series involved treatment with pegylated liposomal doxoribucin,5 prior case reports suggest it is most common following administration of high-dose cytarabine or methotrexate,2-4, 6-10 possibly because these two agents are used more frequently. PPES appears to be more prevalent in adults than in children,9 although the reason for this difference is unknown. Notably, while hand-foot syndrome has also been used to describe the relatively common hyper-keratosis that develops on pressure points with the use of multi-kinase inhibitors, this side effect is pathologically distinct from PPES due to cytotoxic chemotherapies.11

Here, we report a case-series of 22 patients who developed PPES following treatment with either high-dose cytarabine or high-dose methotrexate. We examine predisposing factors in these patients and describe the incidence of recurrence with ongoing therapy. Finally, we demonstrate the challenges of using genome-wide association studies (GWAS) to identify genetic predispositions for rare complications of cancer care.

Methods

Patient Selection

St. Jude therapeutic protocols were selected based on chemotherapy regimens likely to cause PPES due to the inclusion of high-dose cytarabine (≥500mg/m2/dose) or high-dose methotrexate (≥1g/m2/dose, requiring leucovorin rescue). Patients treated on AML0212 and AML08 (NCT00703820) protocols for acute myeloid leukemia received high-dose cytarabine, while patients on OS08 (NCT00667342) were treated for osteosarcoma with high-dose methotrexate. Patients on SJBCII (NCT00187161) and SJBCIII (NCT01046825) were treated for mature B-cell lymphoma/leukemia with both high-dose methotrexate and high-dose cytarabine. Patients treated for acute lymphoblastic leukemia (ALL) on TOTAL13a13 and TOTAL13b14 received high-dose methotrexate. Finally, patients treated for ALL on TOTALXIV (NCT00187005), TOTALXV(NCT00137111)15 and TOTALXVI (NCT00549848) were treated with high-dose methotrexate, and, in the case of standard- and high-risk patients, high-dose cytarabine. All grade 2 or higher non-hematologic toxicities were recorded in protocol adverse events databases, which were reviewed at the time of the data-freeze (11/20/2013) to identify grade 2 or greater skin or soft tissue toxicity. Medical records were then reviewed to confirm the presence of PPES and document the course and interventions provided. Reports of hand or foot pain also prompted medical record review unless the pain was reported to be neuropathic. Patients were considered cases if they experienced both pain and erythema (equivalent to Common Terminology Criteria for Adverse Events V4.0 grade 2 or higher) and the treating clinician diagnosed the patient with PPES. Patients were excluded if the rash was vesicular or associated with viral stomatitis. Patients treated with kinase inhibitors prior to the onset of the rash were also excluded. The duration of symptoms was measured from the onset of pain and/or erythema to the resolution of physical findings and the completion of therapeutic interventions targeting PPES. Controls for the GWAS were selected for genotyping in a 3:1 ratio and matched for treatment, age, and self-identified race.

All patients older than 18 years old and parents of minors consented to pharmacogenetic analysis. Minors provided age appropriate assent. All parents/participants on clinical trials provided consent/assent for treatment consistent with the Declaration of Helsinki. The clinical trials and this study were approved by the institutional review board.

Ancestry Determination

Patient's self-described ancestry was categorized as white if the patient declared they were non-Hispanic white, black if they described themselves as black or African-American, and other for all others. Genetic ancestry for genotyped patients was determined using STRUCTURE v2.2.3 as previously described.16 When ancestry was treated as a categorical variable, individuals were classified as white, black, or other based on inferred genetic ancestry as follows: those with >90% Northern European (CEU) were classified as white; those with >70% West African (YRI) classified as black; those not classified as white or black, including Asians (those with >90% east Asian [CHB/JPT]) and Hispanics (those with Native American ancestry >10% and greater than the % West African ancestry) were categorized as Other.

Genotyping and GWAS Quality Control

Germline DNA was obtained from peripheral blood mononuclear cells following appropriate consent. For leukemia patients, samples were obtained following remission; for solid tumor and lymphoma patients, samples were obtained when peripheral blood leukocyte counts were adequate for sample collection. DNA was genotyped on the Illumina Human Exome Beadchip v1.1 or 1.2 as well as the Affymetrix GeneChip Genome-Wide Human SNP Array 6.0.

Genotyping results for patients were excluded if the call-rate for the patient was <95%. Single nucleotide polymorphisms (SNPs) were excluded if their call-rate was <95% or if they were in Hardy Weinberg disequilibrium (P<1×10-4) in ancestral whites. SNPs with a minor allele frequency of less than 0.5% were excluded. To reduce false discovery due to the small sample size, only SNPs in which the minor allele was associated with an increased risk of PPES were included.

Statistical Analysis

Patient characteristics were tested for association with the development of PPES using chi-square for univariate analyses and ANOVA for multivariate analyses using R v3.2.2.17 SNPs were evaluated for association with PPES adjusting for genetic ancestry using a logistic regression implemented in PLINK v1.90b3.38.18 To evaluate possible functional effects of the top ranked SNPs, the association of SNP genotypes with gene expression was evaluated in GTEx19; SNPs associated with changes in gene-expression in queried tissues at P<0.05 were considered expression quantitative trait loci (eQTL).

Results

Patient Characteristics

A total of 1720 patients were enrolled on the trials described above, including 946 patients who received only high-dose methotrexate, 205 patients who received only high-dose cytarabine, and 569 patients who received both high-dose methotrexate and high-dose cytarabine. There were 39 episodes of PPES in 22 patients (1.3% of patients; mean 1.8 episodes/patient, range 1-4 episodes/patient; Table 1). The mean duration of the first episode was 5.8 days (range 2-16 days), and the mean duration of subsequent episodes in the 11 patients with more than one episode was 6.8 days (range 2-14 days). Initial episodes involved both the hands and feet in 15 patients (68%), only the hands in 4 patients, and only the feet in 3 patients.

Table 1.

Characteristics of 22 patients who developed palmar-plantar erythrodysesthesia syndrome.

Age Primary diagnosis Implicated drug (number of episodes) Recurrence (# events/# courses) Location of reaction (hand/feet) Duration of longest episode (days) Treatment for symptoms
4 BCL cytarabine 2/2 both (3) 7 oral opiates, antihistamine
5* AML cytarabine 0/2 hands 15 oral opiates
7 ALL methotrexate 0/3 hands 10 topical steroid
9 BCL methotrexate (1), cytarabine (2) 0/1 (MTX)1/1 (ARAC) both (3) 10 oral opiates, IV opiates, gabapentin, steroids
12 OS methotrexate 1/1 both, feet 4 oral opiates
12 BCL methotrexate# 0/1 both 8 oral opiates, steroid
14 OS methotrexate 3/7 feet (4) 8 oral opiates, IV opiates, gabapentin, steroid
14 BCL cytarabine 0/1 both 3 antihistamine
14 AML cytarabine (2) 1/2 both (2) 14 oral opiates
15 AML cytarabine (2) 1/2 both, feet 5 oral opiates, antihistamine, steroid
16 ALL methotrexate 0/3 both 14 IV opiates
16 BCL cytarabine (2) 1/1 both (2) 13 oral opiates, antihistamine
16 OS methotrexate (2) 1/9 feet (2) 5 steroid
17 BCL cytarabine 0/0 both 5 antihistamine
17 BCL cytarabine (2), methotrexate (1) 1/1 (ARAC)0/2 (MTX) hands (2), both (1) 6 oral opiates, gabapentin
17 AML cytarabine 0/0 both 16 oral opiates
17 AML cytarabine 0/2 both 3 oral opiates
17 BCL methotrexate (1), cytarabine (2) 0/1 (MTX)1/1 (ARAC) hands (1), both (2) 7 oral opiates
17 AML cytarabine (2) 1/2 both, feet 10 oral opiates, IV opiates, gabapentin
18 BCL methotrexate# 0/1 both 3 IV opiates, steroids
18 OS methotrexate 0/6 feet 7 oral opiates
18 AML cytarabine 0/2 both 5 IV opiates
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*

No genetic material available, not included in genome wide association study

#

Therapy prior to onset of PPES included high-dose methotrexate (3 g/m2 over 3 hours) and cytarabine (100 mg/m2 daily ×5 days).

BCL- mature B-cell leukemia/lymphoma; ALL- acute lymphoblastic leukemia; OS- osteosarcoma; AML- acute myeloid leukemia.

Recurrence indicates number of times PPES returned and the number of times patients were rechallenged with the same chemotherapy as preceded the initial PPES episode.

Cytarabine was the implicated drug in 23 events (14 cases) and methotrexate was implicated in 16 events (11 cases), although 2 patients (2 events) also received intermediate-dose cytarabine (100mg/m2 IV daily) along with high-dose methotrexate during the course prior to PPES onset. Although 7 cases were exposed to both high-dose cytarabine and high-dose methotrexate during separate courses of therapy, only 3 had PPES following both drugs. Although high-dose cytarabine has previously been implicated in PPES, 3 events in 3 patients occurred following intermediate-dose cytarabine (without methotrexate). All 3 of these patients had experienced prior episodes following high-dose cytarabine. Patients received a total of 54 courses of similar therapy (i.e. high-dose methotrexate or cytarabine) after their first episode, and experienced recurrent PPES symptoms in 14 (26%). In univariate analysis, PPES occurred less commonly in patients receiving methotrexate alone (occurring in 0.7% of patients) than cytarabine alone (3.4%, P=0.005), but was similar to rates in those receiving both drugs (1.4%, P=0.32, Table 2).

Table 2. Characteristics associated with the development of palmar-plantar erythrodysesthesia syndrome.

Cases (n=22) Controls (n=1698) P (univariate) Odds ratio (95% CI) P (multivariate)
age (mean; range) 14.3 (4-18) 7.7 (0-20) 7.5×10-7 1.3; 1.2-1.4 1.1×10-4
Non-Hispanic white 13 1285 REFERENCE Not evaluated in model
• Black 6 295 0.16 2; 0.7-5.1
• Other ancestry 3 118 0.16 2.5; 0.6-7.9
Male 10 965 REFERENCE
• Female 12 733 0.39 0.63; 0.27-1.5
Chemotherapy received
• Received high-dose methotrexate 7 939 REFERENCE
• Received high-dose cytarabine 7 198 0.005 4.7; 1.6-14
• Received both high-dose methotrexate and cytarabine 8 561 0.32 1.9; 0.69-5.3
Methotrexate infusion rate
• Slow (<1 g/m2/hour) 1 962 REFERENCE
• Fast (≥1 g/m2/hour) 14 538 1.5×10-5 25; 3.3-190 0.065
Cytarabine administration
• With dexamethasone 1 531 REFERNCE
• Without dexamethasone 15 179 2.5×10-6 29; 3.8-220 0.038
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Other ancestry: Not black or non-Hispanic white. Odds ratios for age indicate odds per year of age at diagnosis 95% CI: 95% confidence interval

Because cytarabine and methotrexate are administered in different combinations and schedules for different diseases, we evaluated the impact of methotrexate administration rate and cytarabine co-administration with glucocorticoids on PPES following these drugs. Among patients receiving high-dose methotrexate, PPES was more common (occurring in 2.5% of patients) when methotrexate was infused rapidly (≥1g/m2/hour) compared to slower infusion rates (0.1% of patients, P=1.5×10-5, Table 2). Among patients receiving high-dose cytarabine, PPES was less common when dexamethasone was administered with cytarabine (0.2%) than when cytarabine was given without glucocorticoids (5.2%, P=2.5×10-6, Table 2).

In univariate analysis, older age was the only demographic feature associated with PPES (mean in cases 14.3 years, mean in controls 7.7 years, P=7.5×10-7). There was no gender difference in the frequency of PPES, with 1.6% of females and 1% of males symptomatic (P=0.39). The PPES frequency was similar across patients of different self-declared races, with 1% of white, 2% of black, and 2.5% of other race patients having symptoms (P=0.16).

In multivariable analysis, older age (P=1.1×10-4) and cytarabine administration without dexamethasone (P=0.038) were associated with higher rates of PPES, while faster methotrexate infusion rate trended toward a higher rate of PPES (P=0.065, Table 2).

Therapeutic interventions

28 episodes in 15 patients required treatment with oral opiates, and 9 episodes in 6 patients required parenteral opiates for symptom control. Gabapentin was prescribed for 4 patients (9 episodes). Anti-histamines were given to 5 patients (6 episodes), while 7 patients (9 episodes) received systemic steroids to treat their symptoms (Table 1). In one episode, no new interventions were prescribed; however, that patient had previously been prescribed oral opioids for disease related pain, and that patient required oral opioids in two subsequent episodes.

Genome-Wide Association Study

In a genome-wide association study adjusting for ancestry, no SNPs reached the genome-wide significance threshold of 5×10-8. There were 10 SNPs representing 8 genetic regions associated with the development of PPES at P<1×10-4 (Figure 1; Table 3). The top SNP was rs4799679, an intronic SNP within CCDC178 [G risk allele frequency (RAF) 0.4 in cases and 0.07 in controls, P=1.1×10-5, odds ratio (OR) with 95% confidence interval 24 (5.8-97)]. The top non-synonymous variant was rs346803 in SPHK1 [G RAF 0.33 in cases and 0.07 in controls, P=1.2×10-4, OR 10 (3.1-34)]. Variants related to folate metabolism were also weakly associated with PPES, with the A risk allele frequency in rs803446 (intronic in MTHFD1L) of 0.38 of cases and 0.22 of controls [P=0.03, OR 2.8 (1.1-7.3)]. Interestingly, 12 of the top 50 SNPs in the GWAS were eQTLs in sun-unexposed skin, including SNPs in COX7C, AUTS2, NISCH, and HRH2. In contrast, only 1 of the top 50 SNPs was an eQTL in liver, and only 2 were eQTLs in EBV-transformed lymphocytes (P<0.01 for both).

Figure 1.

Figure 1

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Manhattan plot of SNPs associated with PPES after adjusting for ancestry Top variants associated with PPES included rs4799679 in CCDC178 and rs11764092 in AUTS2. The AUTS2 variant was also an eQTL in sun un-exposed skin.

Table 3.

SNPs associated with PPES with P<1×10-4 after adjusting for ancestry.

rsID OR (95% CI) P Risk allele Alt allele RAF cases RAF controls Gene
rs4799679 23 (5.8-97) 1.10×10-5 G C 0.4 0.07 CCDC178
rs6924770 24 (5.4-103) 2.59×10-5 G C 0.29 0.05 Intergenic
rs2180134 T C
rs2937084 10 (3.4-30) 3.30×10-5 T A 0.69 0.34 COX7C*
rs7004242 61 (6-8448) 6.24×10-5 T C 0.14 0 KIF13B
rs11764092 15 (4-56) 6.45×10-5 G T 0.38 0.08 AUTS2*
rs10246207 7.3 (2.7-20) 7.65×10-5 C A 0.79 0.38 Intergenic
rs17572851 14 (3.7-50) 7.79×10-5 G A 0.3 0.07 MAPT
rs887717 6.8 (2.6-18) 9.81×10-5 A T 0.76 0.37 Intergenic
rs10441051 G C
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CI: confidence interval; RAF: risk allele frequency

*

SNP is eQTL in sun un-exposed skin.19

Discussion

Palmar-plantar erythrodysesthesia syndrome is a rare but distressing side effect that results in significant morbidity in patients receiving high-dose methotrexate or cytarabine. Due to its rarity (the largest pediatric case series to our knowledge yet published contains six patients receiving pegylated liposomal doxorubicin,5 while the largest case series with conventional cytotoxic agents includes only two patients9), limited information is available on its risk factors, natural history, or prognosis. Herein, we report the largest case series to date of PPES following these agents, the largest case series in pediatrics, and describe its risk factors. Within our population, 18 of 22 patients (82%) required treatment with opiates for pain relief, and almost a quarter of episodes [9 of 39 episodes (23.1%) in 6 of 22 patients (27.3%)] required admission for parenteral pain management. Importantly, although PPES is a rare event in children, symptoms recurred in half of our population with subsequent courses of therapy, and more than 25% of subsequent courses were complicated by PPES. Thus, the risk of recurrence is high.

In our study, patients treated with high-dose cytarabine experienced PPES more frequently than did those treated with high-dose methotrexate (P=0.005). Interestingly, differences in administration appear to alter the risk of PPES. More rapid infusion of methotrexate appears to increase the risk of PPES by 25-fold (2.5% vs. 0.1%), perhaps due to greater tissue penetration associated with the higher peak concentrations associated with rapid infusion,20 although this effect was attenuated in multivariate analysis. This suggests that patients with solid tumors receiving methotrexate may be more likely to develop PPES than patients with leukemia, due to their tendency to receive more rapid infusions to achieve higher peak levels in their tumors.21 Other chemotherapy administered coincident with cytarabine may also alter the risk of PPES. Of the 7 patients with AML developing PPES, 4 developed it while receiving clofarabine in addition to high-dose cytarabine, consistent with prior reports of an increased risk of PPES with this combination.22 Notably, 2 of these patients had a recurrence of their PPES during later exposure to cytarabine alone, indicating their symptoms were not dependent on their exposure to clofarabine.

Our data also suggests that dexamethasone may diminish the risk of PPES when co-administered with high-dose cytarabine (PPES in 5.2% of patients treated with cytarabine without dexamethasone and 0.2% of patients when administered with dexamethasone, 0.2%, P=2.5×10-6). This is consistent with prior case-series reports suggesting dexamethasone may prevent recurrence of PPES due to vinorelbine23 and pegylated-doxorubicin.24 While leukocyte mediated inflammation does not appear to play a major role in the pathogenesis of PPES,11, 25 it is possible the anti-inflammatory properties of dexamethasone contribute to this effect. While our data suggests dexamethasone may be effective in reducing PPES due to cytarabine, we are unable to provide evidence for its role in methotrexate associated PPES, as those therapies were not combined in any of the treatments we evaluated.

The relative rarity of PPES makes genomic analysis of its predisposition challenging. No genetic variants in our analysis reached the genome-wide significance level of 5×10-8. There are multiple possible explanations for this finding. The first is that, despite screening a large population of patients for the development of PPES through adverse events databases, the limited number of cases identified provided insufficient power to detect causal variants. The relative rarity of PPES in this population suggests either that there is little genetic basis for this toxicity, or that causative variants are relatively rare or that have modest effect sizes. Our study suggests that multiple variants are likely to be contributory, as no individual variant accounting for all cases was identified. Additionally, half of patients experienced a recurrence of their symptoms while receiving further therapy, but only 25% of future courses were complicated by PPES. This suggests there are unidentified non-genetic modifiers altering the risk of developing PPES, which may vary relatively rapidly (i.e. can change between courses of therapy). For example, a 14 year old receiving methotrexate for osteosarcoma had recurrence of PPES in 3 of the 7 courses of therapy following her initial episode (Table 1). The limited sample size may also have limited our ability to identify associations between additional clinical factors and the development of PPES. Validation of these clinical and genetic findings in additional cohorts is needed.

Despite these limitations, our study provides interesting insights into possible genetic risk factors for PPES in children. Patients carrying the G risk allele in rs11764092, intronic in AUTS2, were significantly more likely to develop PPES than were patients with the TT genotype (P=6.45×10-5, OR 15). This SNP has previously been shown to be an eQTL in skin; patients with the variant G allele had lower expression of AUTS2 in their skin. Interestingly, AUTS2 has previously been shown to be expressed at lower levels in skin from older donors compared to skin from younger donors.26 Because PPES is also seen more commonly in adults11 and, in our study, older children, gene-age interactions in AUTS2 expression may combine to contribute to PPES. It also suggests the effect of AUTS2 variants may be less apparent in an adult oncology cohort, in which AUTS2 expression has already decreased due to aging.

This is the first study to evaluate the clinical and genetic predisposing factors for developing PPES with methotrexate or cytarabine exposure, and the first to study this side effect in children. The only prior GWAS to evaluate PPES was among adults receiving capecitabine for either breast or colon cancer, in which 111 patients across 2 cohorts developed PPES.27 That analysis was further supplemented by a GWAS of SNPs conferring sensitivity to capecitabine in vitro. Our GWAS was unable to replicate the findings of this prior work, suggesting that the risk variant previously identified is either age or capecitabine specific and did not influence the development of PPES after methotrexate or cytarabine (P=0.55 for rs9936750 in our data). However, our power was limited due to the small sample size. Top SNPs identified in our analysis were not among the 16 SNPs identified in the prior analysis, suggesting replication of our genetic findings in an appropriate cohort is needed.

Conclusion

The rarity of PPES limited our power to identify predisposing factors. Nevertheless, we showed, for the first time, that older age predisposes to PPES within the pediatric population. Our evaluation of genetic features suggests that this toxicity is not monogenic, but rather results from an interaction of patient characteristics (e.g. age), genetic predispositions (e.g. variants in skin eQTLs which alter skin susceptibility to therapy), and therapy schedule (e.g. methotrexate infusion time and cytarabine co-administration with dexamethasone). Further studies will be required to extend these findings to identification of interventions to minimize this rare but troubling toxicity.

Acknowledgments

Funding Support: CA21765 and GM115279 from the National Institutes of Health, American Lebanese Syrian Associated Charities (ALSAC)

Footnotes

Author contributions: Seth E. Karol: conceptualization, data curation, formal analysis, investigation, methodology, software, visualization, writing- original draft, writing- review and editing, validation. Wenjian Yang: software, formal analysis, validation. Colton Smith: software, formal analysis. Cheng Cheng: data curation, methodology, validation. Clinton Stewart: resources, writing- review and editing. Sharyn Baker: resources. John Sandlund: resources, writing- review and editing. Jeffrey Rubnitz: resources, writing- review and editing. Michael Bishop: resources, writing- review and editing. Alberto Pappo: resources, writing- review and editing. Sima Jeha: resources, writing- review and editing. Ching-Hon Pui: resources, writing- review and editing. Mary Relling: conceptualization, methodology, writing- review and editing, resources, supervision, funding acquisition.

Conflicts of interest: The authors declare no competing conflicts of interest.

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