Association of Leukemia Cutis With Survival in Acute Myeloid Leukemia

Key Points

Question  What is the association of leukemia cutis with a patient’s acute myeloid leukemia course?

Findings  In this matched-cohort study of 1683 patients with acute myeloid leukemia, the presentation of leukemia cutis was associated with significantly decreased overall and leukemia-specific survival.

Meaning  The study suggests that leukemia cutis is associated with a poor prognosis for patients with systemic acute myeloid leukemia and that these patients may require more aggressive treatment and intensive monitoring throughout their clinical course.

Importance  Leukemia cutis (LC) is an important yet understudied extramedullary manifestation of leukemia. Previous reports have suggested poor prognosis for patients with LC, but these reports have largely consisted of descriptive studies with a limited number of patients.

Objectives  To identify patient factors associated with LC and characterize the association of LC with the course of acute myeloid leukemia (AML).

Design, Setting, and Participants  This retrospective, matched-cohort study included 1683 patients with AML diagnosed from January 1, 2005, to April 1, 2017, with and without biopsy-proven LC seen at a single-center, tertiary care hospital in St Louis, Missouri. To specifically evaluate differences in survival, propensity scoring was used to match patients with AML with LC to patients with AML without LC off the logit of propensity score based on age, race/ethnicity, sex, and leukemia type. Kaplan-Meier methods were used to compare cumulative probability survival. Matched survival analysis was performed with extended Cox regression to determine factors associated with leukemia-specific and overall survival.

Main Outcomes and Measures  Leukemia-specific survival and overall survival.

Results  A total of 1683 patients were reviewed, including 78 patients with biopsy-proven LC of the AML type and 1605 patients with AML without LC. A total of 62 of the patients with AML and LC (mean [SD] age, 58.2 [11.7] years; 33 [53.2%] male) were matched in a 1:3 ratio to 186 patients with AML without LC (mean [SD] age, 58.2 [13.5] years; 103 [55.4%] male). The 5-year survival among the 62 patients with AML with LC was 8.6%, shorter than the 28.3% among the 186 matched patients with AML without LC. Matched survival analysis revealed that patients with AML and LC compared with those without LC had hazard ratios of 2.06 (95% CI, 1.26-3.38; P = .004) for leukemia-specific death and of 1.66 (95% CI, 1.06-2.60; P = .03) for all-cause death. In addition, matched patients with LC had greater odds of extramedullary organ burden (odds ratio, 3.48; 95% CI, 1.72-7.05; P < .001).

Conclusions and Relevance  The results suggest that the presentation of LC in patients with AML is associated with decreased overall survival and leukemia-specific survival. Patients with AML presenting with LC may require more intensive treatment and monitoring of their leukemic disease.

Leukemia cutis (LC), also known as cutaneous myeloid sarcoma, is an extramedullary manifestation of leukemia in the skin.¹ This condition may occur with any type of leukemia but is most common in acute myeloid leukemia (AML), with an estimated incidence of up to 50% in the French-American-British (FAB) M4 (acute myelomonocytic leukemia) and M5 (acute monocytic leukemia) subtypes.²

Of note, LC has long been suggested to indicate a poor prognosis. As many as 90% of patients with LC have been reported to have other extramedullary involvement³ of sites such as the central nervous system, orbita, and ovaries.^3,4 Moreover, in 1984, Su et al⁵ and Su⁶ reported that 88% of patients with LC die within 1 year of the diagnosis. However, recent literature has been more equivocal about the association of LC with prognosis. For example, a 2001 study by Agis et al⁷ found that the complete remission rate was similar in patients with AML with and without LC who received chemotherapy, with no difference in the rate of early deaths or resistance to treatment. To date, the pathogenesis behind LC remains unclear, although various cytogenetic and molecular features have been implicated. Translocation 8;21, which generally suggests a favorable prognosis, and trisomy 8, which suggests a poor prognosis, have been linked with LC.¹ Other features that have been associated with extramedullary involvement include inversion of chromosome 16, chromosome 11q23 rearrangement that involves the MLL gene (10962), NPM1 mutation (4869), and FLT3-ITD (2322).¹

The literature on LC has primarily been limited to studies that are largely descriptive, with small sample sizes, and/or with a histopathologic rather than a clinical focus.^2,4-13 We therefore conducted this propensity score (PS)–matched cohort study to examine the patient factors associated with LC and the prognostic significance of LC in a patient’s leukemic course, specifically in AML.

Patients with AML and LC were identified from a search of the Department of Pathology, Washington University School of Medicine in St Louis, database. These patients needed to (1) have biopsy-confirmed LC, (2) be older than 18 years, and (3) have a first leukemia diagnosis between January 1, 2005, and April 1, 2017. Patients with AML but without LC were drawn from an internal data tracking system belonging to the Division of Oncology, Washington University School of Medicine, from the same period with the same inclusion criteria of age older than 18 years and a first leukemia diagnosis between January 1, 2005, and April 1, 2017. Informed consent was not required because this was a retrospective study. Data were deidentified after medical record review. This retrospective, matched-cohort study was approved by the Washington University School of Medicine Institutional Review Board.

Data were retrieved from electronic medical records and managed using REDCap (Research Electronic Data Capture) tools hosted at Washington University School of Medicine. Acute myeloid leukemia was classified according to the FAB criteria¹⁴ based on results of bone marrow biopsies or peripheral blood sample analyses, except in the case of exclusively aleukemic LC. Dates of diagnoses for LC and systemic leukemia were identified as dates of biopsy collection. To account for comorbidity burden, each patient was scored according to the original weighted Charlson Comorbidity Index (CCI), a validated and frequently used prognostic measure of baseline disease burden that reflects 10-year mortality.^15-17 Comorbidities were assessed based on records before first presentation of leukemia. Dates, causes of death, and association of death with active leukemia were determined from hospital records and death certificates.

The primary outcome was leukemia-specific survival (LSS). Secondary outcomes included overall survival (OS) and odds of extramedullary organ involvement, secondary leukemia (leukemia that evolves from prior myelodysplastic or myeloproliferative disease or results from chemoradiotherapy exposure), chromosome 8 abnormalities, inversion of chromosome 16, MLL gene rearrangement, NPM1 mutation, FLT3-ITD, prior bone marrow transplant, and CCI greater than 4 (scores that indicate nearly 100% likelihood of 10-year mortality).¹⁵

To evaluate differences in survival, we undertook a PS-matched analysis to compare patients with AML and LC with patients with AML without LC.^18,19 Key baseline demographic and leukemia characteristics (age at leukemia diagnosis, sex, race/ethnicity, and FAB classification) were used to construct the PS using logistic regression in SAS software (SAS Institute Inc). Matching was performed in a 1:3 ratio using the greedy matching algorithm in SAS software with a caliper width of 0.2 × SD of the logit of PS.²⁰ Patients were excluded from matching if they had acute promyelocytic leukemia (APML) because APML is clinically different from the other AML subtypes and there were no LC cases with this subtype. Patients were also excluded from matching if they had no systemic leukemia or definitive FAB classification or had insufficient follow-up (follow-up <1 year unless there was a documented death date). The matching process is fully outlined in Figure 1.

Before matching, groups were compared using 2-tailed, unpaired t and χ² tests. On match completion, balance was assessed through standardized mean differences. After matching, variables were evaluated through univariate conditional logistic regression (accounting for matching) to determine odds ratios (ORs). Cumulative probabilities of survival were compared using Kaplan-Meier estimates and the log-rank test. Time zero was defined as the earliest date of any histopathologic diagnosis of leukemic involvement. Matched survival analysis was completed using extended Cox regression with stratification by the matched set. All-cause deaths (ACDs) and leukemia-specific deaths (LSDs) were counted as events. Leukemia-specific death was defined as death attributable to active leukemia, determined through death certificates and inpatient death notes. Patients without events were censored at the time of the last follow-up. Patients who had known death dates but unclear cause (unknown if attributable to active leukemia) did not count as having an LSD and thus were censored at their time of death for LSS, while the case counted as an event for OS. Extended Cox regression was performed to evaluate factor association to survival with hazard ratios (HRs). The assumption of proportionality was tested and met for all variables in initial Cox proportional hazard regression analysis, except for prior bone marrow transplant. An extended Cox model was therefore used to account for first bone marrow transplant as a time-varying covariate.²¹ Statistical tests were 2-sided and significant at P < .05. All data were analyzed using SAS software. This statistical plan is illustrated in the eFigure in the Supplement.

A total of 1683 patients were reviewed, including 78 patients with biopsy-proven LC of the AML type and 1605 patients with AML without LC. A total of 62 of the patients with AML and LC (mean [SD] age, 58.2 [11.7] years; 33 [53.2%] male) were matched in a 1:3 ratio to 186 patients with AML without LC (mean [SD] age, 58.2 [13.5] years; 103 [55.4%] male). All matched covariates had standardized mean differences less than 0.1, indicating excellent balance of matched covariates.²² The final study population is described in Table 1.

No difference was found between the matched cohorts in the odds of having a CCI greater than 4 (OR, 0.78; 95% CI, 0.40-1.51; P = .45) (Table 2). On multivariate extended Cox regression, a CCI greater than 4 was associated with an increased hazard of both LSD (HR, 3.25; 95% CI, 1.80-5.86; P < .001) and ACD (HR, 3.08; 95% CI, 1.84-5.17; P < .001) compared with a CCI of 4 or less (Table 3).

In terms of important clinical, cytogenetic, and molecular features of AML, no differences were found in the odds of having secondary leukemia, NPM1 mutation, FLT3-ITD, MLL gene rearrangement, inversion of chromosome 16, or translocation that involved chromosome 8 (Table 2). However, compared with those without LC, patients with AML and LC had higher odds of having other extramedullary organ involvement (OR, 3.48; 95% CI, 1.72-7.05; P < .001) and additional chromosome 8 (OR, 2.13; 95% CI, 1.10-4.12; P = .03) (Table 2).

Moreover, the patients with AML and LC had decreased OS and LSS compared with the patients with AML without LC. Of the 248 total patients (62 with AML and LC and 186 with AML without LC), there were 188 ACDs (55 in the group with LC and 133 in the group without LC) and 148 LSDs (49 in the group with LC and 99 in the group without LC). The patients with AML and LC had a median OS of 13.03 months (95% CI, 10.02-16.62 months), which was shorter than the 17.21 months (95% CI, 13.54-21.26 months) for those without LC (P = .01 for survival curves) (Figure 2A). Similarly, the median LSS was 13.86 months (95% CI, 10.02-17.74 months) in the group with LC and 22.21 months (95% CI, 17.05-42.51 months) among those without LC (P = .002 for survival curves) (Figure 2B). The 5-year OS among the patients with AML and LC was 8.6%, shorter than the 28.3% OS among those without LC. Matched survival analyses further elucidated poorer survival in the patients with AML and LC (Table 3 and eTable in the Supplement). On multivariate analysis, the HRs among the patients with AML and LC vs those without LC were 2.06 (95% CI, 1.26-3.38; P = .004) for LSD and 1.66 (95% CI, 1.06-2.60; P = .03) for ACD.

This retrospective, matched-cohort study contributes to the limited literature on LC by further examining patient factors associated with LC and suggesting that LC is negatively associated with prognosis in AML. In concordance with a previous study,²³ patients with AML and LC had significantly higher odds of extramedullary involvement (OR, 3.48). The predilection of patients with AML and LC to have additional sites of extramedullary involvement may reflect distinctive biological characteristics of these leukemic cells. Although the pathogenesis remains unclear, a variety of cytogenetic and molecular genetic features have been linked with LC or other extramedullary involvement.^24-26 In the present study, the patients with LC had greater odds of an additional chromosome 8 (OR, 2.13), although differences between the remaining cytogenetic and molecular features did not reach statistical significance. It remains undetermined which genes affected by aneuploidy of chromosome 8 may predispose patients to LC.³

Most important, this study suggests that LC is negatively associated with the prognosis in the clinical course of AML. Patients with AML and LC were 2.06 times more likely to die of leukemia, were 1.66 times more likely to die of all causes, and had a worse 5-year survival (8.6% vs 28.3%) compared with the matched patients with AML without LC. For reference, the most recent Surveillance, Epidemiology, and End Results data from 2008 to 2014 estimate 5-year survival for all patients with AML to be 27.4%.²⁷

These differences in survival have several plausible explanations. The skin may function as a sanctuary for leukemic cells, with continued subclinical involvement despite bone marrow clearance. In fact, there is evidence that chemotherapy sufficient to induce and sustain remission in the marrow may not eliminate cutaneous involvement.^1,4 This finding could lead to a greater incidence of subsequent relapse and death. In addition, AML that presents with LC could represent distinct biological subtypes that are more aggressive or intractable to therapy.

The poor outcomes in the patients with AML and LC raise the question of the optimal treatment of patients who present with LC. Management of LC thus far has been focused on treatment of the underlying leukemia,¹ with different strategies that depend on patient factors, such as age, fitness, and comorbidity level.²⁸ As expected, patients in our study with CCIs greater than 4 (overall higher baseline comorbidity burden) had an increased hazards of both LSD (HR, 3.25; 95% CI, 1.80-5.86) and ACD (HR, 3.08; 95% CI, 1.84-5.17) compared with those with CCIs of 4 or less. Of note, no difference was found between AML with and without LC in the odds of having a CCI greater than 4, suggesting grossly similar baseline disease burden between the 2 groups regardless of LC presentation. Previous studies^29-31 have demonstrated that even patients with AML with significant comorbidity can tolerate and achieve complete remission with intensive chemotherapy regimens. As treatments and supportive measures are enhanced over time, it is likely that an even greater proportion of patients with AML will be able to tolerate the aggressive therapy that could be required to eliminate cutaneous involvement. At any rate, we suggest that patients with AML who present with LC may benefit from closer monitoring and more intensive treatment strategies to eradicate their disease compared with similar patients without this presentation.

Major limitations include the study’s small sample size, retrospective nature, the primarily white sample, and restriction to a single institution, which by nature of being a tertiary care center, may receive more acute case referrals. The cases were also classified according to the FAB classification rather than the World Health Organization classification, an alternative system that relies on molecular diagnostics.³²

In this matched-cohort study, patients with AML and LC had greater extramedullary organ involvement, decreased OS, and decreased LSS than similar patients with AML without LC. Further investigations are needed to understand the biological mechanisms behind leukemic infiltration of the skin and its association with patient survival, as well as to determine the most salient treatment strategies for these cases.

Accepted for Publication: January 12, 2019.

Corresponding Author: Milan J. Anadkat, MD, Division of Dermatology, Washington University School of Medicine in St Louis, 660 S Euclid Ave, Campus Box 8123, St Louis, MO 63110 (manadkat@wustl.edu).

Published Online: April 10, 2019. doi:10.1001/jamadermatol.2019.0052

Author Contributions: Ms Wang had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Wang, Anadkat.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Wang.

Administrative, technical, or material support: Pusic, Anadkat.

Supervision: Pusic, Anadkat.

Conflict of Interest Disclosures: Dr Anadkat reported receiving honoraria for consulting and/or speaking engagements in the past from Adgero, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Biogen, Eli Lilly and Company, Genentech, ImClone, Therakos, Xoma, and Eisai and serving as a principal investigator for Biogen, Veloce, Xoma, Hana Biosciences, and InflamRx. Dr. Anadkat will be serving as a principal investigator for clinical studies run by Lutris and Novartis as of March 31, 2019. No other disclosures were reported.