A population‐based study of acute panmyelosis with myelofibrosis in the United States: 2004–2015

To The Editor: Acute panmyelosis with myelofibrosis (APMF) is a rare subtype of acute myeloid leukemia (AML) characterized by acute panmyeloid proliferation with increased blasts, cytopenias, bone marrow fibrosis, and absence of splenomegaly. APMF is estimated to account for <1% of AML.1 There is controversy regarding how to differentiate APMF from other myeloid malignancies such as AML with fibrosis, acute megakaryoblastic leukemia, or myelodysplastic syndrome with fibrosis.2 There is a paucity of studies describing the clinical features and outcomes of APMF. The prognosis of APMF is very poor, with a reported median survival of 1–9 months.1, 3 No consensus in treatment exists. No study has yet utilized the National Cancer Database (NCDB) or Surveillance, Epidemiology, and End Results (SEER) database to report risk factors, treatments received, and additional clinical features. Our study utilizes SEER and the NCDB to better describe the outcomes and survival trends of patients diagnosed with APMF from 2004 to 2015.4, 5 We queried the United States SEER database and NCDB using the ICD-O-3 code 9931/3. The NCDB is a joint project of the Commission on Cancer of American College of Surgeons and the American Cancer Society that is a nationwide oncology outcomes database for >1500 cancer programs in the US and Puerto Rico, capturing 70% of all newly diagnosed cases of cancer in the US.4 SEER is a program of the National Cancer Institute that collects and publishes cancer incidence and survival data covering about 28% of the US population.5 Due to the challenges of diagnosing APMF, we only included patients in our cohort if the diagnostic confirmation included those with recorded positive histology or positive histology plus positive immunophenotyping and/or positive genetic studies. The SEER 17 registries (2004–2015) were used to find data on incidence, overall survival (OS), and relative survival (RS); the Alaska Native Tumor registry was excluded from this analysis. Incidence was age-adjusted to the U.S. 2000 standard population. Incidence ratios (IRs) were calculated with SEER*Stat software (version 8.3.6; NCI, Bethesda, MD). Descriptive statistics such as median, interquartile range (IQR), and OS were calculated by analyzing SEER data in BlueSky (Version 7.10). Relative survival (RS) was defined as the ratio of observed survivors in the group of APMF patients to the expected survivors in a comparable set of individuals without APMF. This was adjusted for the general survival of the US population by race, sex, age, and year of diagnosis. We utilized SEER*Stat to calculate standardized mortality ratios (SMRs) for all-cause mortality. SMR is the number of observed deaths in the study population divided by the number of expected deaths. Thus, SMR depicts the risk of death in APMF patients compared with the general US population. The NCDB data included those diagnosed between 2004 and 2015. Comorbid disease burden was calculated using the Deyo adaptation (1992) of Charlson's comorbidity index, which considers as many reported ICD-9-CM or ICD-10 secondary diagnosis codes for the patient of interest and is reported as the Charlson Deyo Score (CDS). Overall survival (OS) was analyzed using the Kaplan–Meier method. Hazard ratios (HR) with confidence intervals (CI) were calculated using a Cox proportional hazards model. Variables significant in univariate analysis were included in a multivariate analysis. Statistical analyses for NCDB were performed using SAS version 9.4. We identified 260 APMF patients using the SEER database. The median age at diagnosis was 67 years (range 20–93); 142 (55%) were male. 201 (77%) were non-Hispanic White (NHW), 26 (10%) were non-Hispanic Black (NHB), 20 (8%) were Hispanic, and 13 (5%) were non-Hispanic Asian Pacific Islander (NHAPI). The overall IR of APMF was 0.3 cases/million individuals and did not change significantly between the years 2004–2015. The IRs according to gender and racial groups were male 0.4, female 0.3, NHW 0.4, NHB 0.4, Hispanic 0.2, and NHAPI 0.2. With a median follow up of 6.9 years (95% CI 6.1–7.8), the median OS was 2.3 years (95% CI 1.7–2.8; Figure S1). In the general US population, the expected survival at 1, 3, and 5 years was 97%, 93%, and 89%. In contrast, RS for patients with APMF was 71%, 45%, and 34%, respectively (Figure S1). The standardized mortality ratio (SMR) for all-cause mortality was 10.15 and statistically significant (95% CI: 8.74–11.72). We identified 530 APMF patients using the NCDB. The median age at diagnosis was 67 years (range 22–90) and 311 (59%) were male. With a median follow up of 5 years (95% CI 3.0–7.6), the median OS was 2.3 years (95% CI: 0.8–6.5, Figure 1A). OS was 69%, 31%, and 18% at 1-, 5-, and 10- years, respectively. Four hundred three patients (76%) had a CDS of 0, 83 had a CDS of 1 (16%), and 44 had a CDS of 2+ (8%). Patients were grouped by year of diagnosis, specifically 2004–2007, 2008–2011, and 2012–2015. Patients diagnosed in 2012–2015 had a significantly improved OS compared to those diagnosed in 2004–2007 (HR 0.65, 95% CI 0.49–0.85; p = .002). Two hundred seventy-one patients (53%) received chemotherapy as first-line therapy. The median time from diagnosis to chemotherapy was 25 days (range 0–532 days). The OS for those that received chemotherapy was 70% at 1- and 30% at 5-years versus 70% and 32% at 1- and 5- years for those who did not (p = .99). Fifty-two patients (10%) underwent hematopoietic cell transplantation (HCT) as first-line therapy and the OS of those patients was 90% at 1 year and 45% at 5 years versus 67% and 29% at 1- and 5- years for those who did not (HR: 1.7 [95% CI: 1.2–2.6], p = .006). Among the 51 patients who underwent allogenic transplantation, 46 (90%) had a CDS of 0, 3 (6%) had a CDS of 1, and 2 (4%) had a CDS of 2+. In univariable analysis, factors predicting inferior OS were age ≥65 years at diagnosis (HR 1.8, 95% CI 1.5–2.3; p < .001), male sex (HR 1.5, 95% CI 1.2–1.8; p < .001), CDS ≥1 (HR: 1.5 [95% CI: 1.2–2.0], p < .001), government insurance (HR 1.8, 95% CI 1.4–2.3; p < .001), diagnosis at a non-academic facility (HR 1.6, 95% CI 1.2–2.0, p < .001), and not receiving HCT as first-line therapy (HR 1.7, 95% CI 1.2–2.6; p = .006). In multivariate analysis, factors predicting inferior OS were age ≥65 years at diagnosis (HR 1.4, 95% CI 1.1–2.0; p = .02), male sex (HR 1.7, 95% CI 1.3–2.1; p < .001), CDS ≥1 (HR 1.4, 95% CI 1.1–1.8; p = .006), and diagnosis at a non-academic facility (HR 1.5, 95% CI 1.2–1.9; p < .001). Table S1 shows the univariate and multivariate analysis of factors predicting inferior OS. Figure 1B–E show the survival estimates based on age, insurance type, year of diagnosis, and facility type. This is the largest retrospective study examining the incidence, OS trends, and factors predicting inferior OS of APMF at the population level. Prior series have reported widely variable survival ranging from 2 to 9 months.6 A series by Thiele et al., had a similar median age at diagnosis, but there was significant discrepancy between the median OS (2.3 years in our series vs. 9 months in Thiele et al.).3 The exact reasons for the discrepancy are unclear. One possibility is the misdiagnoses in our cohort given the challenge in diagnosing APMF. In addition, the median comorbidity in our cohort was low, whereas Thiele et al. did not report comorbidity. Finally, there was a significant male preponderance (74% male) in the series by Theiele et al., whereas our population-based cohort was more balanced (55% and 59% for SEER and NCDB, respectively). In a series of 40 younger patients who underwent HCT, median post-HCT survival was <1 year and male sex was associated with a significantly inferior survival.7 A potentially significant finding emerging from our study is that despite a low comorbidity burden, only 10% patients underwent HCT early in the course. Those undergoing HCT early had a significant survival advantage compared to those who did not (45% vs. 29% at 5 years). Therefore, HCT should be considered early in APMF. Strengths of our study include the larger sample sizes found in the SEER and NCDB databases compared to the case series in the available published literature. We found significant similarities between the SEER and NCDB databases in terms of clinical characteristics and survival, reinforcing the consistency of our findings. Limitations include the possibility of diagnostic error due to our inability to independently review the histopathology to confirm the diagnosis. SEER and NCDB also do not provide specifics on the agents used in treatment. In addition, these databases do not include data on those that go on to receive chemotherapy or HCT following their first treatment regimen. Our study confirms that APMF remains an exceedingly rare disease with a poor prognosis, with a 10-fold increased risk of death for those with APMF. The incidence of APMF has not changed between 2004 and 2015, but OS for 2012–2015 was improved compared to 2004–2007. While early utilization of chemotherapy did not improve outcomes, early utilization of HCT was associated with improved OS. Given the lack of standard of care and poor prognosis associated with APMF, further studies are needed to better understand potential therapeutic options. The data that support the findings of this study are openly available in [repository name e.g “figshare”] at http://doi.org/[doi], reference number [reference number]. Figure S1. Survival curves from the Surveillance, Epidemiology and End Results (SEER) cohort. Expected, observed, and Acute Panmyelosis with Myelofibrosis (APMF)-specific relative survival (mean ± standard error of mean). Table S1. Univariate and multivariate analysis of factors predicting inferior overall survival (OS) from the National Cancer Database (NCDB) cohort. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.