Acute Leukemias of Ambiguous Lineage: The Roswell Park Experience
Authors: Wang Eunice S. , Agwa Eberechi , Zhang Shanxiang , Merzianu Mihai 
Published: October 2019

Abstract
Abstract 2546
Acute leukemias of ambiguous lineage (ALAL) are defined by the lack of clear evidence of differentiation along a single lineage and include mixed-phenotype acute leukemias (MPAL) and acute undifferentiated leukemia (AUL). These rare acute leukemias (AL) pose diagnostic and therapeutic challenges. Criteria for ALAL/MPAL diagnosis were proposed by the European Group for the Immunological Characterization of Leukemias (EGIL) and incorporated into the 2001 World Health Organization (WHO) classification of myeloid neoplasms. The most recent 2008 WHO classification proposed a much simplified diagnostic approach to MPAL/ALAL that requires clinical validation.
We retrospectively analyzed the pathologic and clinical features of 29 cases of acute leukemia diagnosed and treated at our institution between 1995–2010. All AL patients with any of the following key words identified in the pathology and flow cytometry databases were reviewed: T/myeloid, B/myeloid, undifferentiated, mixed phenotype, anomalous expression, unclassified, biphenotypic, bilineal, biclonal. Pathology, flow cytometry, and cytogenetics reports were reviewed by 2 hematopathologists and reclassified according to EGIL and 2008 WHO criteria. Treatment regimens were reviewed and overall survival assessed for each patient.
There were 29 patients,19 adults and 10 children, with a median age of 39 years (range 2–87). Eighteen were male and 11 female. Using EGIL, 10/29 (34%) were classified as ALAL as compared to 2008 WHO where only 6/29 (21%) fulfilled the new criteria. Based on either EGIL and/or 2008 WHO classification scheme,13 out of 29 cases (45%) were classified as ALAL. The remaining 16 cases were non-ALAL, most concordant in both systems: B-cell lymphoblastic leukemia (B-ALL) (n=11, 38%) and T ALL (n=3, 10%) and discrepant in only 2 cases (7%), both classified as acute myeloid leukemia (AML) by EGIL and B-ALL by 2008 WHO. The most common cytogenetic change was t(9;22), present in 6 (33%) of non-ALAL and 2/13 (15%) ALAL. A single 11q23 translocation case was seen in the non-ALAL group. We compared ALAL (n=13) vs. non-ALAL (n=16) clinical characteristics and treatment outcome and found no significant difference in age at leukemia diagnosis, presenting white blood cell count, hemoglobin, and platelet count, or marrow blast percentage between ALAL and non-ALAL patients. Significantly more ALAL patients were treated with acute myeloid leukemia (AML) based regimens (70%) than non-ALAL patients (12.5%) (p= 0.0016), since 14 of 16 non-ALAL cases were ALL with aberrant myeloid marker expression at re-review. Patients classified as ALAL (n=13) demonstrated a trend to worse overall survival than non-ALAL patients (median 12.25 vs. 20 months, p=0.08) (Figure 1) and potentially worse overall survival following AML than ALL therapy (median 14 vs 17 months, p=0.38). The ALAL patients with the longest survival following AML induction chemotherapy (i.e. 70.6, 27.1, and 17 months) were those who underwent subsequent allogeneic stem cell transplantation. This was not true in the non-ALAL patients and ALAL patients treated with ALL regimens where long-term survival was achieved following chemotherapy in the absence of transplantation. Among all 29 patients identified here, administration of ALL-based chemotherapy independent of EGIL/WHO classification was significantly associated with improved overall survival (p=0.015) (Figure 2).Figure 1.Figure 1. Figure 2.Figure 2.
In summary, this single institution retrospective review shows that 2008 WHO classification simplifies the diagnosis and limits the number of ALAL/MPAL compared to EGIL score system but this rare entity remains a diagnostic challenge. Over half of these 29 cases preliminarily diagnosed as acute leukemia with dual or uncertain lineage were re-classified as ALL. Although limited by small patient numbers, our preliminary findings suggest that patients diagnosed with ALAL using either EGIL or WHO criteria fare worse than non-ALAL patients and achieve better outcomes (in the absence of allogeneic stem cell transplantation) following ALL-based chemotherapy. Given the overall difficulty in assigning ALAL vs. non-ALAL diagnoses based on EGIL vs. WHO criteria, our results support the upfront treatment of AL of unclear lineage with ALL-based chemotherapy regimens.

Disclosures:
No relevant conflicts of interest to declare.