Cytogenetic and Molecular Characterization of Extramedullary Disease (EMD) in Patients (pts) with Acute Myeloid Leukemia (AML).

Abstract 2592 [][1] Background: The phenomenon of EMD in pts with AML has been previously noted. However, little is known about the cytogenetic and molecular characterization of these pts in the modern era of AML prognostic cytogenetic and molecular markers. Methods: We conducted a retrospective review of 2,181 consecutive pts with AML who underwent induction chemotherapy and were treated at our institution from 2000–2011. All pts included in this analysis had histologically-proven EMD-AML. Chi-squared test was used to assess complete response (CR) probability and Kaplan-Meier method was used to assess CR duration and overall survival (OS) outcomes. Results: Overall, 1,120 pts underwent biopsies/tissue sampling during the study period to evaluate for EMD-AML. 244 pts (11% of total group, 22% of those biopsied) were diagnosed (dx) with histologically proven EMD. 47 pts (2% of total group, 4% of pts biopsied, 19% of EMD pts) had EMD-AML at multiple sites. Median age of AML dx was 57 years (range 14–82 years). 135 pts were male (55%). Baseline CBC parameters at AML dx: WBC 9.5 (0–433), platelets 53 (0–581), Hb 8.7 (0–15.6). Median blasts at baseline AML dx: Peripheral 22% (0–99%) and bone marrow 56% (0–98%). EMD occurred at all phases of AML therapy course, with majority of EMD dx occurring at or after time of relapse (n=112, 46%), followed by concomitant at AML dx (28%), during induction therapy (15%) and prior to AML dx (11%). EMD sites were found throughout all major organ systems ([Table 1][2]). The specific sites most commonly affected by EMD included skin (n=84), CSF (n=76), pleural fluid (n=41), ascitic fluid (n=7), abdominal wall soft tissue (n=6), pelvic/inguinal lymph node (n=6), stomach (n=5), liver (n=5), cervical/neck lymph node (n=5), and bone (n=5). Cytogenetic abnormalities and molecular mutations were frequent features of EMD pts ([Table 2][3], [Table 3][4]). Pts with EMD (n=156, 64%) were more likely to achieve CR than pts without EMD (n=1079, 56%, p=0.01). For those pts with EMD, CR duration was 59.0 months (95% CI 54.8–63.2 months), which was longer than for pts without EMD (CR duration, 43.5 months, 95% CI 40.7–46.4 months, p<0.0001). Overall survival (OS) of EMD pts (30.9 months, 95% CI 25.3–36.6 months) was significantly less than OS of non-EMD pts (43.5 months, 95% CI 40.7–46.4 months, p=0.04). Conclusion: Incidence of EMD in AML pts is common (11%) and occurs at all phases of disease course. Almost every organ system/tissue demonstrates involvement with EMD AML. Cytogenetic and molecular abnormalities are commonly associated with EMD AML pts, with FLT3 mutation being the most common molecular abnormality in this cohort (30% of evaluable pts) and deletion of chromosome 7 being most common chromosomal abnormality (14% of pts). While pts with EMD-AML had significantly longer CR duration, interestingly these pts were noted to have significantly shorter OS in this analysis, suggesting the unique biologic and clinical features of this subset of AML pts. | Organ system or region with EMD | Number of pts | % (out of 244 pts with EMD) | |:------------------------------------------------------------------------------------------------:| ------------- | --------------------------- | | Skin | 84 | 34.4 | | Central nervous system: Cerebrospinal fluid, brain | 78 | 32.0 | | Respiratory: Pleural fluid, lung | 43 | 17.6 | | Soft/connective tissue: Pelvic, inguinal, abdominal wall, thoracic, flank, neck, head, arm, leg | 27 | 11.1 | | Gastrointestinal: Ascitic fluid, stomach, liver, small bowel, root of mesentery, colon, appendix | 23 | 9.4 | | Lymph node: Pelvic, inguinal, neck, axillary, abdominal, mammary, periaortic, thigh | 21 | 8.6 | | Pelvis/inguinal: Uterus, ovary, fallopian tube, labia, testicle, epididymis, spermatic cord | 15 | 6.1 | | Naso-oropharynx: Tongue, palate, buccal mucosa, tonsil, nasopharynx, parotid gland | 8 | 3.3 | | Musculoskeletal: Bone, skeletal muscle | 7 | 2.9 | | Cardiovascular: Pericardial fluid, heart, blood vessel | 4 | 1.6 | | Urinary: Kidney, bladder, ureter | 4 | 1.6 | | Eye: Conjunctiva | 1 | <0.1 | | Thymus | 1 | <0.1 | Table 1. Organ systems and regions involved by EMD AML | Cytogenetics | Number of pts | % (out of 244 pts with EMD) | |:------------:| ------------- | --------------------------- | | Diploid | 91 | 37.3 | | Complex | 63 | 25.8 | | -7/7q- | 34 | 13.9 | | -5/5q- | 22 | 9.0 | | Trisomy 8 | 22 | 9.0 | | Abnormal 11q | 16 | 6.6 | | Inv(16) | 15 | 6.1 | | t(8;21) | 6 | 2.5 | | t(15;17) | 3 | 1.2 | | Ph+ | 2 | 0.8 | Table 2. Cytogenetics in AML pts with EMD (n=244) | Molecular Abnormality | Number evaluable | Number with mutation | % (out of 244 pts with EMD) | |:---------------------:| ---------------- | -------------------- | --------------------------- | | FLT3 | 184 | 56 | 23.0 | | D835 | | 14 | 5.7 | | ITD | | 42 | 17.2 | | RAS | 143 | 25 | 10.2 | | NRAS | | 20 | 8.2 | | KRAS | | 4 | 1.6 | | NRAS and KRAS | | 1 | 0.4 | | NPM1 | 77 | 14 | 5.7 | | CBFb-MYH11 | 44 | 5 | 2.0 | | CEBPA | 27 | 2 | 0.8 | | JAK2 | 6 | 1 | 0.4 | | IDH1 | 17 | 1 | 0.4 | | IDH2 | 17 | 3 | 1.2 | | KIT | 62 | | | Table 3: Molecular Abnormalities in AML pts with EMD (n=244) Disclosures: No relevant conflicts of interest to declare. [1]: #fn-2 [2]: #T1 [3]: #T2 [4]: #T3