ARTICLE
Myeloproliferative Disorders
The clinical and molecular diversity of mast cell leukemia with or without associated hematologic neoplasm
EUROPEAN HEMATOLOGY ASSOCIATION
Ferrata Storti Foundation
Mohamad Jawhar,1,2 Juliana Schwaab,1,2 Manja Meggendorfer,3 Nicole Naumann,1,2 Hans-Peter Horny,4 Karl Sotlar,5 Torsten Haferlach,3 Karla Schmitt,6 Alice Fabarius,1,2 Peter Valent,7 Wolf-Karsten Hofmann,1,2 Nicholas C.P. Cross,8,9 Georgia Metzgeroth1,2 and Andreas Reiter1,2
Department of Hematology and Oncology, University Medical Centre Mannheim, Germany; 2Medical Faculty Mannheim, University of Heidelberg, Germany; 3Munich Leukemia Laboratory, Germany; 4Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany; 5University Institute of Pathology, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria; 6Department of Hematology and Oncology, University Hospital Aachen, Germany; 7Department of Internal Medicine I, Division of Hematology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria; 8Wessex Regional Genetics Laboratory, Salisbury, UK and 9Faculty of Medicine, University of Southampton, UK 1
Haematologica 2017 Volume 102(6):1035-1043
ABSTRACT
M
ast cell leukemia is a rare variant of advanced systemic mastocytosis characterized by at least 20% of mast cells in a bone marrow smear. We evaluated clinical and molecular characteristics of 28 patients with (n=20, 71%) or without an associated hematologic neoplasm. De novo mast cell leukemia was diagnosed in 16 of 28 (57%) patients and secondary mast cell leukemia evolving from other advanced systemic mastocytosis subtypes in 12 of 28 (43%) patients, of which 7 patients progressed while on cytoreductive treatment. Median bone marrow mast cell infiltration was 65% and median serum tryptase was 520 μg/L. C-findings were identified in 26 of 28 (93%) patients. Mutations in KIT (D816V, n=19; D816H/Y, n=5; F522C, n=1) were detected in 25 of 28 (89%) patients and prognostically relevant additio-nal mutations in SRSF2, ASXL1 or RUNX1 (S/A/Rpos) in 13 of 25 (52%) patients. Overall response rate in 18 treatment-naïve patients was 5 of 12 (42%) on midostaurin and 1 of 6 (17%) on cladribine, and after switch 1 of 4 (25%) on midostaurin and 0 of 3 on cladribine, respectively. S/A/Rpos adversely affected response to treatment and progression to secondary mast cell leukemia (n=6) or acute myeloid leukemia (n=3) while on treatment (P200 μg/L, n (%) KIT D816V EAB in PB, %; median (range) Splenomegaly Spleen volume, mL; median (range) (n=15) Marked splenomegaly (≥ 1200 mL), n (%) Alkaline phosphatase, U/L; median (range) >150 U/L, n (%) Treatment modalities Midostaurin, n (%) Cladribine, n (%) Midostaurin and cladribine (vice versa), n (%) Molecular profile KIT mutations D816V Other None Additional mutations S/A/Rpos, n (%) S/A/Rneg, n (%) Outcome Death, n (%)
MCL
de novo MCL
Secondary MCL
28 67 (45-82) 16 (57)
16 69 (47-82) 10 (63)
12 65 (45-73) 6 (50)
8 (29) 20 (71) 8 (40) 5 (25) 5 (25) 2 (10)
6 (38) 10 (62) 4 (40) 0 5 (50) 1 (10)
2 (17) 10 (83) 4 (40) 5 (50) 0 1 (10)
-
-
2 (17) 10 (83) 18 (4-71)
8.9 (7.9-14.3) 69 (21-795) 26 (93) 13 (46) 11 (39) 12 (43)
9.2 (7.9-13.3) 64 (21-795) 15 (94) 7 (44) 5 (31) 8 (50)
8.7 (7.9-14.3) 86 (26-331) 11 (92) 6 (50) 6 (50) 4 (33)
65 (20-95) 25 (20-95) 520 (157-1854) 26 (93) 43 (20-98) 28 (100) 1079 (283-2442) 8 (53) 181 (59-548) 20 (71)
60 (20-95) 25 (20-100) 520 (157-1854) 15 (94) 43 (21-54) 16 (100) 1058 (758-2058) 4 (50) 161 (59-548) 10 (62)
65 (30-95) 20 (20-50) 544 (160-1250) 11 (92) 42 (20-98) 12 (100) 1240 (539-2442) 4 (57) 186 (103-424) 10 (83)
13 (52) 2 (7) 10 (36)
8 (57) 1 (7) 5 (36)
5 (45) 1 (8) 5 (42)
19 (68) 6 (21) 3 (11)
10 (63) 4 (25) 3 (19)
9 (75) 2 (17) 0
13 (52) 12 (48)
7 (50) 7 (50)
6 (55) 5 (45)
18 (64)
10 (63)
8 (67)
*Cytopenia: hemoglobin
Myeloproliferative Disorders
The clinical and molecular diversity of mast cell leukemia with or without associated hematologic neoplasm
EUROPEAN HEMATOLOGY ASSOCIATION
Ferrata Storti Foundation
Mohamad Jawhar,1,2 Juliana Schwaab,1,2 Manja Meggendorfer,3 Nicole Naumann,1,2 Hans-Peter Horny,4 Karl Sotlar,5 Torsten Haferlach,3 Karla Schmitt,6 Alice Fabarius,1,2 Peter Valent,7 Wolf-Karsten Hofmann,1,2 Nicholas C.P. Cross,8,9 Georgia Metzgeroth1,2 and Andreas Reiter1,2
Department of Hematology and Oncology, University Medical Centre Mannheim, Germany; 2Medical Faculty Mannheim, University of Heidelberg, Germany; 3Munich Leukemia Laboratory, Germany; 4Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany; 5University Institute of Pathology, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria; 6Department of Hematology and Oncology, University Hospital Aachen, Germany; 7Department of Internal Medicine I, Division of Hematology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria; 8Wessex Regional Genetics Laboratory, Salisbury, UK and 9Faculty of Medicine, University of Southampton, UK 1
Haematologica 2017 Volume 102(6):1035-1043
ABSTRACT
M
ast cell leukemia is a rare variant of advanced systemic mastocytosis characterized by at least 20% of mast cells in a bone marrow smear. We evaluated clinical and molecular characteristics of 28 patients with (n=20, 71%) or without an associated hematologic neoplasm. De novo mast cell leukemia was diagnosed in 16 of 28 (57%) patients and secondary mast cell leukemia evolving from other advanced systemic mastocytosis subtypes in 12 of 28 (43%) patients, of which 7 patients progressed while on cytoreductive treatment. Median bone marrow mast cell infiltration was 65% and median serum tryptase was 520 μg/L. C-findings were identified in 26 of 28 (93%) patients. Mutations in KIT (D816V, n=19; D816H/Y, n=5; F522C, n=1) were detected in 25 of 28 (89%) patients and prognostically relevant additio-nal mutations in SRSF2, ASXL1 or RUNX1 (S/A/Rpos) in 13 of 25 (52%) patients. Overall response rate in 18 treatment-naïve patients was 5 of 12 (42%) on midostaurin and 1 of 6 (17%) on cladribine, and after switch 1 of 4 (25%) on midostaurin and 0 of 3 on cladribine, respectively. S/A/Rpos adversely affected response to treatment and progression to secondary mast cell leukemia (n=6) or acute myeloid leukemia (n=3) while on treatment (P200 μg/L, n (%) KIT D816V EAB in PB, %; median (range) Splenomegaly Spleen volume, mL; median (range) (n=15) Marked splenomegaly (≥ 1200 mL), n (%) Alkaline phosphatase, U/L; median (range) >150 U/L, n (%) Treatment modalities Midostaurin, n (%) Cladribine, n (%) Midostaurin and cladribine (vice versa), n (%) Molecular profile KIT mutations D816V Other None Additional mutations S/A/Rpos, n (%) S/A/Rneg, n (%) Outcome Death, n (%)
MCL
de novo MCL
Secondary MCL
28 67 (45-82) 16 (57)
16 69 (47-82) 10 (63)
12 65 (45-73) 6 (50)
8 (29) 20 (71) 8 (40) 5 (25) 5 (25) 2 (10)
6 (38) 10 (62) 4 (40) 0 5 (50) 1 (10)
2 (17) 10 (83) 4 (40) 5 (50) 0 1 (10)
-
-
2 (17) 10 (83) 18 (4-71)
8.9 (7.9-14.3) 69 (21-795) 26 (93) 13 (46) 11 (39) 12 (43)
9.2 (7.9-13.3) 64 (21-795) 15 (94) 7 (44) 5 (31) 8 (50)
8.7 (7.9-14.3) 86 (26-331) 11 (92) 6 (50) 6 (50) 4 (33)
65 (20-95) 25 (20-95) 520 (157-1854) 26 (93) 43 (20-98) 28 (100) 1079 (283-2442) 8 (53) 181 (59-548) 20 (71)
60 (20-95) 25 (20-100) 520 (157-1854) 15 (94) 43 (21-54) 16 (100) 1058 (758-2058) 4 (50) 161 (59-548) 10 (62)
65 (30-95) 20 (20-50) 544 (160-1250) 11 (92) 42 (20-98) 12 (100) 1240 (539-2442) 4 (57) 186 (103-424) 10 (83)
13 (52) 2 (7) 10 (36)
8 (57) 1 (7) 5 (36)
5 (45) 1 (8) 5 (42)
19 (68) 6 (21) 3 (11)
10 (63) 4 (25) 3 (19)
9 (75) 2 (17) 0
13 (52) 12 (48)
7 (50) 7 (50)
6 (55) 5 (45)
18 (64)
10 (63)
8 (67)
*Cytopenia: hemoglobin
