1Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatrics, Capital Medical University; Key Laboratory of Major Diseases in Children, Ministry of Education; Hematology Oncology Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
2Laboratory of Hematologic Diseases, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
Copyright © 2021 by the Korean Cancer Association
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Improvement in Pituitary Imaging After Targeted Therapy in Three Children with BRAF-Mutated Langerhans Cell Histiocytosis with Pituitary Involvement
Details of each patient’s disease characteristics
Case No. | Sex | Age at disease onset (yr) | Age started taking dabrafenib (yr) | Affected organs | Complicated with HLH | Disease state before dabrafenib treatment | Disease state level at the end of dabrafenib treatment | cfBRAFV600E level before dabrafenib treatment | cfBRAFV600E level at the end of dabrafenib treatment | Duration of dabrafenib treatment (mo) |
---|---|---|---|---|---|---|---|---|---|---|
1 | M | 1.7 | 2.9 | Skin, bones, lung, liver, ear, lymph nodes | N | AD-Worse | AD-Better | + (5.00%) | - | 3.9 |
2 | M | 0.1 | 2.1 | Skin, bones, lung, liver, spleen, ear lymph nodes, thymus | N | AD-Stable | AD-Better | + (5.00%) | + (1.73%) | 17.7 |
3 | F | 1.4 | 2.3 | Skin, bones, lung, liver, spleen, hematopoietic system, lymph nodes | Y | AD-Stable | AD-Better | - | - | 3.7 |
4 | M | 1.2 | 3.1 | Liver, spleen, ear, pituitary, thyroid | N | AD-Worse | AD-Better | + (6.31%) | - | 6.1 |
5 | F | 0.3 | 0.8 | Skin, bones, lung, liver, spleen, hematopoietic system, ear, lymph nodes | Y | AD-Worse | AD-Better | + (2.80%) | + (0.51%) | 19.2 |
6 | M | 1.0 | 2.1 | Skin, bones, liver, spleen, ear | N | AD-Worse | AD-Better | + (0.20%) | - | 6.4 |
7 | M | 3.2 | 4.3 | Bones, liver, pituitary, thyroid, biliary tract | N | AD-Worse | AD-Mixed | + (0.75%) | - | 7.0 |
8 | M | 1.0 | 2.4 | Bones, pituitary, oral cavity | N | AD-Stable | AD-Better | - | - | 9.8 |
9 | M | 5.1 | 6.5 | Bones, pituitary | N | AD-Stable | AD-Stable | - | - | 12.1 |
10 | M | 1.1 | 2.7 | Skin, bones, lung, liver, ear | N | AD-Worse | AD-Better | - | - | 13.0 |
11 | F | 0.1 | 0.8 | Skin, bones, lung, liver, spleen, hematopoietic system, lymph nodes, thymus | N | AD-Worse | AD-Better | + (24.05%) | - | 18.4 |
12 | M | 2.0 | 2.6 | Bones, liver, spleen, ear | N | AD-Worse | AD-Better | + (0.51%) | - | 11.7 |
13 | M | 2.5 | 3.5 | Skin, bones, ear, pituitary | N | AD-Worse | AD-Stable | + (0.27%) | - | 11.1 |
14 | F | 1.0 | 3.3 | Skin, bones, lung, ear, pituitary | N | AD-Worse | AD-Worse | - | - | 4.4 |
15 | M | 0.8 | 0.9 | Skin, bones, ear pituitary | N | AD-Worse | AD-Better | + (3.28%) | + (0.24%) | 14.0 |
16 | M | 0.2 | 0.6 | Skin, liver, spleen, hematopoietic system | Y | AD-Worse | AD-Better | + (3.29%) | + (1.13%) | 16.5 |
17 | F | 0.2 | 0.8 | Skin, bones, lung, liver, spleen, hematopoietic system, lymph nodes | Y | AD-Worse | AD-Better | + (22.52%) | + (0.13%) | 13.8 |
18 | M | 0.9 | 1.1 | Skin, lung, liver, hematopoietic system, ear, biliary tract, thyroid | Y | AD-Stable | AD-Worse | + (1.80%) | + (0.89%) | 10.0 |
19 | M | 0.3 | 1.2 | Skin, bones, lung, liver | N | AD-Mixed | AD-Worse | + (0.18%) | - | 18.3 |
20 | F | 1.6 | 2.6 | Bones, thyroid | N | AD-Worse | AD-Worse | + (1.03%) | - | 3.1 |
AD, active disease; F, female; HLH, hemophagocytic lymphohistiocytosis; M, male; N, no; Y, yes.
Details of the evaluation results at each observation point
Observation points | AD-Better | AD-Stable | AD-Mixed | AD-Worse | Drug withdrawal |
---|---|---|---|---|---|
Month 1 | 15 | 2 | 3 | 0 | 0 |
Month 3 | 13 | 2 | 2 | 3 | 0 |
Month 6 | 13 | 2 | 1 | 1 | 3 |
Month 9 | 7 | 1 | 2 | 2 | 8 |
Month 12 | 6 | 1 | 1 | 1 | 11 |
AD, active disease.
Details of five patients complicated by HLH
Case 3 | Case 5 | Case 16 | Case 17 | Case 18 | |
---|---|---|---|---|---|
Before dabrafenib | |||||
Temperature (°C) | Normal | Normal | 38.6 | Normal | 39 |
CRP (mg/L) | 24 | 57 | 57 | 62 | 45 |
Hemoglobin (g/L) | 105 | 72 | 74 | 87 | 80 |
Platelet (×109/L) | 68 | 271 | 28 | 165 | 172 |
Neutrophil (×109/L) | 1.37 | 5.38 | 0.84 | 1.84 | 0.61 |
Splenomegaly (below the left costal margin) (cm) | 4.0 | 6.5 | 5.7 | 3.0 | 1.3 |
Triglyceride (mmol/L) | 2.04 | 4.04 | 6.57 | 6.88 | 5.18 |
Fibrinogen (g/L) | 2.90 | 0.87 | 1 | 1.45 | 1.16 |
Hemophagocytosis | + | + | + | + | – |
NK-cell activity (%) | 13.62 | 17.01 | NA | 14.49 | 11.46 |
Ferritin (μg/L) | NA | NA | 124.2 | 135.2 | 98.8 |
sCD25 (U/mL) | NA | NA | 20,725 | 22,803 | 14,242 |
Three days after starting dabrafenib | |||||
Temperature (°C) | Normal | Normal | Normal | Normal | Normal |
CRP (mg/L) | < 5 | < 5 | < 5 | 8 | < 5 |
Hemoglobin (g/L) | 127 | 112 | 96 | 92 | 91 |
Platelet (×109/L) | 180 | 302 | 100 | 347 | 409 |
Neutrophil (×109/L) | 2.40 | 1.87 | 0.38 | 2.24 | 1.80 |
Splenomegaly (below the left costal margin) | NA | NA | NA | NA | NA |
Triglyceride (mmol/L) | 1.33 | NA | 4.42 | 3.85 | NA |
Fibrinogen (g/L) | NA | 0.87 | 1.01 | NA | NA |
Hemophagocytosis | NA | NA | NA | NA | NA |
NK-cell activity (%) | NA | NA | NA | NA | NA |
Ferritin (μg/L) | NA | 548.9 | NA | 132.5 | NA |
sCD25 (U/ml) | NA | NA | NA | NA | NA |
One month after starting Dabrafenib | |||||
Temperature (°C) | Normal | Normal | Normal | Normal | Normal |
CRP (mg/L) | NA | NA | NA | NA | NA |
Hemoglobin (g/L) | 127 | 131 | 118 | 118 | 115 |
Platelet (109/L) | 180 | 283 | 370 | 530 | 567 |
Neutrophil (109/L) | 2.40 | 5.37 | 3.49 | 3.12 | 5.44 |
Splenomegaly (below the left costal margin) (cm) | 3.8 | 2.3 | No splenomegaly | No splenomegaly | No splenomegaly |
Triglyceride (mmol/L) | 0.7 | 0.9 | 1 | 0.8 | 2.73 |
Fibrinogen (g/L) | 11.9 | NA | NA | 3.2 | 2.36 |
Hemophagocytosis | NA | NA | NA | NA | NA |
NK-cell activity (%) | 14.83 | NA | NA | NA | NA |
Ferritin (μg/L) | NA | 521.2 | NA | NA | NA |
sCD25 (U/mL) | NA | NA | NA | NA | NA |
CRP, C-reactive protein; HLH, hemophagocytic lymphohistiocytosis; NA, not available; NK-cell, natural killer cell; sCD25, soluble CD25.
a)The diagnosis of HLH can be established if one of either 1 or 2 below is fulfilled: (1) a molecular diagnosis consistent with HLH, (2) diagnostic criteria for HLH fulfilled (five out of the eight criteria below): (a) fever, (b) splenomegaly, (c) cytopenias (affecting ≥ 2 of 3 lineages in the peripheral blood): hemoglobin < 90 g/L (in infants < 4 weeks: hemoglobin < 100 g/L), platelets < 100×109/L, neutrophils < 1.0×109/L, (d) ferritin ≥ 500 μg/L, (e) hypertriglyceridemia and/or hypofibrinogenemia: fasting triglycerides ≥ 3.0 mmol/L, fibrinogen ≤ 1.5 g/L, (f) hemophagocytosis in bone marrow or spleen or lymph nodes, (g) soluble CD25 (i.e., soluble IL-2 receptor) ≥ 2,400 U/mL, (h) NK-cell activity < 15.11% (according to our laboratory reference).
Different grades of treatment-related adverse events
Adverse events | Grade | No. of cases |
Adverse events occurred after starting targeted treatment (wk) |
---|---|---|---|
Maculopapule | 1 | 3 | 1–16 |
2 | 4 | 0–2 | |
3 | 1 | 1 | |
Diarrhea | 1 | 2 | 4 |
Skin pain | 2 | 1 | 1 |
Eye swelling and conjunctival petechia | 2 | 1 | 4 |
Blurred vision and photophobia | 1 | 1 | 4 |
Vomiting | 1 | 1 | 5 |
Ostealgia | 1 | 1 | 12 |
Fever | 1 | 2 | 0–1 |
a)Some patients had more than one adverse event.
AD, active disease; F, female; HLH, hemophagocytic lymphohistiocytosis; M, male; N, no; Y, yes.
AD, active disease.
CRP, C-reactive protein; HLH, hemophagocytic lymphohistiocytosis; NA, not available; NK-cell, natural killer cell; sCD25, soluble CD25. The diagnosis of HLH can be established if one of either 1 or 2 below is fulfilled: (1) a molecular diagnosis consistent with HLH, (2) diagnostic criteria for HLH fulfilled (five out of the eight criteria below): (a) fever, (b) splenomegaly, (c) cytopenias (affecting ≥ 2 of 3 lineages in the peripheral blood): hemoglobin < 90 g/L (in infants < 4 weeks: hemoglobin < 100 g/L), platelets < 100×109/L, neutrophils < 1.0×109/L, (d) ferritin ≥ 500 μg/L, (e) hypertriglyceridemia and/or hypofibrinogenemia: fasting triglycerides ≥ 3.0 mmol/L, fibrinogen ≤ 1.5 g/L, (f) hemophagocytosis in bone marrow or spleen or lymph nodes, (g) soluble CD25 (i.e., soluble IL-2 receptor) ≥ 2,400 U/mL, (h) NK-cell activity < 15.11% (according to our laboratory reference).
Some patients had more than one adverse event.