Individual patient data of cases with ALK-positive histiocytosis (n = 39) or atypical ALK-rearranged histiocyte-rich tumors (n = 3)
| No. . | Gene fusion . | Sex . | Age* . | Sites of disease . | First-line treatment . | Response . | Progression /relapse . | Second- and further-line treatment . | Last response . | Therapy ongoing . | Outcome (follow-up†) . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Group 1A: infants with multistemic disease with liver and hematopoietic involvement | |||||||||||
| 1‡ | N/A | F | 0 d | Liver, hematopoietic system, spleen, lung, possibly kidney | IVIG (2 d), corticosteroids (tapered after diagnosis), and supportive care (transfusions) | CR | No | — | — | No | Alive with no disease (3.5 y) |
| 2‡ | ALK-FISH+ | F | 27 d | Liver, hematopoietic system, spleen, + kidney at relapse | Chemotherapy (VBL/PRED, 6 mo) | PR | Yes | Chemotherapy | CR | No | Alive with no disease (7 y)§ |
| 3 | KIF5B-ALK | M | 1 mo | Liver, hematopoietic system, spleen, kidney, skin | Chemotherapy (VBL/DEX/MTX, 3 wk) | PD | Yes | Chemotherapy (2-CDA, 1 wk) | PD | No | Died of coagulopathy and sepsis (1 mo) |
| 4 | N/A | F | 2 mo | Liver, hematopoietic system, spleen | Supportive care (transfusions) | CR | No | — | — | No | Alive with no disease (4.5 y) |
| 5 | ALK-FISH+ | F | 4 mo | Liver, hematopoietic system | N/A | N/A | N/A | N/A | N/A | N/A | N/A (lost to follow-up) |
| 6 | CLTC-ALK | M | 5 mo | Liver, hematopoietic system, spleen | Corticosteroids (PRED 40mg/m2, 2.5 wk), followed by chemotherapy (VBL + tapered PRED, 2.5 wk) | PD | Yes | Dexamethasone + anakinra (1 mo), followed by anakinra (3 mo) + azathioprine (4.5 mo) | CR | No | Alive with no disease (4 y) |
| Group 1B: other patients with multisystemic disease | |||||||||||
| 7 | TPM3-ALK | F | 3 mo | Bone, lung, liver | Chemotherapy (VBL/PRED/6MP, 18 mo) | CR | No | — | — | No | Alive with no disease (2 y) |
| 8 | ALK-FISH+ | F | 9 mo | Lung, skin, kidney | Chemotherapy (VBL/PRED, 12 mo) | CR | No | — | — | No | Alive with no disease (2 y) |
| 9‡ | KIF5B-ALK | M | 10 mo | CNS, lung, liver, soft tissue (peritoneum) | Chemotherapy (VBL/PRED), combined with ALK inhibition (alectinib) | CR | No | — | — | Yes (VBL/PRED + alectinib) | Alive with no disease (13 mo) |
| 10 | KIF5B-ALK | F | 2 y | CNS, bone, lung, liver, skin, soft tissue (perineal mass), lymph node, kidney, breast, pancreas | Chemotherapy (VBL/PRED, 6 wk induction) | SD | No | ALK inhibition (lorlatinib) | PR | Yes (lorlatinib) | Alive with regressive disease (21 mo) |
| 11 | KIF5B-ALK | F | 10 y | CNS, bone, lung, lymph node, cervix, thyroid, submandibular salivary gland | ALK inhibition (crizotinib) | CR | No | — | — | Yes (crizotinib) | Alive with no disease (2 y) |
| 12 | KIF5B-ALK | F | 19 y | CNS/PNS, bone, lung, liver, lymph node, breast, pancreas | Chemotherapy (2-CDA, 3 cycles), followed by ALK inhibition (alectinib) | PR | No | — | — | Yes (alectinib) | Alive with stable (PETnegative) bone lesions on MRI; other lesions regressed (2 y) |
| 13 | TFG-ALK | M | 21 y | Liver, skin, colorectum | Corticosteroids (high-dose) | PR | Yes‖ | — | — | No | Died of sepsis (2 mo) |
| 14 | KIF5B-ALK | F | 28 y | CNS/PNS, bone | ALK inhibition (alectinib) | PR | No | — | — | Yes (alectinib) | Alive with regressive (PETnegative) disease (9 mo) |
| 15 | KIF5B-ALK | M | 29 y | PNS (incl. cerebrospinal fluid pleocytosis), bone | Corticosteroids, followed by pegylated interferon-α (with escalation to 180μg/wk, 4 mo) | SD | No | ALK inhibition (brigatinib) | CR | Yes (brigatinib) | Alive with no disease (2.5 y) |
| 16‡ | KIF5B-ALK | F | 41 y | CNS, bone, lung, skin, soft tissue (omentum/peritoneum), lymph node | Interferon-α (16 mo) | PD | Yes | ALK inhibition (crizotinib) | PR | Yes (crizotinib) | Alive with regressive disease (6 y) |
| Group 2: single-system neurologic disease | |||||||||||
| 17 | KIF5B-ALK | F | 7 mo | CNS: thalamus | Corticosteroids, followed by ALK inhibition (lorlatinib) | PR | No | — | — | Yes (lorlatinib) | Alive with regressive disease (5 mo) |
| 18 | ALK-FISH+ | F | 9 mo | CNS: cerebellum | N/A | N/A | N/A | N/A | N/A | N/A | N/A (lost to follow-up) |
| 19 | KIF5B-ALK | M | 2.5 y | CNS: right medulla tumor extending through the foramen of Luschka | Chemotherapy (Headstart protocol, 1 cycle) | PD | Yes | ALK inhibition (alectinib) | CR | Yes (alectinib) | Alive with no disease (16 mo) |
| 20 | KIF5B-ALK | F | 3 y | CNS: cerebellum, cranial nerves, spinal cord, cerebrospinal fluid | Corticosteroids, followed by surgery (subtotal resection cerebellar tumor) | CR | No | — | — | No | Alive with no disease (12 mo) |
| 21 | KIF5B-ALK | F | 3 y | PNS: left oculomotor nerve with extraneural extension | Corticosteroids, followed by surgery (subtotal resection) and chemotherapy (VBL/PRED, 6 mo) | PR | No | — | — | No | Alive with mildly regressive disease (2.5 y) |
| 22 | KIF5B-ALK | F | 7 y | CNS: left medulla | Chemotherapy (Clofarabine, 6 cycles) | CR | No | — | — | No | Alive with no disease (6 mo) |
| 23‡ | KIF5B-ALK | F | 11 y | CNS: right frontal lobe | Surgery (total resection) | CR | No | — | — | No | Alive with no disease (9 mo) |
| 24 | ALK-FISH+ | M | 11 y | PNS: left trigeminal nerve | Surgery (subtotal resection) | CR | No | — | — | No | Alive with no disease (18 y) |
| 25 | KIF5B-ALK | M | 12 y | PNS: intradural extramedullary tumor at level C1-C2 | Surgery (total resection), followed by chemotherapy (VBL/PRED, 12 mo) | CR | No | — | — | No | Alive with no disease (2.5 y) |
| 26 | KIF5B-ALK | F | 13 y | CNS/PNS: left insula, cranial & spinal nerves, pituitary stalk, + cerebrospinal fluid at relapse | Surgery (subtotal resection insula tumor) | PD | Yes | ALK inhibition (alectinib) | PR | Yes (alectinib) | Alive with minor, regressive disease (2.5 y) |
| 27 | KIF5B-ALK | M | 20 y | PNS: 3 intradural extramedullary lesions at levels L3 and S1 | Not treated yet | Not yet evaluable | Not yet evaluable | — | — | No | Alive with active disease (7 mo) |
| 28 | KIF5B-ALK | M | 20 y | CNS: right frontal lobe | Surgery (total resection) | CR | No | — | — | No | Alive with no disease (10 mo) |
| Group 2: single-system nonneurologic disease | |||||||||||
| 29 | KIF5B-ALK | F | 6 mo | Skin: retroauricular scalp lesion | Active monitoring (4 mo), followed by surgery (subtotal resection) | CR | No | — | — | No | Alive with no disease (2 y) |
| 30 | KIF5B-ALK | M | 7 mo | Skin: papular lesion on the back | Surgery (total resection) | CR | No | — | — | No | Alive with no disease (13 mo) |
| 31 | KIF5B-ALK | F | 21 mo | Skin: midline posterior scalp lesion | Surgery (total resection) | CR | No | — | — | No | Alive with no disease (2 y) |
| 32 | KIF5B-ALK | M | 2 y | Soft tissue: subcutaneous tumor left lower leg with infiltration in the musculature | Active monitoring | PR | No | — | — | No | Alive with regressive disease (14 mo) |
| 33 | KIF5B-ALK | F | 3 y | Soft tissue: perineal mass | Surgery (total resection) | CR | No | — | — | No | Alive with no disease (14 mo) |
| 34‡ | KIF5B-ALK | M | 3 y | Soft tissue: subglottic mass | Corticosteroids, followed by surgery (total resection) | CR | No | — | — | No | Alive with no disease (3 y) |
| 35 | KIF5B-ALK | F | 10 y | Skin: single nodule on the right breast (7mm; exclusively dermal/cutaneous) | Surgery (total resection) | CR | No | — | — | No | Alive with no disease (1 mo) |
| 36 | KIF5B-ALK | F | 10 y | Bone: right scapular lesion with soft tissue extension | Surgery (total resection) | CR | No | — | — | No | Alive with no disease (5 y) |
| 37 | KIF5B-ALK | M | 11 y | Soft tissue: 2 tumors in omentum and mesenterium | Surgery (subtotal resection) | PD | Yes | Chemotherapy (VBL/PRED, 12 wk, IC-1/IC-2, → PD), followed by active monitoring¶ | SD | No | Alive with stable disease (15 mo) |
| 38 | EML4-ALK | M | 17 y | Lung: single mass (10 × 9 × 8 cm) within the left lower lobe extending into the pulmonary vein and left atrium | N/A | N/A | N/A | N/A | N/A | N/A | N/A (lost to follow-up) |
| 39 | DCTN1-ALK | F | 41 y | Bone: right clavicular lesion with significant soft tissue extension (total size >10 cm) | Radiotherapy (22 Gy in 12 fractions) | PR | No | ALK inhibition (crizotinib → severe anaphylaxis), followed by chemotherapy (VBL/PRED, 4 courses, → PD), and then ALK inhibition (alectinib) | PR | Yes (alectinib) | Alive with regressive disease (2 y) |
| Atypical: ALK-rearranged histiocyte-rich tumors | |||||||||||
| A1 | EML4-ALK | F | 51 y | CNS, bone, lung, + subcutaneous tumors at relapse | Surgery (L1 tumor), chemotherapy (TC, 1 cycle) and radiotherapy (32 Gy L1 tumor; 20 Gy whole brain) | PD | Yes | ALK inhibition (alectinib for 16 mo, followed by lorlatinib for 14 mo, and then ceritinib for 7 wk), followed by antalgic radiotherapy of 2 metastases and chemotherapy (VBL/PRED) | SD | Yes (VBL/Pred) | Alive with stable disease (3 y) |
| A2 | SQSTM1-ALK | F | 53 y | Soft tissue: large mesenteric tumor, + subcutaneous and liver tumors at relapse | Surgery (total resection) | PD | Yes | ALK inhibition (crizotinib) | SD | Yes (crizotinib) | Alive with stable disease (13 mo) |
| A3 | EML4-ALK | F | 4 y | Soft tissue: obstructing yellow nodule in the left main bronchus | Surgery (endoscopic resection) | N/A | Yes | Surgery (endoscopic reresection 1 and 2 y after first surgery) | CR | No | Alive with no disease (17 y) |
| No. . | Gene fusion . | Sex . | Age* . | Sites of disease . | First-line treatment . | Response . | Progression /relapse . | Second- and further-line treatment . | Last response . | Therapy ongoing . | Outcome (follow-up†) . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Group 1A: infants with multistemic disease with liver and hematopoietic involvement | |||||||||||
| 1‡ | N/A | F | 0 d | Liver, hematopoietic system, spleen, lung, possibly kidney | IVIG (2 d), corticosteroids (tapered after diagnosis), and supportive care (transfusions) | CR | No | — | — | No | Alive with no disease (3.5 y) |
| 2‡ | ALK-FISH+ | F | 27 d | Liver, hematopoietic system, spleen, + kidney at relapse | Chemotherapy (VBL/PRED, 6 mo) | PR | Yes | Chemotherapy | CR | No | Alive with no disease (7 y)§ |
| 3 | KIF5B-ALK | M | 1 mo | Liver, hematopoietic system, spleen, kidney, skin | Chemotherapy (VBL/DEX/MTX, 3 wk) | PD | Yes | Chemotherapy (2-CDA, 1 wk) | PD | No | Died of coagulopathy and sepsis (1 mo) |
| 4 | N/A | F | 2 mo | Liver, hematopoietic system, spleen | Supportive care (transfusions) | CR | No | — | — | No | Alive with no disease (4.5 y) |
| 5 | ALK-FISH+ | F | 4 mo | Liver, hematopoietic system | N/A | N/A | N/A | N/A | N/A | N/A | N/A (lost to follow-up) |
| 6 | CLTC-ALK | M | 5 mo | Liver, hematopoietic system, spleen | Corticosteroids (PRED 40mg/m2, 2.5 wk), followed by chemotherapy (VBL + tapered PRED, 2.5 wk) | PD | Yes | Dexamethasone + anakinra (1 mo), followed by anakinra (3 mo) + azathioprine (4.5 mo) | CR | No | Alive with no disease (4 y) |
| Group 1B: other patients with multisystemic disease | |||||||||||
| 7 | TPM3-ALK | F | 3 mo | Bone, lung, liver | Chemotherapy (VBL/PRED/6MP, 18 mo) | CR | No | — | — | No | Alive with no disease (2 y) |
| 8 | ALK-FISH+ | F | 9 mo | Lung, skin, kidney | Chemotherapy (VBL/PRED, 12 mo) | CR | No | — | — | No | Alive with no disease (2 y) |
| 9‡ | KIF5B-ALK | M | 10 mo | CNS, lung, liver, soft tissue (peritoneum) | Chemotherapy (VBL/PRED), combined with ALK inhibition (alectinib) | CR | No | — | — | Yes (VBL/PRED + alectinib) | Alive with no disease (13 mo) |
| 10 | KIF5B-ALK | F | 2 y | CNS, bone, lung, liver, skin, soft tissue (perineal mass), lymph node, kidney, breast, pancreas | Chemotherapy (VBL/PRED, 6 wk induction) | SD | No | ALK inhibition (lorlatinib) | PR | Yes (lorlatinib) | Alive with regressive disease (21 mo) |
| 11 | KIF5B-ALK | F | 10 y | CNS, bone, lung, lymph node, cervix, thyroid, submandibular salivary gland | ALK inhibition (crizotinib) | CR | No | — | — | Yes (crizotinib) | Alive with no disease (2 y) |
| 12 | KIF5B-ALK | F | 19 y | CNS/PNS, bone, lung, liver, lymph node, breast, pancreas | Chemotherapy (2-CDA, 3 cycles), followed by ALK inhibition (alectinib) | PR | No | — | — | Yes (alectinib) | Alive with stable (PETnegative) bone lesions on MRI; other lesions regressed (2 y) |
| 13 | TFG-ALK | M | 21 y | Liver, skin, colorectum | Corticosteroids (high-dose) | PR | Yes‖ | — | — | No | Died of sepsis (2 mo) |
| 14 | KIF5B-ALK | F | 28 y | CNS/PNS, bone | ALK inhibition (alectinib) | PR | No | — | — | Yes (alectinib) | Alive with regressive (PETnegative) disease (9 mo) |
| 15 | KIF5B-ALK | M | 29 y | PNS (incl. cerebrospinal fluid pleocytosis), bone | Corticosteroids, followed by pegylated interferon-α (with escalation to 180μg/wk, 4 mo) | SD | No | ALK inhibition (brigatinib) | CR | Yes (brigatinib) | Alive with no disease (2.5 y) |
| 16‡ | KIF5B-ALK | F | 41 y | CNS, bone, lung, skin, soft tissue (omentum/peritoneum), lymph node | Interferon-α (16 mo) | PD | Yes | ALK inhibition (crizotinib) | PR | Yes (crizotinib) | Alive with regressive disease (6 y) |
| Group 2: single-system neurologic disease | |||||||||||
| 17 | KIF5B-ALK | F | 7 mo | CNS: thalamus | Corticosteroids, followed by ALK inhibition (lorlatinib) | PR | No | — | — | Yes (lorlatinib) | Alive with regressive disease (5 mo) |
| 18 | ALK-FISH+ | F | 9 mo | CNS: cerebellum | N/A | N/A | N/A | N/A | N/A | N/A | N/A (lost to follow-up) |
| 19 | KIF5B-ALK | M | 2.5 y | CNS: right medulla tumor extending through the foramen of Luschka | Chemotherapy (Headstart protocol, 1 cycle) | PD | Yes | ALK inhibition (alectinib) | CR | Yes (alectinib) | Alive with no disease (16 mo) |
| 20 | KIF5B-ALK | F | 3 y | CNS: cerebellum, cranial nerves, spinal cord, cerebrospinal fluid | Corticosteroids, followed by surgery (subtotal resection cerebellar tumor) | CR | No | — | — | No | Alive with no disease (12 mo) |
| 21 | KIF5B-ALK | F | 3 y | PNS: left oculomotor nerve with extraneural extension | Corticosteroids, followed by surgery (subtotal resection) and chemotherapy (VBL/PRED, 6 mo) | PR | No | — | — | No | Alive with mildly regressive disease (2.5 y) |
| 22 | KIF5B-ALK | F | 7 y | CNS: left medulla | Chemotherapy (Clofarabine, 6 cycles) | CR | No | — | — | No | Alive with no disease (6 mo) |
| 23‡ | KIF5B-ALK | F | 11 y | CNS: right frontal lobe | Surgery (total resection) | CR | No | — | — | No | Alive with no disease (9 mo) |
| 24 | ALK-FISH+ | M | 11 y | PNS: left trigeminal nerve | Surgery (subtotal resection) | CR | No | — | — | No | Alive with no disease (18 y) |
| 25 | KIF5B-ALK | M | 12 y | PNS: intradural extramedullary tumor at level C1-C2 | Surgery (total resection), followed by chemotherapy (VBL/PRED, 12 mo) | CR | No | — | — | No | Alive with no disease (2.5 y) |
| 26 | KIF5B-ALK | F | 13 y | CNS/PNS: left insula, cranial & spinal nerves, pituitary stalk, + cerebrospinal fluid at relapse | Surgery (subtotal resection insula tumor) | PD | Yes | ALK inhibition (alectinib) | PR | Yes (alectinib) | Alive with minor, regressive disease (2.5 y) |
| 27 | KIF5B-ALK | M | 20 y | PNS: 3 intradural extramedullary lesions at levels L3 and S1 | Not treated yet | Not yet evaluable | Not yet evaluable | — | — | No | Alive with active disease (7 mo) |
| 28 | KIF5B-ALK | M | 20 y | CNS: right frontal lobe | Surgery (total resection) | CR | No | — | — | No | Alive with no disease (10 mo) |
| Group 2: single-system nonneurologic disease | |||||||||||
| 29 | KIF5B-ALK | F | 6 mo | Skin: retroauricular scalp lesion | Active monitoring (4 mo), followed by surgery (subtotal resection) | CR | No | — | — | No | Alive with no disease (2 y) |
| 30 | KIF5B-ALK | M | 7 mo | Skin: papular lesion on the back | Surgery (total resection) | CR | No | — | — | No | Alive with no disease (13 mo) |
| 31 | KIF5B-ALK | F | 21 mo | Skin: midline posterior scalp lesion | Surgery (total resection) | CR | No | — | — | No | Alive with no disease (2 y) |
| 32 | KIF5B-ALK | M | 2 y | Soft tissue: subcutaneous tumor left lower leg with infiltration in the musculature | Active monitoring | PR | No | — | — | No | Alive with regressive disease (14 mo) |
| 33 | KIF5B-ALK | F | 3 y | Soft tissue: perineal mass | Surgery (total resection) | CR | No | — | — | No | Alive with no disease (14 mo) |
| 34‡ | KIF5B-ALK | M | 3 y | Soft tissue: subglottic mass | Corticosteroids, followed by surgery (total resection) | CR | No | — | — | No | Alive with no disease (3 y) |
| 35 | KIF5B-ALK | F | 10 y | Skin: single nodule on the right breast (7mm; exclusively dermal/cutaneous) | Surgery (total resection) | CR | No | — | — | No | Alive with no disease (1 mo) |
| 36 | KIF5B-ALK | F | 10 y | Bone: right scapular lesion with soft tissue extension | Surgery (total resection) | CR | No | — | — | No | Alive with no disease (5 y) |
| 37 | KIF5B-ALK | M | 11 y | Soft tissue: 2 tumors in omentum and mesenterium | Surgery (subtotal resection) | PD | Yes | Chemotherapy (VBL/PRED, 12 wk, IC-1/IC-2, → PD), followed by active monitoring¶ | SD | No | Alive with stable disease (15 mo) |
| 38 | EML4-ALK | M | 17 y | Lung: single mass (10 × 9 × 8 cm) within the left lower lobe extending into the pulmonary vein and left atrium | N/A | N/A | N/A | N/A | N/A | N/A | N/A (lost to follow-up) |
| 39 | DCTN1-ALK | F | 41 y | Bone: right clavicular lesion with significant soft tissue extension (total size >10 cm) | Radiotherapy (22 Gy in 12 fractions) | PR | No | ALK inhibition (crizotinib → severe anaphylaxis), followed by chemotherapy (VBL/PRED, 4 courses, → PD), and then ALK inhibition (alectinib) | PR | Yes (alectinib) | Alive with regressive disease (2 y) |
| Atypical: ALK-rearranged histiocyte-rich tumors | |||||||||||
| A1 | EML4-ALK | F | 51 y | CNS, bone, lung, + subcutaneous tumors at relapse | Surgery (L1 tumor), chemotherapy (TC, 1 cycle) and radiotherapy (32 Gy L1 tumor; 20 Gy whole brain) | PD | Yes | ALK inhibition (alectinib for 16 mo, followed by lorlatinib for 14 mo, and then ceritinib for 7 wk), followed by antalgic radiotherapy of 2 metastases and chemotherapy (VBL/PRED) | SD | Yes (VBL/Pred) | Alive with stable disease (3 y) |
| A2 | SQSTM1-ALK | F | 53 y | Soft tissue: large mesenteric tumor, + subcutaneous and liver tumors at relapse | Surgery (total resection) | PD | Yes | ALK inhibition (crizotinib) | SD | Yes (crizotinib) | Alive with stable disease (13 mo) |
| A3 | EML4-ALK | F | 4 y | Soft tissue: obstructing yellow nodule in the left main bronchus | Surgery (endoscopic resection) | N/A | Yes | Surgery (endoscopic reresection 1 and 2 y after first surgery) | CR | No | Alive with no disease (17 y) |
2-CDA, cladribine; 6MP, mercaptopurine; CNS, central nervous system; CR, complete response; F, female; Gy, gray; IVIG, intravenous immunoglobulin; M, male; N/A, not available; PD, progressive disease; PNS, peripheral nervous system; PR, partial response; PRED, prednisone; SD, stable disease; TC, paclitaxel and cyclophosphamide; VBL, vinblastine.
Age at presentation in hospital.
Follow-up since presentation in hospital.
Previously reported cases (Case 1,47 Case 2,30,31 Case 9,39 Case 16,6 Case 23,39 Case 3444).
This patient experiences chronic renal insufficiency, hypertension, and hypergammaglobulinemia.
Death.
Abdominal MRI after chemotherapy demonstrated disease progression. Subsequent abdominal ultrasound exams at 2 and 4 mo after abdominal MRI showed stable disease; the patient has been asymptomatic since he received chemotherapy. Therefore, no second-line therapy was given at last follow-up, but active monitoring was executed. Active monitoring was performed using abdominal ultrasound because of significant distress of the child during MRI.