Treatments and clinical trials for ECD
| Class of treatment Medication . | Dose and schedule . | Comment . |
|---|---|---|
| BRAF inhibitors | ||
| Vemurafenib | 480-960 mg twice daily | Nearly 100% metabolic response in several case series, and in 1 prospective clinical trial3,59,60,62-66 US-FDA approval in November 2017; start with 240-480 mg twice daily and modify based on observed response and toxicities; most common adverse effects include cutaneous complications (rash, squamous cell cancer), arthralgia, QTc prolongation, and fatigue; pretreatment dermatology examination and electrocardiogram; monitoring with electrocardiogram every 3 mo and semiannual dermatology examination |
| Dabrafenib | 75-150 mg twice daily | Successful treatment reported in several case reports and 1 series20,61,67 ; anecdotal experience reflects similar efficacy to vemurafenib, and less cutaneous toxicity than vemurafenib; start with 50-75 mg twice daily and modify based on observed response and toxicities; pretreatment dermatology examination and electrocardiogram; monitoring every 3 mo with electrocardiogram and semiannual dermatology examination |
| MEK inhibitors | ||
| Cobimetinib | 20-60 mg daily for 21 of 28-d cycle | 3 published cases/series and a prospective clinical trial of responses to single-agent cobimetinib therapy in BRAF-V600E and BRAF-V600–wild type2,67,72,114 ; notable toxicities include serous retinopathy (reversible), rash, cardiomyopathy, and rarely rhabdomyolysis; pretreatment echocardiogram, ophthalmologic, and dermatologic evaluation; recheck ophthalmologic examination 2-3 wk after initiation and then every 3-4 mo for the first year of treatment; monitoring every 3 mo with echocardiogram and semiannual dermatology examination |
| Trametinib | 1-2 mg daily | Two cases of response to single-agent trametinib for ECD with KRAS,20 MAP2K1,2 and NRAS mutations21 ; anecdotal experience reflects similar efficacy and toxicity to cobimetinib; pretreatment echocardiogram, ophthalmologic, and dermatologic evaluation; recheck ophthalmologic examination 2-3 wk after initiation; monitoring every 3 monthly echocardiogram and semiannual dermatology examination |
| Combined BRAF and MEK inhibitors | ||
| Vemurafenib + cobimetinib or dabrafenib + trametinib | Doses similar as above | Case reports of combination therapy with dabrafenib and trametinib with robust responses in BRAF-V600-ECD6,73 ; Similar anecdotal experience with vemurafenib and cobimetinib; may consider in rare instances of suboptimal response to BRAF-inhibitor or toxicity necessitating dose reduction |
| First-line conventional therapy | ||
| PEG-IFN-α | 135 μg SC/wk (standard dose) or 180 μg SC/wk (high dose) | Currently, the conventional therapy with largest evidence-base in ECD79-84 ; case series have demonstrated survival benefit with the use of some form of IFN-α; high-dose IFN-α for patients with CNS or cardiac involvement; major limitation is the high frequency of systemic adverse effects |
| IFN-α | 3 mIU SC TIW (standard dose) or 6-9 mIU SC TIW (high dose) | Currently, the conventional therapy with largest evidence-base in ECD79-84 ; case series have demonstrated survival benefit with the use of some form of IFN-α; high-dose IFN-α for patients with CNS or cardiac involvement; major limitation is the high frequency of systemic adverse effects |
| Cladribine | 5 mg/m2 IV daily for 5 d Q4 wk 0.10 μg/kg SC daily for 5 d Q4 wk | 3 published cases and a retrospective series of 21 patients treated with cladribine was published demonstrating ∼50% clinical or radiologic response rate94,95,98 ; prophylactic antimicrobials against Pneumocystis jirovecii (cotrimoxazole) and viruses (acyclovir, valacyclovir) should be added during the duration of the treatment and until the lymphocyte count normalize |
| Anakinra | 100 mg SC daily or up to 2 mg/kg/d | Several case reports of successful treatment, mainly of less severe forms of ECD,86,87 but limited reports of CNS17 or cardiac87 disease with favorable response; especially effective for bone pain and constitutional symptoms; injection site reactions may be seen occasionally but otherwise well tolerated |
| Second-line conventional therapy | ||
| Sirolimus and prednisone | Sirolimus dosed to level of 8-12 ng/mL | 8 of 10 patients had a favorable response in a prospective clinical trial75 ; only one-third of patients with CNS or bone disease had a response |
| Imatinib | 400 mg PO daily | Mixed results in 7 ECD patients treated with imatinib76,77 ; lack of efficacy in several other cases anecdotally |
| Infliximab | 5 mg/mg IV Q6 wk | 2 patients with cardiac disease refractory to treatment with IFN-α had clinical improvement when treated infliximab,91 and another case series of 12 patients showed ∼40% response rates mainly cardiac and cerebellar92 |
| Tocilizumab | 8 mg/kg IV Q4 wk or 162 mg SC weekly | 2 of 3 patients in a pilot phase 2 trial had a favorable response, both without CNS involvement93 ; may be considered in patients with bone only or cardiac disease |
| Methotrexate | 7.5-25 mg PO or SC/wk | 3 of 13 patients had a partial response in a case series, ongoing responses seen in conjunctival and choroidal disease107 ; may be considered in ocular disease |
| High-dose methotrexate (3.5 mg/m2 IV) | One case of response to high-dose methotrexate103 | |
| Clinical trials (experimental) | ||
| Dabrafenib + trametinib | Dabrafenib 150 mg twice daily | Phase 2; NCT03794297; BRAF-V600–mutant ECD without prior BRAF-inhibitor or MEK-inhibitor therapy |
| Trametinib 2 mg once daily | ||
| PLX8394 (BRAF-inhibitor) | Dose escalation study | Phase 1/2; NCT02428712; previously treated BRAF mutated |
| Bevacizumab (VEGF-inhibitor) and Temsirolimus (mTOR-inhibitor) alone or combination with valproic acid or cetuximab (EGFR-inhibitor) | Dose escalation study | Phase 1/2; NCT01552434; newly diagnosed or previously treated |
| Cobimetinib (MEK-inhibitor) | 60 mg oral daily for days 1-21 of each 28-d cycle | Phase 2; NCT02649972; newly diagnosed or previously treated; interim results show promising activity in ECD patients114 |
| Cobimetinib (MEK-inhibitor) | 40 mg oral daily for days 1-21 of each 28-d cycle | Phase 2: NCT04007848; newly diagnosed or previously treated BRAF–wild-type histiocytosis, 2:1 randomized trial with placebo control |
| Cobimetinib (MEK-inhibitor) | 60 mg oral daily for days 1-21 of each 28-d cycle | Phase 2; NCT04079179; newly diagnosed or previously treated histiocytosis; pediatric and adult patients |
| Class of treatment Medication . | Dose and schedule . | Comment . |
|---|---|---|
| BRAF inhibitors | ||
| Vemurafenib | 480-960 mg twice daily | Nearly 100% metabolic response in several case series, and in 1 prospective clinical trial3,59,60,62-66 US-FDA approval in November 2017; start with 240-480 mg twice daily and modify based on observed response and toxicities; most common adverse effects include cutaneous complications (rash, squamous cell cancer), arthralgia, QTc prolongation, and fatigue; pretreatment dermatology examination and electrocardiogram; monitoring with electrocardiogram every 3 mo and semiannual dermatology examination |
| Dabrafenib | 75-150 mg twice daily | Successful treatment reported in several case reports and 1 series20,61,67 ; anecdotal experience reflects similar efficacy to vemurafenib, and less cutaneous toxicity than vemurafenib; start with 50-75 mg twice daily and modify based on observed response and toxicities; pretreatment dermatology examination and electrocardiogram; monitoring every 3 mo with electrocardiogram and semiannual dermatology examination |
| MEK inhibitors | ||
| Cobimetinib | 20-60 mg daily for 21 of 28-d cycle | 3 published cases/series and a prospective clinical trial of responses to single-agent cobimetinib therapy in BRAF-V600E and BRAF-V600–wild type2,67,72,114 ; notable toxicities include serous retinopathy (reversible), rash, cardiomyopathy, and rarely rhabdomyolysis; pretreatment echocardiogram, ophthalmologic, and dermatologic evaluation; recheck ophthalmologic examination 2-3 wk after initiation and then every 3-4 mo for the first year of treatment; monitoring every 3 mo with echocardiogram and semiannual dermatology examination |
| Trametinib | 1-2 mg daily | Two cases of response to single-agent trametinib for ECD with KRAS,20 MAP2K1,2 and NRAS mutations21 ; anecdotal experience reflects similar efficacy and toxicity to cobimetinib; pretreatment echocardiogram, ophthalmologic, and dermatologic evaluation; recheck ophthalmologic examination 2-3 wk after initiation; monitoring every 3 monthly echocardiogram and semiannual dermatology examination |
| Combined BRAF and MEK inhibitors | ||
| Vemurafenib + cobimetinib or dabrafenib + trametinib | Doses similar as above | Case reports of combination therapy with dabrafenib and trametinib with robust responses in BRAF-V600-ECD6,73 ; Similar anecdotal experience with vemurafenib and cobimetinib; may consider in rare instances of suboptimal response to BRAF-inhibitor or toxicity necessitating dose reduction |
| First-line conventional therapy | ||
| PEG-IFN-α | 135 μg SC/wk (standard dose) or 180 μg SC/wk (high dose) | Currently, the conventional therapy with largest evidence-base in ECD79-84 ; case series have demonstrated survival benefit with the use of some form of IFN-α; high-dose IFN-α for patients with CNS or cardiac involvement; major limitation is the high frequency of systemic adverse effects |
| IFN-α | 3 mIU SC TIW (standard dose) or 6-9 mIU SC TIW (high dose) | Currently, the conventional therapy with largest evidence-base in ECD79-84 ; case series have demonstrated survival benefit with the use of some form of IFN-α; high-dose IFN-α for patients with CNS or cardiac involvement; major limitation is the high frequency of systemic adverse effects |
| Cladribine | 5 mg/m2 IV daily for 5 d Q4 wk 0.10 μg/kg SC daily for 5 d Q4 wk | 3 published cases and a retrospective series of 21 patients treated with cladribine was published demonstrating ∼50% clinical or radiologic response rate94,95,98 ; prophylactic antimicrobials against Pneumocystis jirovecii (cotrimoxazole) and viruses (acyclovir, valacyclovir) should be added during the duration of the treatment and until the lymphocyte count normalize |
| Anakinra | 100 mg SC daily or up to 2 mg/kg/d | Several case reports of successful treatment, mainly of less severe forms of ECD,86,87 but limited reports of CNS17 or cardiac87 disease with favorable response; especially effective for bone pain and constitutional symptoms; injection site reactions may be seen occasionally but otherwise well tolerated |
| Second-line conventional therapy | ||
| Sirolimus and prednisone | Sirolimus dosed to level of 8-12 ng/mL | 8 of 10 patients had a favorable response in a prospective clinical trial75 ; only one-third of patients with CNS or bone disease had a response |
| Imatinib | 400 mg PO daily | Mixed results in 7 ECD patients treated with imatinib76,77 ; lack of efficacy in several other cases anecdotally |
| Infliximab | 5 mg/mg IV Q6 wk | 2 patients with cardiac disease refractory to treatment with IFN-α had clinical improvement when treated infliximab,91 and another case series of 12 patients showed ∼40% response rates mainly cardiac and cerebellar92 |
| Tocilizumab | 8 mg/kg IV Q4 wk or 162 mg SC weekly | 2 of 3 patients in a pilot phase 2 trial had a favorable response, both without CNS involvement93 ; may be considered in patients with bone only or cardiac disease |
| Methotrexate | 7.5-25 mg PO or SC/wk | 3 of 13 patients had a partial response in a case series, ongoing responses seen in conjunctival and choroidal disease107 ; may be considered in ocular disease |
| High-dose methotrexate (3.5 mg/m2 IV) | One case of response to high-dose methotrexate103 | |
| Clinical trials (experimental) | ||
| Dabrafenib + trametinib | Dabrafenib 150 mg twice daily | Phase 2; NCT03794297; BRAF-V600–mutant ECD without prior BRAF-inhibitor or MEK-inhibitor therapy |
| Trametinib 2 mg once daily | ||
| PLX8394 (BRAF-inhibitor) | Dose escalation study | Phase 1/2; NCT02428712; previously treated BRAF mutated |
| Bevacizumab (VEGF-inhibitor) and Temsirolimus (mTOR-inhibitor) alone or combination with valproic acid or cetuximab (EGFR-inhibitor) | Dose escalation study | Phase 1/2; NCT01552434; newly diagnosed or previously treated |
| Cobimetinib (MEK-inhibitor) | 60 mg oral daily for days 1-21 of each 28-d cycle | Phase 2; NCT02649972; newly diagnosed or previously treated; interim results show promising activity in ECD patients114 |
| Cobimetinib (MEK-inhibitor) | 40 mg oral daily for days 1-21 of each 28-d cycle | Phase 2: NCT04007848; newly diagnosed or previously treated BRAF–wild-type histiocytosis, 2:1 randomized trial with placebo control |
| Cobimetinib (MEK-inhibitor) | 60 mg oral daily for days 1-21 of each 28-d cycle | Phase 2; NCT04079179; newly diagnosed or previously treated histiocytosis; pediatric and adult patients |
EGFR, epidermal growth factor receptor; Q4, every 4; Q6, every 6; PO, postoperatively; SC, subcutaneously; TIW, 3 times a week; VEGF, vascular endothelial growth factor.