Response to immunomodulatory drug-based regimens in heavily pretreated patients with recurrent/refractory adult Langerhans cell histiocytosis CURRENT STATUS: POSTED

Purpose: Langerhans cell histiocytosis (LCH) is a clonal histiocytic neoplasm and, because of its rarity in adults, there is no standard treatment for adult LCH. Immunomodulatory drugs (IMiDs) have been used to treat patients with low risk recurrent/refractory LCH but their effectiveness in adult LCH patients is unclear. Methods: We retrospectively evaluated the response rate to IMiDs-based regimens in ten heavily pretreated recurrent/refractory adult LCH patients at Peking Union Medical College Hospital. Results: A total of 10 patients (four males and six females) were included in this study. Median age at diagnosis was 33 years (range, 28–54 years). All patients had multisystem involvement and the median number of organs involved was 5 (range, 5–7). Seven patients had high risk organs involved, including seven patients with liver involvement and one with spleen involvement. All 10 patients had received at least one chemotherapy before the IMiDs-based regimen. The median number of previous lines of chemotherapy was 2 (range, 1–4). Eight patients received thalidomide, dexamethasone and cyclophosphamide, and two patients received lenalidomide and dexamethasone. The median time that patients received thalidomide treatment was 15 months and the duration of the two patients on lenalidomide regimen was 3 months and 12 months separately. Treatment responses in eight recurrent LCH patients included non-active disease in one patient and regressive disease in seven patients. The two refractory patients who had progression during the last treatment had stable disease after IMiDs therapy. During a median 15-months follow-up period, no disease reactivation or death was observed. Conclusions: IMiDs combined with dexamethasone and cyclophosphamide, may be a salvage therapy for recurrent/refractory adult LCH patients.


Introduction
Langerhans cell histiocytosis (LCH) is a rare, heterogeneous histiocytic disorder occurring most commonly in children. [1] The clinical presentation and outcome of LCH are extremely variable, ranging from isolated, spontaneously remitting pulmonary LCH to multisystem disease, with lifethreatening organ dysfunction. LCH lesions are defined histologically by langerin-positive (CD207 + ) histiocytes on an inflammatory background that includes lymphocytes, eosinophils and macrophages. [2] There is substantial evidence, including the discovery of the BRAF V600E mutation in LCH in 2010, that LCH is driven by pathological MAPK activation in myeloid precursors. [3,4] LCH is now believed to have both inflammatory and neoplastic characteristics and is designated an "inflammatory myeloid neoplasm". [5] The current standard treatment protocol for children with de novo multisystem LCH is vinblastine plus prednisone.
[6] Because of the rarity of LCH in adults and a lack of prospective randomized trials, the treatment strategy for adults is mostly based on pediatric protocols. The overall response rate of therapy based on vinblastine plus prednisone in adults is lower than in children and the treatment tends to show higher toxicity.
[7] A retrospective study showed an advantage for cytarabine monotherapy compared with vinblastine/prednisone in bone LCH patients.
[8] Although the overall survival in adult LCH was over 2 decades, disease recurred at least once in 40% of patients. [9,10] There is little data to guide therapy after frontline treatment has failed. Nucleoside analogues may be a reasonable class of drugs to treat LCH, but are associated with prolonged hospitalization and high rates of treatment-related death. [11,12] A retrospective study from Mayo showed cladribine and vemurafenib, a BRAF inhibitor, had an overall response rate of 50-69%. [13] Immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide, strongly boost the immune response and are widely used to treat plasma cell diseases. In a phase 2 trial, thalidomide as monotherapy gave a 70% response rate in recurrent/refractory low risk LCH but there were no responses in six high risk children. [14] IMiDs combined with dexamethasone have been successfully used to treat high risk children as well as adult LCH patients. [15,16] Cyclophosphamide has been used as part of combination chemotherapy regimens to treat adult LCH, such as such as MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, bleomycin and prednisone). [17] We have, therefore, retrospectively analyzed the efficacy and toxicity of IMiDs combined with dexamethasone and cyclophosphamide regimens in the treatment of recurrent/refractory LCH among adult patients at our hospital. Response criteria All patients were followed up every 3 months. The assessment was performed by laboratory tests, clinical assessment, physical examination and imaging as appropriated for the LCH location. Imaging data were collected by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) from 2 patients, thoracic high resolution computed tomography (HRCT) and cerebral magnetic resonance imaging (MRI). Disease was assessed using standard evaluations, as defined by Histiocyte Society criteria.
[6] If all signs and symptoms were resolved, the patients were classified as having non-active disease (NAD). Otherwise, they were classified as having active disease (AD). AD was further subdivided into regressive disease (signs and symptoms were improved with no new lesions), stable disease (persistence of signs and symptoms) or progressive disease (progression and/or appearance of new lesions). The response was assessed by review of records.

Data analysis
Overall survival (OS) was defined as the duration from initiation of treatment with thalidomide-or lenalidomide-based therapy to the date of death or last follow-up. Progression-free survival (PFS) was calculated from the date of initiation of thalidomide-or lenalidomide-based therapy until the date of disease progression, relapse, death from any cause or last follow-up.

Data sharing statement
Individual participant data will not be available

Patient Characteristics
A total of 10 patients (four males and six females) were included in this retrospective study. Median age at diagnosis was 33 years (range, 28-54 years). All patients had multisystem involvement and the median number of organs involved was 5 (range, 5-7). Detailed information for the patients included in this study is shown in Table 1. Seven patients had a high risk organ involved, including seven with liver involvement and one with spleen involvement (Patient 5 had both liver and spleen involved). The most commonly affected organs were lung (9/10), pituitary (9/10), bone (8/10), liver (7/10) and lymph node (7/10). All 10 patients had received at least one prior of chemotherapy before the IMiDs-based regimen. The median number of previous lines of chemotherapy was 2 (range, 1-4).
All the patients had relapsed or refractory to the initial therapies, which included cytarabine monotherapy (2/10), cytarabine combined with methotrexate (8/10), vindesine and prednisone-based regimen (4/10), cladribine monotherapy (2/10) or cladribine combined with cytarabine (2/10). One patient had a liver transplantation because of severe involvement of the liver. The median time from diagnosis to the initiation of IMiDs-based treatment was 29.5 months (range, 4-96 months). Before the IMiDs-based regimens, eight patients had recurrent LCH and two patients had progression during the last treatment (Patients 9 and 10).

Treatment and response
Eight patients with recurrent/refractory LCH received TCD. The median time that patients received thalidomide treatment was 15 months (range, 5-24 months). Two patients received RD, one for 3 months and one for 12 months. In the eight recurrent LCH cases, treatment led to NAD in one patient and regressive disease in seven patients. The two patients who had progression during the last treatment had stable disease after receiving IMiDs-based treatment for 3 and 14 months.
Of the seven patients who had liver involvement, 5/6 (83.3%) had elevated levels of alkaline phosphatase (ALP), 6/6 had elevated levels of γ-glutamyl transpeptidase (GGT) and 5/7 (71.4%) had elevated levels of total bilirubin (Tbil) before initiation of the IMiDs-based regimen. After treatment, In term of adverse events, one patient developed septic shock caused by infectious diarrhea during the treatment (Patient 2). After the infection was controlled, the patient continued TCD treatment without further infections. Two patients had grade 1 peripheral neuropathy (Patients 1 and 6) and two patients had grade 2 hyperglycemia (Patients 2 and 3). Patients 2 and 3 discontinued dexamethasone after 11 and 18 months of TCD treatment, respectively, because of hyperglycemia but continued with thalidomide and cyclophosphamide therapy.

Follow-up
The median follow-up time for this cohort was 15 months (range, 3-25 months). No disease reactivation or death was observed. The median PFS and OS were not reached yet. One patient had oral squamous cell carcinoma (Patient 3).

Discussion
LCH is a heterogeneous disease, the clinical manifestations of which are related to the pattern of organ involvement. Patients with localized disease in "low risk" organs typically have a good prognosis whereas multisystem disease, especially involving "high risk" organs (liver, spleen and bone marrow) increases the likelihood of poor outcomes and disease reactivation following frontline therapy. [1,6] There are no universally accepted standard guidelines for the treatment of adult LCH patients. The majority of treatment reports are retrospective case studies based on small cohorts.
There are even fewer reports describing treatment of recurrent/refractory disease. In this retrospective study, we have demonstrated the efficacy of IMiDs combined with dexamethasone and cyclophosphamide, in recurrent/refractory LCH patients.
Thalidomide monotherapy has been used to treat LCH in low risk patients but failed in children with high risk LCH. [14] In our cohort, seven patients had liver involvement and one patient also had spleen involvement. All of the patients had relapsed or refractory to initial therapies, including cytarabine. Four patients had failed on a vindesine and prednisone-based regimen and three on a cladribine-based regimen. Our patients thus had severe LCH and had been heavily pretreated before the IMiDs-based treatments. After received TCD or RD treatment, 10% of patients had NAD, 70% of patients had regressive disease and 20% of patients had stable disease. During a median of 15months follow-up, no disease reactivation or death was observed. Our use of doublet or triplet regimens instead of monotherapy may explain why our results differ from the earlier reports. [14] Another reason may be that the patients involved in our cohort were all adult patients instead of children.
The pathogenesis of LCH remains largely obscure. The current understanding is that LCH is an inflammatory myeloid neoplasm, driven by pathological MAPK pathway activity. The hypothesis is that langerin-positive histiocytes, harboring an oncogenic mutation, migrate to the site of lesions, where they recruit and activate various inflammatory cells 5 . In LCH lesions, the pathological histiocytes constitute approximately 8% of the granulomatous lesion. [18] The remainder of the lesion is composed of inflammatory infiltrate, including activated T cells on the background of a cytokine storm. [19] Studies of other conditions have demonstrated that the MAPK pathway does influence tumor necrosis factor (TNF)-α function. [20,21] IMiDs inhibit the production of TNF-α, [22] inhibit the activity of NF-κB [23] and have anti-inflammatory effects. [24] IMiDs have also been shown to act synergistically with dexamethasone, both in vitro and in vivo [25] in mantle cell lymphoma. These data led to the hypothesis that IMiDs combined with dexamethasone and cyclophosphamide, might be a promising treatment for recurrent/refractory adult LCH patients, as shown in our cohort.
Since recurrent somatic activating mutations of BRAF V600E and additional genetic drivers of ERK pathway activation have been identified. [3,4] There were small studies demonstrated the efficacy of targeted therapies, BRAF or MEK inhibitors in LCH. [12,26] Monotherapy might be better tolerated than triplet regimens, but prospective studies should be designed to test the efficacy and toxicity of targeted therapies in adult LCH.
This study has several limitations. First, it is a single-institution retrospective study and the number of subjects enrolled in the study was relatively small, which might limit the generalizability of our results. However, all the records were reviewed independently by two hematologists to minimize bias or errors in data collection. Second, BRAF mutation status were not available in this cohort. Most of patients did not have an adequate amount of tissue available for genomic testing. Lastly, since we used doublet or triplet regimens in this study, it is difficult to conclude the treatment result were from IMiDs. An ongoing clinical trial at Dana Farber for lenalidomide monotherapy in adult LCH patients (NCT02523040) may provide more data at this point. And further prospective study may be needed to confirm the advantage of IMiDs-based therapy for the treatment of adult LCH patients.