<scp>MACOP</scp> ‐B in Adult Langerhans Cell Histiocytosis Confirms Durable Organ Responses at an Updated Long‐Term Follow‐Up

Langerhans cell histiocytosis (LCH) is a tissue proliferation of hematopoietic-derived cells with the features of both an inflammatory and neoplastic disease, thus being modernly defined an “inflammatory myeloid neoplasm” [1]. The neoplastic nature of the disease is confirmed by the almost universal activation of the mitogen-activated protein kinase pathway due to mutations of genes encoding BRAF and other downstream kinases [2]. Children show significantly higher incidence than adults [3], roughly 4.6 cases/million under the age of 15 compared to 1–2 cases/million in adults, being highest (11.6/million) among infants and lowest (0.9/million) in those aged 60 years or more, according to a recently published English registry study [4]. LCH has protean manifestations ranging from asymptomatic localized lesions to severe and life-threatening widespread multisystem (MS) disease, both in children and adults. At present, there is no consensus regarding the optimal frontline treatment of adult patients, especially as far as a disseminated or MS disease is concerned [5]. Current frontline practice with pediatric patients is 1 year treatment with vinblastine and prednisone (±6-mercaptopurine), as suggested by the LCH-III trial [6]. Further guidance in treatment duration and drug implementation in higher risk disease will come from the ongoing LCH-IV trial. Vinblastine-based approaches, however, have significant limitations in adults: responses tend to be less robust than in children [4, 7], while at the same time an unacceptably high incidence of vinblastine-associated neurotoxicity [8] and the detrimental effects of prolonged steroid treatment severely jeopardize patients' safety and impair their quality of life [9, 10]. Our experience with a short course of the methotrexate, doxorubicin, cyclophosphamide, vincristine, bleomycin, and prednisolone (MACOP-B) regimen was preliminarily reported [11]. Purpose of the current retrospective/prospective study is to present the updated results of an expanded cohort of patients, provided they were all evaluated by both positron emission tomography (PET) and computed tomography (CT) scan before and after treatment in order to classify responses as recommended by international consensus [5]. In this work, we have focused specifically on organ responses, according to PET scan results, as explained in Supporting Information. We also provided an extended follow-up. Twelve adult LCH patients in need of frontline treatment or requiring a systemic approach after initial local therapy were treated with MACOP-B on outpatient basis on a weekly schedule for 12 consecutive weeks [12], as outlined in Table S1. Cotrimoxazole prophylaxis against Pneumocystis jiroveci pneumonia was always applied throughout treatment courses. Patients with single-system pulmonary disease were excluded. Median age at diagnosis was 44 years (range 21–62). Seven patients were female and 5 were male. Five patients displayed MS disease, 5 had single-system multifocal (SSM) disease and 2 had unifocal presentation (SSU) at parietal bone and jaw, respectively (Table S2). Patients affected by SSU disease were considered candidates for systemic therapy due to failure of previous local approaches (i.e., surgery on parietal bone) and severe symptoms (consequence of destructing jaw involvement). The predominantly affected sites were represented by: skull and axial skeleton (41.7% of the cases each), lower extremities (25%), gums and oral cavity (16.7%), upper extremities, jaws and lymph nodes (8.3%). Three patients (25%) had synchronous lung disease and two (16.7%) showed hypophyseal involvement with clinically overt diabetes insipidus. Nine patients (75%) received MACOP-B as their frontline approach, while 2 were treated after initial surgical excision and one after external radiation therapy. Eleven patients were evaluable for response, as one patient died prematurely because of a sudden cardiopulmonary event after receiving the eighth cycle. All the evaluable patients received the full planned chemotherapy program. All patients responded, with 7 complete responses (CR) and 4 partial responses (PR), yielding a CR rate of 63.6% and a PR rate of 36.4%. Responses were seen across all organs and systems involved by the disease (Table 1, Figure S1) and in cases of both localized and disseminated presentation. Two patients who achieved a PR, one with SSU and one with SSM disease at presentation, further received radiotherapy consolidation (both on jaw PET-positive residues) and obtained a CR. 1 skull; 2 upper extremity; 3 axial skeleton 4 lower extremity; 5 lymph nodes; 6 gums/oral cavity 7 lung; 8 CNS; 9 jaws Color key: black, involved site; white, uninvolved site; light gray, site complete response; dark gray, site partial response. Crossed box means: response not assessed. Among the 5 patients with MS disease, the CR rate was 80.0% (4 patients out of 5), with 3 patients (60.0%) never experiencing disease progression after a follow-up ranging between 10.4 and 14.5 years. One of the two patients who showed disease progression did so after almost 7 years from initial therapy; the other obtained a PR to MACOP-B and disease progressed only 3 months after chemotherapy. Among the 4 assessable patients with SSM disease, 50% achieved a CR and required no further therapy at a follow-up of 7 and 21 years, respectively. Three patients relapsed, two within a year after the achievement of PR and one almost 7 years after MACOP-B, while in CR. Post-relapse treatments included radiotherapy in 2 cases and high-dose chemotherapy followed by autologous transplantation (ASCT) in one case. None of these treatments was sufficient to ensure good disease control, thus all these patients required further therapy, including ASCT and vemurafenib. At a median follow-up of 10.2 years, the PFS rate was 75% at 2 years and 67% at 20 years (Figure 1A). Apart from the patient who died while on therapy, the other single death event occurred 23 years after chemotherapy in a heavily-treated patient due to cardiac failure, as a consequence of dilated cardiomyopathy possibly secondary to anthracycline use. Overall survival (OS) at 20 years reached 91.7% (Figure 1B), and none of the reported deaths was attributed directly to histiocytosis. The most relevant grade 2–3 toxicity was represented by drug-induced oral mucositis, not sufficiently controlled by post-methotrexate leucovorin. One patient developed grade 3 asymptomatic neutropenia and one required short hospitalization due to febrile neutropenia, promptly resolved with large-spectrum antibiotics and filgrastim support. No cases of unexplained cytopenia or myelodysplasia were documented during follow-up. Lack of standard approach to adult LCH has prompted the exploration of diverse chemotherapy approaches for MS disease [13]. There is insufficient evidence that pediatric approaches consisting of an induction and a maintenance phase can be translated effectively and safely into adult practice [7, 9, 10, 13]. Single-agent cladribine is recognized as an attractive frontline treatment due to its cytotoxic effects on myeloid- and monocyte-derived dendritic cells. A recently reported multicenter experience from the United States with 38 adult LCH patients, 29 of them treated frontline, displayed an overall response rate of 79%, including a CR in 26% of the cases. Cladribine was given for 5 consecutive days on a monthly basis, with a median of 4 cycles. Albeit with the limitations of the small cohort, efficacy was similar in both pre-treated and treatment-naïve patients. At a median follow-up of 6.3 years, the 5-year PFS and OS were 58% and 75%, respectively. Causes of death were apparently unrelated to LCH but rather to comorbidities [14]. Recently, the Japanese team updated the results of a phase 2 prospective trial with methotrexate (1 g/m2) and low-dose cytarabine (MTX/ARAC) applied as upfront treatment, given for 6 cycles every 35 days. They obtained a response rate of 90%, with a proportion of patients with inactive disease after therapy of 48%, and a 5-year event-free survival of 60%. Notably, grade 3–4 neutropenia was observed in 89% of treated patients, with 45% of them experiencing febrile neutropenia. Four patients (4.2%) developed secondary malignancies within 4 and 8 years after treatment [15]. MACOP-B was specifically designed for the treatment of aggressive non-Hodgkin lymphomas [12], although it is still used at some institutions in Italy to treat diffuse malignant histiocytosis as a more intensive variant of the cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) regimen. Our experience compares favorably with literature on cladribine and MTX/ARAC (Table S3). Projected PFS at 20 years of 67% suggests that treated patients can be considered cured, and the 20-year OS of almost 92% points towards its long-term safety. In summary, MACOP-B represents a feasible and effective short-course fixed-duration treatment for adult LCH patients delivered on an outpatient basis, yielding high remission rates across a wide spectrum of sites with potential curative intent. The authors have nothing to report. The study had an official approval by the local Ethical Committee (approval id 1043/2021/Oss/AOUBo). Written informed consent was always obtained prior to any procedure and prior to collecting and analyzing patients' data. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1: ajh70245-sup-0001-Supinfo.docx. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.