Methotrexate and Cytarabine for Adult Patients with Newly Diagnosed Langerhans Cell Histiocytosis: A Single Arm, Single Center, Prospective Phase 2 Study

Backgroud: Langerhans cell histiocytosis (LCH) is a rare, heterogeneous histiocytic disorder occurring in patients of all ages from neonates to the elderly. The features of LCH are well described in children, however, they remain poorly defined in adults. There is no standard first-line treatment for adult LCH. The current standard treatment protocol for children is vinblastine plus prednisone, which has never been proven effective for adults in a prospective study. Considering the relatively high frequency of pituitary involvement and late onset of neurodegenerative symptoms, patients may benefit from the combination of cytarabine and methotrexate as both these drugs cross the blood-brain barrier. Methods: This phase 2, prospective, single-center study enrolled 83 newly diagnosed adults multisystem (MS)-LCH or LCH with multifocal single system (SS-m) involved between January 2014 and March 2019 (NCT 02389400). The methotrexate (1g/m2by 24-hour infusion on day 1) and cytarabine (100 mg /m2by 24-hour infusion for 5 days) was administered every 35 days for a cycle and 6 cycles totally. The primary endpoint was event-free survival (EFS). Events were defined as a poor response to chemotherapy, reactivation after chemotherapy or death from any cause. Results: The median age was 33 years (range 18-65 years). Forty-nine patients were male (59.0%). Six patients were SS-m LCH (7.2%), 77 patients were MS LCH (92.8%). The most common organ involved in the total cohort was bone (78.3%), followed by lung (67.5%), pituitary (62.7%) and lymph nodes (38.6%). Twenty-three patients had liver involvement (27.7%), 11 patients with spleen involvement (13.3%), no patients had hematologic involvement. All patients received at least one course of chemotherapy, with median 6 (1-6) courses. Overall 69 patients (83.1%) completed protocol treatment, 14 patients (16.9%) went off protocol (13 patients' decision, 1 poor response). The overall response rate was 87.9%. including 43 patients (51.8%) as having non-active disease and 30 patients (36.1%) as active disease (AD)/better. After a median of 23 months (range 7-79 months) follow-up, one patient died of disease progression and 25 patients had reactivation of the disease. The estimated 3-year OS and EFS were 97.7% and 68.0% separately (Figure 1). To evaluate the prognostic factors of EFS using univariate analysis, liver, spleen, lung and skin involvement at baseline had significantly shorter EFS. EFS were also evaluated using multivariate Cox regression model, liver involvement remained predictive of poorer EFS (P = 0.012; HR 0.339, 95% CI 0.146-0.784). The most common toxicity was hematologic adverse events. All patients experienced neutropenia and thrombocytopenia. Thirty-five patients (42.2%) had grade 4 neutropenia, 43 patients (51.8%) had grade 3 neutropenia. Fourteen patients (16.9%) had grade 4 thrombocytopenia, 13 patients (15.7%) had grade 3 thrombocytopenia. No patients received prophylactic antimicrobial treatment during any of the cycles. Forty patients (48.2%) experienced febrile neutropenia, including 38 (45.8%) grade 3 and 2 (2.4%) grade 4. The most common non-hematological toxicities were gastrointestinal complications. Two patients developed grade 3 nausea. Grade 3 alanine aminotransferase increased occurred in in two patients. No treatment related death. One patient had secondary primary malignancy (oral squamous cell carcinoma), 56 months after the last course of MA regimen. Fifty-two of 82 surviving patients experienced sequelae to the disease that were not influenced by therapy. Forty-eight patients had diabetes insipidus and 4 presented with hypothyroidism. Conclusion: Methotrexate and cytarabine is an efficient and safe regimen for newly diagnosed adult LCH. The involvement of liver at baseline indicates a worse prognosis in adult LCH. Disclosures No relevant conflicts of interest to declare.

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Methotrexate and cytarabine for adult patients with newly diagnosed Langerhans cell histiocytosis: A single arm, single center, prospective phase 2 study

American Journal of Hematology ◽

10.1002/ajh.25864 ◽

2020 ◽

Vol 95 (9) ◽

Cited By ~ 1

Author(s):

Xin‐Xin Cao ◽

Jian Li ◽

Ai‐Lin Zhao ◽

Tian‐Hua He ◽

Xue‐Min Gao ◽

...

Keyword(s):

Langerhans Cell Histiocytosis ◽

Langerhans Cell ◽

Adult Patients ◽

Phase 2 ◽

Newly Diagnosed ◽

Single Center ◽

Phase 2 Study ◽

Prospective Phase

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The Efficacy of Vemurafenib in Erdheim-Chester Disease and Langerhans Cell Histiocytosis: Preliminary Results from VE-Basket Study

Blood ◽

10.1182/blood.v124.21.635.635 ◽

2014 ◽

Vol 124 (21) ◽

pp. 635-635 ◽

Cited By ~ 2

Author(s):

David M. Hyman ◽

Eli Diamond ◽

Vivek Subbiah ◽

Jean-Yves Blay ◽

A. Craig Lockhart ◽

...

Keyword(s):

Langerhans Cell Histiocytosis ◽

Response Rate ◽

Langerhans Cell ◽

Adult Patients ◽

Phase 2 ◽

Overall Response ◽

Phase 2 Study ◽

Grade 3 ◽

Erdheim Chester ◽

Chester Disease

Abstract Background: The systemic histiocytic disorders Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) are rare hematologic malignancies with heterogenous clinical courses and prognoses that share a common primary event: the pathologic accumulation and infiltration of cells thought to be of the monocyte/macrophage lineage in affected tissue. The recent discovery of BRAFV600E mutations in a high proportion (50-60%) of patients with LCH/ECD has provided pivotal insight into the cause and potential management of these disorders. The VE-BASKET study (ClinicalTrials.gov identifier, NCT01524978) was designed to explore the efficacy and safety of vemurafenib, a selective oral inhibitor of mutated BRAFV600 kinase, in non–melanoma, non–papillary thyroid cancers harboring BRAFV600 mutations. The preliminary efficacy data in adult patients with ECD/LCH are presented herein. Methods: Simon 2-stage adaptive-design, open-label, multicenter, multinational, phase 2 study of vemurafenib in patients with cancer harboring BRAFV600 mutations. The primary objective was to evaluate the efficacy of vemurafenib in patients with BRAFV600 mutation–positive cancers at week 8 by investigator-assessed response rate using RECIST version 1.1. Tumor assessment was performed by computed tomography, magnetic resonance imaging, or physical examination every 8 weeks. Patients without RECIST v1.1 measurable disease were followed up by use of positron emission tomography; these response data will be presented separately. Data cutoff was March 18, 2014. Results: Fifteen patients with ECD/LCH (6 male, 9 female) have been enrolled. Median age is 67 years (range, 35-83). Eleven of 15 patients (73%) received at least 1 prior therapy. Median duration of vemurafenib treatment was 94 days (range, 6-478). Maximal percentage change from baseline in target lesion diameter sum and best overall response are shown in Figure 1A. To date, in 11 patients assessed by RECIST v1.1, overall response rate was 36.4% (95% CI, 10.9-69.2) and clinical benefit rate was 90.9% (95% CI, 58.7-99.8). No patient experienced progression while taking vemurafenib. Best overall responses by RECIST 1.1 are as follows: 1 (9.1%) complete, 3 (27.3%) partial, 6 (54.6%) stable, 0 progressive, and 1 (9.1%) not evaluable. Three patients (20%) discontinued treatment because of adverse events (AEs; grade 3 gastric infection, grade 3 arthralgia, and grade 4 alanine transaminase level elevation); 12 patients are still receiving treatment. Thirteen patients (87%) had at least 1 grade 3 or 4 AE—most commonly skin squamous cell carcinoma (40%)—and actinic keratosis, keratoacanthoma, maculopapular rash, arthralgia, and dehydration (each 13%). No patient died during the study. Two representative patient vignettes are presented herein. Patient 1 is a 68-year-old woman with extensive ECD involving the brain, bones, and retroperitoneum. She previously received high-dose methotrexate and underwent stenting for disease-related renal artery stenosis that resulted in an emergency hypertensive event and renal failure, transiently requiring hemodialysis. At the time of enrollment, this patient had severe gait instability and dysarthria and was unable to perform activities of daily living (ADLs). After 8 weeks of vemurafenib therapy, she achieved partial response (Figure 1B), is ambulating with minimal assistance, and is independent with ADLs. She continues therapy. Patient 2 is a 77-year-old woman with LCH previously treated with vinblastine, methotrexate, an AKT inhibitor, and cladribine. At the time of enrollment she had debilitating cutaneous involvement that required long-term administration of narcotics and resulted in recurrent infection. After 4 weeks of vemurafenib therapy, the patient achieved complete response, including total resolution of skin lesions (Figure 1C). Subsequent biopsy also confirmed complete pathologic response and complete absence of the BRAFV600E mutant protein by immunohistochemistry using the VE1 antibody (Figure 1D). The patient continues therapy. Conclusion: There are no approved therapies for adult patients with multisystem histiocytic disorders. The magnitude and durability of response to vemurafenib in patients with multisystemic BRAFV600-mutated ECD and LCH are encouraging. Updated results will be presented at the American Society of Hematology annual meeting. Figure 1 Figure 1. Disclosures Hyman: Chugai Pharma: Consultancy; Atara Biotherapeutics: Consultancy. Off Label Use: Vemurafenib is a BRAF inhibitor currently approved for treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. The data included in this abstract is a subgroup analysis of VE-BASKET, a phase 2 study of vemurafenib in non-melanoma cancer patients harboring BRAFV600 mutations in order to explore the efficacy of vemurafenib in other cancer populations. Subbiah:MD Anderson Cancer Center: Employment. Blay:University Lyon I: Employment; Centre Leon Berard: Employment. Sirzen:F. Hoffmann-La Roche: Employment, Equity Ownership. Veronese:F. Hoffmann-La Roche: Employment. Laserre:F. Hoffmann-La Roche: Employment. Baselga:Roche: Consultancy.

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Gemcitabine, cisplatin, and dexamethasone (GDP) in combination with methotrexate and pegaspargase is active in newly diagnosed peripheral T cell lymphoma patients: a phase 2, single-center, open-label study in China

Annals of Hematology ◽

10.1007/s00277-018-3488-1 ◽

2018 ◽

Vol 98 (1) ◽

pp. 143-150 ◽

Cited By ~ 1

Author(s):

Yan Zhang ◽

Wei Zhang ◽

Jian Li ◽

Minghui Duan ◽

Bing Han ◽

...

Keyword(s):

T Cell ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Phase 2 ◽

Newly Diagnosed ◽

Single Center ◽

Open Label ◽

Peripheral T Cell Lymphoma ◽

Open Label Study ◽

Label Study

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Phase 2 study using oral thalidomide-cyclophosphamide-prednisone for idiopathic multicentric Castleman disease

Blood ◽

10.1182/blood-2018-11-884577 ◽

2019 ◽

Vol 133 (16) ◽

pp. 1720-1728 ◽

Cited By ~ 9

Author(s):

Lu Zhang ◽

Ai-lin Zhao ◽

Ming-hui Duan ◽

Zhi-yuan Li ◽

Xin-xin Cao ◽

...

Keyword(s):

Treatment Failure ◽

Progression Free Survival ◽

Castleman Disease ◽

Phase 2 ◽

Newly Diagnosed ◽

Free Survival ◽

Multicentric Castleman Disease ◽

End Point ◽

Phase 2 Study ◽

Grade 3

Abstract Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder. The anti–interleukin 6 (IL-6) therapy siltuximab is not available everywhere, and is not effective for over one-half of patients. Alternative treatment approaches are urgently needed. In the first iMCD clinical trial directed against a target other than IL-6 signaling, we investigated a thalidomide-cyclophosphamide-prednisone (TCP) regimen in newly diagnosed iMCD patients. This single-center, single-arm, phase 2 study enrolled 25 newly diagnosed iMCD patients between June 2015 and June 2018. The TCP regimen (thalidomide 100 mg daily for 2 years; oral cyclophosphamide 300 mg/m2 weekly for 1 year; prednisone 1 mg/kg twice a week for 1 year) was administered for 2 years or until treatment failure. The primary end point was durable tumor and symptomatic response for at least 24 weeks. Twelve patients (48%) achieved the primary end point with no relapse, 3 patients (12%) demonstrated stable disease, and 10 patients (40%) were evaluated as treatment failure. Even when considering all patients, there were significant (P < .05) improvements in median symptom score, IL-6 level, hemoglobin, erythrocyte sedimentation rate, albumin, and immunoglobulin G. Among responders, the median levels of all evaluated parameters significantly improved, to the normal range, after treatment. The regimen was well tolerated. One patient died of pulmonary infection and 1 patient had a grade 3 adverse event (rash); 2 patients died following disease progression. Estimated 1-year progression-free survival and overall survival were 60% and 88%, respectively. The TCP regimen is an effective and safe treatment of newly diagnosed iMCD patients, particularly when siltuximab is unavailable. This trial was registered at www.clinicaltrials.gov as #NCT03043105.

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Cladribine Activity in Adult Langerhans-Cell Histiocytosis

Blood ◽

10.1182/blood.v93.12.4125 ◽

1999 ◽

Vol 93 (12) ◽

pp. 4125-4130 ◽

Cited By ~ 83

Author(s):

Alan Saven ◽

Carol Burian

Keyword(s):

Langerhans Cell Histiocytosis ◽

Overall Response Rate ◽

Single Agent ◽

Langerhans Cell ◽

Median Response ◽

Major Activity ◽

Prior Surgery ◽

Grade 3 ◽

Experienced Grade

Abstract Langerhans-cell histiocytosis (LCH) results from the accumulation of tissue histiocytes derived from the same progenitor cells as monocytes. Because cladribine is potently toxic to monocytes, we conducted a phase II trial of cladribine. Cladribine was administered to 13 LCH patients at 0.14 mg/kg per day by 2-hour intravenous infusion for 5 consecutive days, every 4 weeks for a maximum of six courses. Median age was 42 years (range, 19 to 72) and median pretreatment disease duration was 99 months (range, 6 to 252). One patient was untreated, one had received prior prednisone only, one prior radiation only, six prior radiation and chemotherapy, and four prior surgery, radiation, and chemotherapy. Seven patients had cutaneous involvement, six multifocal osseous, six pulmonary, two each with soft tissue and nodal involvement, and four had diabetes insipidus. Of 13 patients, 12 were evaluable for response and all for toxicity. After a median of three courses (range, 1 to 6), seven (58%) patients achieved complete responses (two pathologic and five clinical) and two (17%) patients achieved partial responses; overall response rate, 75%. Median response follow-up duration was 33 months (range, 1 to 65). Seven patients experienced grade 3 to 4 neutropenia. Only one patient had a documented infection, dermatomal herpes zoster. At a median follow-up of 42 months (range, 5 to 76), 12 patients remain alive and one patient has died. Thus, cladribine has major activity in adult LCH and warrants further investigation in both pediatric and adult LCH as a single agent and in combination with other drugs.

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A Prospective, Randomized, Phase III Study of Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) Versus Bortezomib, Melphalan and Prednisone (VMP) in Elderly Newly Diagnosed Myeloma Patients

Blood ◽

10.1182/blood.v112.11.652.652 ◽

2008 ◽

Vol 112 (11) ◽

pp. 652-652 ◽

Cited By ~ 16

Author(s):

Antonio Palumbo ◽

Sara Bringhen ◽

Davide Rossi ◽

Valeria Magarotto ◽

Francesco Di Raimondo ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Chromosomal Abnormalities ◽

Progression Free Survival ◽

Phase Iii ◽

Newly Diagnosed ◽

Gastrointestinal Complications ◽

Free Survival ◽

Weekly Infusion ◽

Grade 3

Abstract Background: In newly diagnosed myeloma patients the combination of bortezomib with melphalan-prednisone (VMP) was superior to MP. In relapsed-refractory patients the 4 drug combination of bortezomib-melphalan-prednisone-thalidomide (VMPT) induced a high proportion of complete responses (CR). Methods: Newly diagnosed myeloma patients (N=393) older than 65 years, from 58 centers in Italy, were randomly assigned to receive VMPT (N=193) or VMP (N=200). Initially, patients were treated with nine 6-week cycles of VMPT (bortezomib 1.3 mg/m2 days 1,4,8,11,22,25,29,32 in cycles 1–4 and days 1,8,22,29 in cycles 5–9; melphalan 9 mg/m2 days 1–4; prednisone 60 mg/m2 days 1–4 and thalidomide 50 mg days 1–42, followed by bortezomib 1.3 mg/m2 every 15 days and thalidomide 50 mg/day as maintenance) or VMP (bortezomib, melphalan and prednisone at the same doses and schedules previously described without maintenance). In March 2007, the protocol was amended: both VMPT and VMP schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (bortezomib 1.3 mg/m2 days 1,8,15,22 in cycles 1–9). Primary end-point was progression-free survival (PFS). Results: Patient characteristics were similar in both groups: median age was 71 years, 23% of patients were aged > 75 years. Patients who received at least 1 cycle were evaluated: 152 patients for VMPT (62 received bortezomib bi-weekly infusion and 90 weekly infusion) and 152 patients for VMP (62 received bortezomib bi-weekly infusion and 90 weekly infusion). Data were analyzed in intention-to-treat. The very good partial response (VGPR) rate was higher in the VMPT group (55% versus 42%, p=0.02), including a CR rate of 31% in the VMPT group and 16% in the VMP group (p=0.003). In the subgroup treated with weekly infusion of bortezomib, VGPR was 59% for VMPT and 37% for VMP (p=0.004), including 28% CR for VMPT and 10% for VMP (p=0.004). Subgroup analyses did not show any statistical difference between responses and either age, B2-microglobulin or chromosomal abnormalities, such as del13, t(4;14), t(14;16) and del17. After a median follow-up of 13.6 months, the 2-year PFS was 83.9% in the VMPT group and 75.7% in the VMP group (HR=0.73, 95% CI 0.38–1.42, p=0.35). In patients who received weekly infusion of bortezomib, the 2-year PFS was 86.8% in the VMPT group and 78.1% in the VMP group (HR=0.65, 95% CI 0.24–1.8, p=0.41). In patients who achieved CR after induction, the 2-year PFS was 100% for VMPT and 79% for VMP (p=0.02). The 3-year overall survival (OS) was 89.5% in the VMPT group and 88.7% in the VMP group (HR=1.02, 95% CI 0.43–2.46, p=0.96). The incidence of grade 3–4 adverse events (AEs) was similar in both groups. In the VMPT patients and in the VMP patients, the more frequent AEs were neutropenia (36% vs 31%), thrombocytopenia (20% vs 19%), peripheral neuropathy (18% vs 12%), infections (14% vs 10%), and gastrointestinal complications (7% vs 8%), respectively. The weekly infusion of bortezomib significantly decreased the incidence of grade 3–4 peripheral neuropathy (9% for VMPT and 3% for VMP). Conclusion: VMPT is superior to VMP in terms of response rates. Longer follow-up is needed to assess their effects on PFS and OS. The weekly infusion of bortezomib significantly reduced the incidence of grade 3–4 peripheral neuropathy without influencing outcome. Table. Complete responses, progression-free survival and peripheral neuropathy in all patients and in those who received weekly infusion of bortezomib VMPT group (n=152) VMP group (n=152) All patients (n=152) Subgroup with bortezomib weekly infusion (n=90) All patients (n=152) Subgroup with bortezomib weekly infusion (n=90) CR rate (%) 31 28 16 10 2-year PFS (%) 84 87 76 78 Grade 3–4 peripheral neuropathy (%) 18 9 12 3

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Cladribine Activity in Adult Langerhans-Cell Histiocytosis

Blood ◽

10.1182/blood.v93.12.4125.412k11_4125_4130 ◽

1999 ◽

Vol 93 (12) ◽

pp. 4125-4130 ◽

Cited By ~ 1

Author(s):

Alan Saven ◽

Carol Burian

Keyword(s):

Langerhans Cell Histiocytosis ◽

Overall Response Rate ◽

Single Agent ◽

Langerhans Cell ◽

Median Response ◽

Major Activity ◽

Prior Surgery ◽

Grade 3 ◽

Experienced Grade

Langerhans-cell histiocytosis (LCH) results from the accumulation of tissue histiocytes derived from the same progenitor cells as monocytes. Because cladribine is potently toxic to monocytes, we conducted a phase II trial of cladribine. Cladribine was administered to 13 LCH patients at 0.14 mg/kg per day by 2-hour intravenous infusion for 5 consecutive days, every 4 weeks for a maximum of six courses. Median age was 42 years (range, 19 to 72) and median pretreatment disease duration was 99 months (range, 6 to 252). One patient was untreated, one had received prior prednisone only, one prior radiation only, six prior radiation and chemotherapy, and four prior surgery, radiation, and chemotherapy. Seven patients had cutaneous involvement, six multifocal osseous, six pulmonary, two each with soft tissue and nodal involvement, and four had diabetes insipidus. Of 13 patients, 12 were evaluable for response and all for toxicity. After a median of three courses (range, 1 to 6), seven (58%) patients achieved complete responses (two pathologic and five clinical) and two (17%) patients achieved partial responses; overall response rate, 75%. Median response follow-up duration was 33 months (range, 1 to 65). Seven patients experienced grade 3 to 4 neutropenia. Only one patient had a documented infection, dermatomal herpes zoster. At a median follow-up of 42 months (range, 5 to 76), 12 patients remain alive and one patient has died. Thus, cladribine has major activity in adult LCH and warrants further investigation in both pediatric and adult LCH as a single agent and in combination with other drugs.

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