sábado, 29 de junio de 2019

Langerhans Cell Histiocytosis Treatment (PDQ®) 4/7 —Health Professional Version - National Cancer Institute

Langerhans Cell Histiocytosis Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute

Langerhans Cell Histiocytosis Treatment (PDQ®)–Health Professional Version

Treatment of Recurrent, Refractory, or Progressive Childhood LCH

Reactivation of Single-System and Multisystem LCH

Reactivation of Langerhans cell histiocytosis (LCH) after complete response is common.[1] In a large study, the percentage of patients with reactivations was 9% to 17.4% for single-site disease; 37% for single-system, multifocal disease; 46% for multisystem (nonrisk organ) disease; and 54% for risk-organ involvement. Forty-three percent of reactivations were in bone, 11% in ears, 9% in skin, and 7% developed diabetes insipidus; a lower percentage of patients had lymph node, bone marrow, or risk-organ relapses.[1] The median time to reactivation was 12 to 15 months in nonrisk patients and 9 months in risk patients. One-third of patients had more than one reactivation varying from 9 to 14 months after the initial reactivation. Patients with reactivations were more likely to have long-term sequelae in the bones, diabetes insipidus, or other endocrine, ear, or lung problems.[1]
A comprehensive review of the German-Austrian-Dutch (Deutsche Arbeitsgemeinschaft für Leukaemieforschung und -therapie im Kindesalter [DAL]) and Histiocyte Society clinical trials revealed a reactivation rate of 46% at 5 years for patients with multisystem LCH, with most reactivations occurring within 2 years of first remission. A second reactivation occurred in 44% of patients, again within 2 years of the second remission. Involvement of the risk organs in these reactivations occurred only in those who were initially in the high-risk group (meaning they had liver, spleen, or bone marrow involvement at the time of original diagnosis).[2][Level of evidence: 3iiiDiii] Most reactivations, even in patients with high-risk disease who initially responded to therapy, were in bone, skin, or other nonrisk locations.
Consistent with these findings, the percentage of reactivations in multisystem disease was 45% in the Japanese trial [3][Level of evidence: 1iiA] and 46% in the HISTSOC-LCH-II trial.[4] There was no statistically significant difference in reactivations between the high-risk and low-risk groups. Both the DAL-HX and Japanese studies concluded that intensified treatment increased the rapidity of response, particularly in young children and infants younger than 2 years, and together with rapid switch to salvage therapy for nonresponders, reduced mortality for patients with high-risk multisystem LCH. Based on the HISTSOC-LCH-III (NCT00276757) randomized trial, prolongation of therapy also significantly reduced the rate of reactivation, although the exact duration of therapy (12 vs. 24 months) is being addressed in the HISTSOC-LCH-IV (NCT02205762) trial.

Treatment of Low-Risk Single-System or Multisystem LCH

The optimal therapy for patients with recurrent, refractory, or progressive LCH has not been determined.
Treatment options for patients with recurrent, refractory, or progressive low-risk single-system or multisystem disease include the following:
  1. Chemotherapy.
  2. Bisphosphonate therapy.
Several chemotherapy regimens exist for the treatment of recurrent, refractory, or progressive low-risk disease.
Evidence (chemotherapy):
  1. Patients with recurrent bone disease that recurs months after vinblastine and prednisone are stopped can benefit from treatment with a reinduction of vinblastine weekly and daily prednisone for 6 weeks. If there is no active disease or very little evidence of active disease, treatment can be changed to every 3 weeks, with the addition of oral mercaptopurine nightly.[5]
  2. An alternative treatment regimen for patients with any combination of low-risk sites employs vincristine, prednisone, and cytosine arabinoside.[6] The prednisone dose is reduced from the dose used in the original publication.
  3. Cladribine at 5 mg/m2 per day for 5 days per course has also been shown to be effective therapy for recurrent low-risk LCH (multifocal bone and low-risk multisystem LCH), with very little toxicity.[7] Cladribine therapy should, if possible, be limited to a maximum of six cycles to avoid cumulative and potentially long-lasting cytopenias.
  4. Clofarabine is a proven effective therapy for patients with multiple relapses of low-risk or high-risk LCH.[8]
  5. Treatment with hydroxyurea, alone or in combination with oral methotrexate, resulted in responses in 12 of 15 of patients with low-risk recurrent LCH.[9]
  6. A phase II trial of thalidomide for patients with LCH (ten low-risk patients; six high-risk patients) who failed primary and at least one secondary regimen demonstrated complete (four of ten) and partial (three of ten) responses for the low-risk patients. Complete remission was defined as healing of bone lesions on plain radiographs (n = 3) or complete resolution of skin rash (n = 4, including 3 with bone lesions that had complete resolution). Partial response was defined as healing of bone lesion, but then worsening of a skin rash that was partially resolved. However, dose-limiting toxicities, such as neuropathy and neutropenia, may limit the overall usefulness of thalidomide.[10] This agent is not used in pediatric patients to a significant degree.
Bisphosphonate therapy is also effective for treating recurrent LCH bone lesions.[11]
Evidence (bisphosphonate therapy):
  1. In a survey from Japan, bisphosphonate therapy successfully treated the bone lesions in 12 of 16 patients. Skin and soft tissue LCH lesions also resolved in the responding patients. None of the patients had risk-organ disease. Most patients received six cycles of pamidronate at 1 mg/kg per course, given at 4-week intervals. Eight of the 12 patients remained disease free at a median of 3.3 years.[12]
  2. Other bisphosphonates, such as zoledronate and oral alendronate, have also been successful in treating bone LCH.[13-15]

Treatment of High-Risk Multisystem LCH

Data from the DAL group studies showed that patients with multisystem high-risk LCH who had progressive disease by week 6 of standard induction treatment or who did not achieve at least a partial response by week 12 had only a 10% chance of survival.[16] These results were consistent with those of the less-intensive HISTSOC-LCH-II trial in which patients treated with vinblastine/prednisone who did not respond well by week 6 had a 27% chance of survival, compared with 52% for good responders.[4][Level of evidence: 1iiA] To improve on these results, patients with poorly responsive disease need to move to salvage strategies by week 6 for progressive disease and no later than week 12 for those without at least a good response.
Treatment options for patients with recurrent, refractory, or progressive high-risk multisystem disease include the following:
  1. Chemotherapy.
  2. Hematopoietic stem cell transplantation (HSCT).
Evidence (chemotherapy):
  1. Cladribine and cytarabine.
    • Ten patients with refractory high-risk organ involvement (liver, spleen, or bone marrow) and resistant multisystem low-risk organ involvement were treated with an intensive acute myeloid leukemia–like protocol consisting of cladribine and cytosine arabinoside.[17][Level of evidence: 3iiiDiv] The follow-up HISTSOC-LCH-S-2005 trial accrued 27 patients and showed a progression-free survival rate of 63% and a 5-year overall survival (OS) rate of 85% in this refractory high-risk patient population. However, all patients developed grade 4 hematologic toxicity, and five of these patients had severe sepsis.[18]
    • For centers that cannot provide the intensive supportive care needed for this protocol, an alternative protocol using lower doses of cladribine (5 mg/m2/day × 5) and cytosine-arabinoside (100 mg/m2/day × 5) was published.[19] Six of nine patients had no active disease, and one patient had improved status after six courses. Some patients had maintenance therapy; ultimately, seven of nine patients remained in complete remission, with a median follow-up of 6.5 years.
  2. Clofarabine. Patients who failed cladribine were reported to respond to treatment with clofarabine.[20]; [21][Level of evidence: 3iiiDii]
    • Eleven patients with recurrent multisystem high-risk and low-risk disease treated with clofarabine had a 90% OS.[8] If confirmed in prospective trials, the reduced toxicity of this regimen compared with the cladribine/cytarabine combination could be advantageous, despite the cost of the drug.
HSCT has been used in patients with multisystem high-risk organ involvement that is refractory to chemotherapy.[11,22-24] Early results showing very high treatment-related mortality in these very ill young infants led to the development of reduced-intensity conditioning.
Evidence (HSCT):
  1. A review from the United Kingdom, however, suggests that in transplant centers with LCH HSCT experience, there was no advantage to reduced-intensity conditioning in their setting. Reduced-intensity conditioning provided no OS advantage over myeloablative conditioning for LCH patients;[25] the relapse rate after reduced-intensity conditioning was significantly higher (28%) than the relapse rate after myeloablative conditioning (8%). However, many of the reduced-intensity conditioning patients who relapsed were successfully re-treated with chemotherapy alone.[25]

Treatment Options Under Clinical Evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
  • HISTSOC-LCH-IV (NCT02205762) (LCH-IV, International Collaborative Treatment Protocol for Children and Adolescents With LCH): On the basis of features at presentation and response to treatment, the LCH-IV study tailors treatment to one of the following seven strata:
    • Stratum I: First-line treatment for multisystem LCH patients (group 1) and patients with single-system LCH with multifocal bone or CNS-risk lesions (group 2).
    • Stratum II: Second-line treatment for nonrisk patients (patients without risk-organ involvement who fail first-line therapy or have a reactivation after completion of first-line therapy).
    • Stratum III: Salvage treatment for risk LCH (patients with dysfunction of risk organs who fail first-line therapy).
    • Stratum IV: Stem cell transplantation for risk LCH (patients with dysfunction of risk organs who fail first-line therapy).
    • Stratum V: Monitoring and treatment of isolated tumorous and neurodegenerative CNS LCH.
    • Stratum VI: Natural history and management of other single-system LCH (patients who do not need systemic therapy at the time of diagnosis).
    • Stratum VII (long-term follow up): All patients, regardless of previous therapy, will be monitored for reactivation or permanent consequences once complete disease resolution has been achieved and the respective protocol treatment has been completed.
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
  • RAS pathway (MAP2K/ERK) inhibitors: The discovery that most patients with LCH have BRAF V600E or other mutations that result in activation of the RAS pathway suggests that new therapies that target molecules within this pathway will become an important part of LCH therapy. Vemurafenib has been shown to induce significant responses in patients with BRAF V600E–positive Erdheim-Chester disease and in multiply relapsed BRAF V600E patients with multisystem LCH.[26]
  • Tyrosine kinase inhibitors: Imatinib has been shown to decrease differentiation of CD34-positive stem cells to dendritic cells; small case reports of its efficacy in patients with LCH have been published.[27,28]
References
  1. Pollono D, Rey G, Latella A, et al.: Reactivation and risk of sequelae in Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (7): 696-9, 2007. [PUBMED Abstract]
  2. Minkov M, Steiner M, Pötschger U, et al.: Reactivations in multisystem Langerhans cell histiocytosis: data of the international LCH registry. J Pediatr 153 (5): 700-5, 705.e1-2, 2008. [PUBMED Abstract]
  3. Morimoto A, Ikushima S, Kinugawa N, et al.: Improved outcome in the treatment of pediatric multifocal Langerhans cell histiocytosis: Results from the Japan Langerhans Cell Histiocytosis Study Group-96 protocol study. Cancer 107 (3): 613-9, 2006. [PUBMED Abstract]
  4. Gadner H, Grois N, Pötschger U, et al.: Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood 111 (5): 2556-62, 2008. [PUBMED Abstract]
  5. Titgemeyer C, Grois N, Minkov M, et al.: Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study. Med Pediatr Oncol 37 (2): 108-14, 2001. [PUBMED Abstract]
  6. Egeler RM, de Kraker J, Voûte PA: Cytosine-arabinoside, vincristine, and prednisolone in the treatment of children with disseminated Langerhans cell histiocytosis with organ dysfunction: experience at a single institution. Med Pediatr Oncol 21 (4): 265-70, 1993. [PUBMED Abstract]
  7. Weitzman S, Braier J, Donadieu J, et al.: 2'-Chlorodeoxyadenosine (2-CdA) as salvage therapy for Langerhans cell histiocytosis (LCH). results of the LCH-S-98 protocol of the Histiocyte Society. Pediatr Blood Cancer 53 (7): 1271-6, 2009. [PUBMED Abstract]
  8. Simko SJ, Tran HD, Jones J, et al.: Clofarabine salvage therapy in refractory multifocal histiocytic disorders, including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease. Pediatr Blood Cancer 61 (3): 479-87, 2014. [PUBMED Abstract]
  9. Zinn DJ, Grimes AB, Lin H, et al.: Hydroxyurea: a new old therapy for Langerhans cell histiocytosis. Blood 128 (20): 2462-2465, 2016. [PUBMED Abstract]
  10. McClain KL, Kozinetz CA: A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 44-9, 2007. [PUBMED Abstract]
  11. Kudo K, Ohga S, Morimoto A, et al.: Improved outcome of refractory Langerhans cell histiocytosis in children with hematopoietic stem cell transplantation in Japan. Bone Marrow Transplant 45 (5): 901-6, 2010. [PUBMED Abstract]
  12. Farran RP, Zaretski E, Egeler RM: Treatment of Langerhans cell histiocytosis with pamidronate. J Pediatr Hematol Oncol 23 (1): 54-6, 2001. [PUBMED Abstract]
  13. Morimoto A, Shioda Y, Imamura T, et al.: Nationwide survey of bisphosphonate therapy for children with reactivated Langerhans cell histiocytosis in Japan. Pediatr Blood Cancer 56 (1): 110-5, 2011. [PUBMED Abstract]
  14. Sivendran S, Harvey H, Lipton A, et al.: Treatment of Langerhans cell histiocytosis bone lesions with zoledronic acid: a case series. Int J Hematol 93 (6): 782-6, 2011. [PUBMED Abstract]
  15. Chellapandian D, Makras P, Kaltsas G, et al.: Bisphosphonates in Langerhans Cell Histiocytosis: An International Retrospective Case Series. Mediterr J Hematol Infect Dis 8 (1): e2016033, 2016. [PUBMED Abstract]
  16. Gadner H, Grois N, Arico M, et al.: A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr 138 (5): 728-34, 2001. [PUBMED Abstract]
  17. Imamura T, Sato T, Shiota Y, et al.: Outcome of pediatric patients with Langerhans cell histiocytosis treated with 2 chlorodeoxyadenosine: a nationwide survey in Japan. Int J Hematol 91 (4): 646-51, 2010. [PUBMED Abstract]
  18. Donadieu J, Bernard F, van Noesel M, et al.: Cladribine and cytarabine in refractory multisystem Langerhans cell histiocytosis: results of an international phase 2 study. Blood 126 (12): 1415-23, 2015. [PUBMED Abstract]
  19. Rosso DA, Amaral D, Latella A, et al.: Reduced doses of cladribine and cytarabine regimen was effective and well tolerated in patients with refractory-risk multisystem Langerhans cell histiocytosis. Br J Haematol 172 (2): 287-90, 2016. [PUBMED Abstract]
  20. Rodriguez-Galindo C, Jeng M, Khuu P, et al.: Clofarabine in refractory Langerhans cell histiocytosis. Pediatr Blood Cancer 51 (5): 703-6, 2008. [PUBMED Abstract]
  21. Abraham A, Alsultan A, Jeng M, et al.: Clofarabine salvage therapy for refractory high-risk langerhans cell histiocytosis. Pediatr Blood Cancer 60 (6): E19-22, 2013. [PUBMED Abstract]
  22. Akkari V, Donadieu J, Piguet C, et al.: Hematopoietic stem cell transplantation in patients with severe Langerhans cell histiocytosis and hematological dysfunction: experience of the French Langerhans Cell Study Group. Bone Marrow Transplant 31 (12): 1097-103, 2003. [PUBMED Abstract]
  23. Nagarajan R, Neglia J, Ramsay N, et al.: Successful treatment of refractory Langerhans cell histiocytosis with unrelated cord blood transplantation. J Pediatr Hematol Oncol 23 (9): 629-32, 2001. [PUBMED Abstract]
  24. Caselli D, Aricò M; EBMT Paediatric Working Party: The role of BMT in childhood histiocytoses. Bone Marrow Transplant 41 (Suppl 2): S8-S13, 2008. [PUBMED Abstract]
  25. Veys PA, Nanduri V, Baker KS, et al.: Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: outcome by intensity of conditioning. Br J Haematol 169 (5): 711-8, 2015. [PUBMED Abstract]
  26. Haroche J, Cohen-Aubart F, Emile JF, et al.: Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 121 (9): 1495-500, 2013. [PUBMED Abstract]
  27. Janku F, Amin HM, Yang D, et al.: Response of histiocytoses to imatinib mesylate: fire to ashes. J Clin Oncol 28 (31): e633-6, 2010. [PUBMED Abstract]
  28. Wagner C, Mohme H, Krömer-Olbrisch T, et al.: Langerhans cell histiocytosis: treatment failure with imatinib. Arch Dermatol 145 (8): 949-50, 2009. [PUBMED Abstract]

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