Management of Relapsed Hairy Cell Leukemia: A Systematic Review of Novel Agents and Targeted Therapies

Siddiqui, Raheel S; Sardar, Muhammad; Shahzad, Moazzam; Jose, Jemin Aby; Selene, Insija Ilyas; Shah, Zunaira Z; Qureshi, Anum; Shafqat, Madeeha; Kashif, Rimsha; Ahmad, Maheen; Mejia-Garcia, Alex; Anwer, Faiz

doi:10.1016/j.clml.2021.06.007

Cited by 4 publications

(5 citation statements)

References 45 publications

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“…RAS/BRAF mutations in myeloma offer a potential opportunity to use a targeted approach with MAPK–ERK inhibitors. Vemurafenib, a BRAF inhibitor, has shown promise in the treatment of patients with metastatic melanoma, non‐small cell lung cancer, papillary thyroid carcinoma, hairy cell leukemia, and Langerhans cell histiocytosis 31–35 . However, vemurafenib as a single agent in the treatment of BRAF ‐mutated myeloma patients has resulted in a low response rate and early resistance 36 .…”

Section: Discussionmentioning

confidence: 99%

“…Vemurafenib, a BRAF inhibitor, has shown promise in the treatment of patients with metastatic melanoma, non‐small cell lung cancer, papillary thyroid carcinoma, hairy cell leukemia, and Langerhans cell histiocytosis. 31 , 32 , 33 , 34 , 35 However, vemurafenib as a single agent in the treatment of BRAF ‐mutated myeloma patients has resulted in a low response rate and early resistance. 36 Subsequently, Ernst et al reported successful treatment with a combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib in a patient with BRAF V600E‐mutated refractory myeloma.…”

Section: Discussionmentioning

confidence: 99%

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Plasma cell myeloma with RAS/BRAF mutations is frequently associated with a complex karyotype, advanced stage disease, and poorer prognosis

Lin

Zuo

et al. 2023

Cancer Medicine

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BACKGROUND:Mutations in the RAS-MAPK pathway, such as KRAS, NRAS, and BRAF, are known as high-risk factors associated with poor prognosis in patients with various cancers, but studies in myeloma have yielded mixed results. METHODS:We describe the clinicopathologic, cytogenetic, molecular features, and outcomes of 68 patients with RAS/BRAF-mutated myeloma, and compare with 79 patients without any mutations. RESULTS:We show that KRAS, NRAS, and BRAF were mutated in 16%, 11%, and 5% of cases, respectively. RAS/BRAF-mutated patients had lower hemoglobin and platelet counts, higher levels of serum lactate dehydrogenase and calcium, higher percentage of bone marrow plasma cells, and more advanced R-ISS stage. RAS/ BRAF mutations were associated with complex karyotype and gain/amplification of CKS1B. The median overall survival and progression-free survival were significantly shorter for RAS/BRAF-mutated patients (69.0 vs. 220.7 months, p = 0.0023 and 46.0 vs. 60.6 months, p = 0.0311, respectively). Univariate analysis revealed that KRAS mutation, NRAS mutation, lower hemoglobin, elevated lactate dehydrogenase, higher R-ISS stage, complex karyotype, gain/amplification of CKS1B, monosomy 13/RB1 deletion and lack of autologous stem cell transplantation were associated with poorer prognosis. Multivariate analysis showed that KRAS mutation, lower hemoglobin level, higher level of serum calcium, higher ISS stage, and lack of autologous stem cell transplantation predict inferior outcome. CONCLUSIONS:RAS/BRAF mutations occur in 30%-40% of myeloma cases and are associated with higher tumor burden, higher R-ISS stage, complex karyotype, and shorter overall survival and progression-free survival. These findings support testing for RAS/BRAF mutations in myeloma patients and underscore the potential therapeutic benefits of RAS/BRAF inhibitors.How to cite this article: Li N, Lin P, Zuo Z, et al. Plasma cell myeloma with RAS/BRAF mutations is frequently associated with a complex karyotype, advanced stage disease, and poorer prognosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Plasma cell myeloma with RAS/BRAF mutations is frequently associated with a complex karyotype, advanced stage disease, and poorer prognosis

Lin

Zuo

et al. 2023

Cancer Medicine

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“…Vemurafenib, a BRAF inhibitor, has shown promise in the treatment of patients with metastatic melanoma, non-small cell lung cancer, papillary thyroid carcinoma, hairy cell leukemia and Langerhans cell histiocytosis. [32][33][34][35][36] However, vemurafenib as a single agent in the treatment of BRAFmutated myeloma patients has resulted in a low response rate and early resistance. 37 Subsequently, Ernst et al reported successful treatment with a combination of the BRAF inhibitor dabrafenib and the…”

Section: Discussionmentioning

confidence: 99%

Plasma cell myeloma with RAS/BRAF mutations: Clinicopathologic, molecular genetic features and outcomes of 68 patients

Li¹,

Lin²,

Zuo

et al. 2022

Preprint

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High-throughput genomic analysis of plasma cell myeloma has identified recurrent gene mutations of prognostic significance. Mutations in the RAS-MAPK pathway, such as KRAS, NRAS, and BRAF, are known as high-risk factors associated with poor prognosis in patients with various types of cancers, but studies in myeloma have yielded mixed results. We describe the clinicopathologic, cytogenetic, molecular features and outcomes of 68 patients with RAS/BRAF-mutated myeloma, and compare this group with 79 myeloma patients without any mutations. We show that KRAS, NRAS and BRAF were mutated in 16%, 11%, and 5% of cases, respectively. The RAS/BRAF-mutated group included 39 men and 29 women with a median age of 63 years (range, 35–82) at initial diagnosis. Patients with RAS/BRAF-mutated myeloma had lower hemoglobin and platelet counts, higher levels of serum lactate dehydrogenase and calcium, higher percentage of bone marrow plasma cells, and more advanced R-ISS stage. In addition, RAS/BRAF mutations were associated with complex karyotype and extra copies of CKS1B. The median overall survival and progression-free survival were significantly shorter for patients in the RAS/BRAF-mutated group (69.0 months vs 220.7 months, p = 0.0023 and 46.0 months vs 60.6 months, p = 0.0311, respectively). Univariate analysis revealed that KRAS mutation, NRAS mutation, lower hemoglobin level, elevated lactate dehydrogenase, higher R-ISS stage, complex karyotype, gain/amplification of CKS1B, monosomy 13/RB1 deletion and lack of autologous stem cell transplantation were associated with poorer prognosis. Multivariate analysis showed that KRAS mutation, lower hemoglobin level, higher level of serum calcium, higher ISS stage and lack of autologous stem cell transplantation predict inferior outcome. In summary, RAS/BRAF mutations occur in 30–40% of myeloma cases and are associated with higher tumor burden, higher R-ISS stage, complex karyotype, and shorter overall survival and progression-free survival. These findings support testing for RAS/BRAF mutations in myeloma patients and underscore the potential therapeutic benefits of RAS/BRAF inhibitors.

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“…No serious side effects were observed during the second treatment with Moxe. The combined treatment of Moxe with rituximab remains in the first phase of clinical trials [39].…”

Section: Moxetumomab Pasudotoxmentioning

confidence: 99%

New therapeutic options for hairy cell leukemia

2022

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Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disorder characterized by pancytopenia, splenomegaly and increased susceptibility to infections. In 2011, BRAF gene mutation was identified in almost all the patients with the classical type of HCL. The purine analogs cladribine and pentostatin induce long-term remission in the majority of patients, and they remain the standard treatment for this type of leukemia.However, more than half of patients in complete response relapse over the long term, with a quarter of them relapsing within the first five years.Recently, new drugs have been developed and have demonstrated efficacy in refractory or relapsed HCL. The immunotoxin Moxetumomab pasudotox was registered for HCL in 2018.The BRAF kinase inhibitors vemurafenib and dabrafenib, as well as the Bruton kinase inhibitor ibrutinib, are also proven highly effective in clinical trials.

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Management of Relapsed Hairy Cell Leukemia: A Systematic Review of Novel Agents and Targeted Therapies

Cited by 4 publications

References 45 publications

Plasma cell myeloma with RAS/BRAF mutations is frequently associated with a complex karyotype, advanced stage disease, and poorer prognosis

Plasma cell myeloma with RAS/BRAF mutations is frequently associated with a complex karyotype, advanced stage disease, and poorer prognosis

Plasma cell myeloma with RAS/BRAF mutations: Clinicopathologic, molecular genetic features and outcomes of 68 patients

New therapeutic options for hairy cell leukemia

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