Hairy cell leukemias with unmutated IGHV genes define the minor subset refractory to single-agent cladribine and with more aggressive behavior

Forconi, Francesco; Sozzi, Elisa; Cencini, Emanuele; Zaja, Francesco; Intermesoli, Tamara; Stelitano, Caterina; Rigacci, Luigi; Gherlinzoni, Filíppo; Cantaffa, Renato; Baraldi, Anna; Gallamini, Andrea; Zaccaria, Alfonso; Pulsoni, Alessandro; Gobbi, Marco; Tassi, Maristella; Raspadori, Donatella; Leoncini, Lorenzo; Rinaldi, Andrea; Sabattini, Elena; Bertoni, Francesco; Pileri, Stefano; Lauria, Francesco

doi:10.1182/blood-2009-03-212449

Cited by 118 publications

(99 citation statements)

References 43 publications

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“…Although the percentage of IGHV4-34 genes that were unmutated was similar for HCLc and HCLv (83% vs 100%, P ϭ .4), the reported percentage of unmutated IGHV4-34 rearrangements in CLL (21% of 159 rearrangements) 6 was much lower than in the present study of HCLc (P ϭ .007) or HCLv (P Ͻ .001). IGHV1-69, observed in HCLc ( Figure 3B; n ϭ 5) but not in HCLv, was always mutated, in contrast to CLL, where 241 (87%) of 277 rearrangements were unmutated (P Ͻ .001) 5,6 Of several independent studies of gene usage in HCL rearrangements from a total of 191 specimens obtained before treatment, 10,[14][15][17][18]23 only one rearrangement expressing IGHV1-69 was reported, and it was also mutated. 23 None of the 5 HCLc IGHV1-69 sequences was from allele *01, compared with 214 (83%) of 259 CLL rearrangements that were from allele *01 (P Ͻ .001), 177 (83%) of which had 100% homology to germline.…”

Section: Igh Mutation Statusmentioning

confidence: 92%

“…IGHV1-69, observed in HCLc ( Figure 3B; n ϭ 5) but not in HCLv, was always mutated, in contrast to CLL, where 241 (87%) of 277 rearrangements were unmutated (P Ͻ .001) 5,6 Of several independent studies of gene usage in HCL rearrangements from a total of 191 specimens obtained before treatment, 10,[14][15][17][18]23 only one rearrangement expressing IGHV1-69 was reported, and it was also mutated. 23 None of the 5 HCLc IGHV1-69 sequences was from allele *01, compared with 214 (83%) of 259 CLL rearrangements that were from allele *01 (P Ͻ .001), 177 (83%) of which had 100% homology to germline. 6 The IGHV3-23 gene, the most common gene found in HCLc, was unmutated only in one case, very different from IGHV4-34 (P Ͻ .001).…”

Section: Igh Mutation Statusmentioning

confidence: 92%

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Evidence of canonical somatic hypermutation in hairy cell leukemia

Arons¹,

Roth²,

Sapolsky³

et al. 2011

Blood

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To compare hairy cell leukemia (HCL) with chronic lymphocytic leukemia (CLL) and normal B cells with respect to their B-cell receptors, somatic hypermutation (SHM) features in HCL were examined in a series of 130 immunoglobulin gene heavy chain rearrangements, including 102 from 100 classic (HCLc) and 28 from 26 variant (HCLv) patients. The frequency of unmutated rearrangements in HCLc was much lower than that in HCLv (17% vs 54%, P < .001) or historically in CLL (17% vs 46%, P < .001), but HCLv and CLL were similar (P ‫؍‬ .45). As previously reported for CLL, evidence of canonical SHM was observed in HCLc rearrangements, including: (1) a higher ratio of replacement to silent mutations in the complementarity determining regions than in the framework regions (2.83 vs 1.41, P < .001), (2) higher transition to transversion ratio than would be expected if mutations were random (1.49 vs 0.5, P < .001), and (3) higher than expected concentration of mutations within RGYW hot spots (13.92% vs 3.33%, P < .001). HCLv met these 3 criteria of canonical SHM to a lesser extent. These data suggest that, whereas

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Section: Igh Mutation Statusmentioning

confidence: 92%

Section: Igh Mutation Statusmentioning

confidence: 92%

Evidence of canonical somatic hypermutation in hairy cell leukemia

Arons¹,

Roth²,

Sapolsky³

et al. 2011

Blood

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“…Splenomegaly (> 3 cm), leukocytosis (>10 × 10 9 /L), hairy cells in the blood (> 5 × 10 9 /L), and high beta2‐microglobulin (> 2N) are associated with a poor prognosis and resistance to purine analogs (PNA) 8. In a similar manner to chronic lymphocytic leukemia (CLL), CD38 expression drives poor prognosis 9.…”

Section: How the Diagnosis Of Hcl And Hcl‐like Disorders Has Improvedmentioning

confidence: 99%

Hairy cell leukemia 2018: Update on diagnosis, risk‐stratification, and treatment

Troussard

Cornet

2017

American J Hematol

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Disease overviewHairy cell leukemia (HCL) and HCL‐like disorders, including HCL variant (HCL‐V) and splenic diffuse red pulp lymphoma (SDRPL), are a very heterogeneous group of mature lymphoid B‐cell disorders, characterized by the identification of hairy cells, a specific genetic profile, a different clinical course and the need for appropriate treatment.DiagnosisDiagnosis of HCL is based on morphological evidence of hairy cells, an HCL immunologic score of 3 or 4 based on the CD11C, CD103, CD123, and CD25 expression, the trephine biopsy which makes it possible to specify the degree of tumoral medullary infiltration and the presence of BRAF V600E somatic mutation.Risk stratificationProgression of patients with HCL is based on a large splenomegaly, leukocytosis, a high number of hairy cells in the peripheral blood and the immunoglobulin heavy chain variable region gene mutational status. VH4‐34 positive HCL cases are associated with poor prognosisRisk adapted therapyPurine analogs (PNA) are indicated in symptomatic first line HCL patients. The use of PNA followed by rituximab represents an alternative option.Management of progressive or refractory diseaseIt is based on the use of BRAF inhibitors associated or not with MEK inhibitors, recombinant immunoconjugates targeting CD22 or BCR inhibitors.

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“…High resolution genomic profiling in HCL, comparing it to HCL-variant, has demonstrated in both diseases a number of chromosome gains and losses, namely in chromosomes 5 and 7q [15]. However and in contrast to HCL-variant, losses at 17p --a region that codes for the tumor suppressor gene TP53 or mutations of this gene --were not found in HCL and have rarely been reported in this disease [16]. The high frequency of TP53 abnormalities in HCL-variant may well underline its refractoriness to agents that are very effective in HCL.…”

Section: Laboratory Featuresmentioning

confidence: 99%

“…Patients with bulky abdominal lymphadenopathy tend to have suboptimal responses to purine analog therapy [10]. One study has suggested that the uncommon HCL cases with IgHV4-34 usage or with unmutated IgVH are those that more often do not respond to the purine analog CDA [16,32]. The very minority of HCL that have TP53 abnormalities may also have an unfavorable outcome.…”

Section: Prognostic Factors and Outcomementioning

confidence: 99%