This cohort, the largest reported to date, increases the spectrum of knowledge on PBL, rarely described. However, specific guidelines to clarify treatment are lacking, and may improve the poor prognosis of this rare disease.
Subclones homozygous for JAK2V617F are more common in polycythemia vera (PV) than essential thrombocythemia (ET), but their prevalence and significance remain unclear. The JAK2 mutation status of 6495 BFU-E, grown in low erythropoietin conditions, was determined in 77 patients with PV or ET. Homozygousmutant colonies were common in patients with JAK2V617F-positive PV and were surprisingly prevalent in JAK2V617F-positive ET and JAK2 exon 12-mutated PV. Using microsatellite PCR to map loss-of-heterozygosity breakpoints within individual colonies, we demonstrate that recurrent acquisition of JAK2V617F homozygosity occurs frequently in both PV and ET. PV was distinguished from ET by expansion of a dominant homozygous subclone, the selective advantage of which is likely to reflect additional genetic or epigenetic lesions. Our results suggest a model in which development of a dominant JAK2V617F-homzygous subclone drives erythrocytosis in many PV patients, with alternative mechanisms operating in those with small or undetectable homozygous-mutant clones. (Blood. 2012;120(13):2704-2707)
IntroductionThe JAK2V617F mutation is found in ϳ 95% of patients with polycythemia vera (PV) and 60% of those with essential thrombocythemia (ET), 1-4 but the mechanisms responsible for the different disease phenotypes remain unclear. Several lines of circumstantial evidence suggest that increased signaling through mutant JAK2 is important: (1) A "homozygous" sequence pattern in granulocytes was identified in ϳ 30% of patients with PV but was rare in ET 1-4 ; (2) in PV patients, JAK2V617F allele burden correlates with higher hemoglobin levels and white cell counts but lower platelet counts 5,6 ; (3) the copy number of mutant JAK2 influences phenotype in mouse models 7,8 ; and (4) JAK2 exon 12 mutations are reported to signal more strongly than JAK2V617F and are associated with PV but not ET. 9 Homozygosity for JAK2V617F results from mitotic recombination, 1-4 and homozygous-mutant BFU-E were present in most patients with PV but not in those with ET. 10 This observation raised the possibilities that patients with PV are more prone to develop a homozygous subclone or that homozygous-mutant cells have a selective advantage in patients with PV but not in those with ET. In either case, it has been widely assumed that homozygousmutant cells in a given patient are usually members of a single clone with a selective advantage and that JAK2V617F homozygosity plays a causal role in PV pathogenesis. However, this model is complicated by several observations: some patients with PV have very small homozygous-mutant clones 10 ; 2 individual patients have been reported to harbor 2 distinct homozygous clones 11,12 ; a defect in STAT1 phosphorylation has been identified in PV patients 13 ; and reports of small numbers of ET patients who harbor homozygousmutant BFU-E 14-16 and of PV patients with none. 14, 15 We have therefore systematically assessed the prevalence and clonal relationship of homozygous-mutant BFU-E precursors in patients with JAK2-mutated...
Anti-PD-1 therapy provides high response rates in Hodgkin lymphoma (HL) patients who have relapsed or are refractory (R/R) to autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV), but median progression free survival (PFS) is only one year. The efficacy of treatment following anti-PD-1 is not well known. We retrospectively investigated the efficacy of salvage therapies for unsatisfactory response to anti-PD-1 therapy, assessed by PET-CT according to the Lugano criteria, in 30 R/R HL patients. Patients were highly pre-treated before anti-PD-1 (70% received ASCT and 93% BV). Unsatisfactory responses to anti-PD1 therapy were progressive disease (PD) (n=24) and partial response (PR) (n=6). For the 24 PD patients, median anti-PD-1 related PFS was 7.5 months (95%CI, 5.7-11.6); 17 received subsequent CT alone (Group 1) and 7 received CT in addition to anti-PD-1 (Group 2). 16/24 patients (67%) obtained an objective response. In the 15 patients treated with the same CT, twelve obtained PR or complete response (CR). In Group 1, there were 7 CR (41%), 3 PR (18%), and 7 PD (41%). In Group 2, there were 4 CR (57%), 2 PR (29%), and 1 SD (14%). No unexpected toxicity was observed. Six patients who achieved response proceeded to allogeneic SCT. With a median follow-up of 12.1 months (7-14.7), the median PFS following the initiation of CT was 11 months (95%CI, 6.3; not reached) and the median of overall survival was not reached. These observations in highly pre-treated HL patients suggest that anti-PD-1 therapy might re-sensitize tumor cells to CT. This article is protected by copyright. All rights reserved.
PURPOSE: The prognosis of elderly patients with diffuse large B-cell lymphoma (DLBCL) is worse than that of young patients. An attenuated dose of chemotherapy—cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R-miniCHOP)—is a good compromise between efficacy and safety in very elderly patients. In combination with R-CHOP (R2-CHOP), lenalidomide has an acceptable level of toxicity and may mitigate the negative prognosis of the non–germinal center B-cell–like phenotype. The Lymphoma Study association conducted a multicentric, phase III, open-label, randomized trial to compare R-miniCHOP and R2-miniCHOP. PATIENTS AND METHODS: Patients of age 80 years or older with untreated DLBCL were randomly assigned into the R-miniCHOP21 group or the R2-miniCHOP21 group for six cycles and stratified according to CD10 expression and age. The first cycle of rituximab was delivered by IV on D1 after a prephase and then delivered subcutaneously on D1 of cycles 2-6. Lenalidomide was delivered at a dose of 10 mg once daily on D1-D14 of each cycle. The primary end point was overall survival (OS). RESULTS: A total of 249 patients with new DLBCL were randomly assigned (127 R-miniCHOP and 122 R2-miniCHOP). The median age was 83 years (range, 80-96), and 55% of the patients were classified as non-GCB. The delivered dose for each R-miniCHOP compound was similar in both arms. Over a median follow-up of 25.1 months, the intention-to-treat analysis revealed that R2-miniCHOP did not improve OS (2-year OS 66% in R-miniCHOP and 65.7% in R2-miniCHOP arm, P = .98) in the overall population or in the non-GCB population. Grade 3-4 adverse events occurred in 53% of patients with R-miniCHOP and in 81% of patients with R2-miniCHOP. CONCLUSION: The addition of lenalidomide to R-miniCHOP does not improve OS. Rituximab delivered subcutaneously was safe in this population.
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