18 research outputs found
Diffuusin suurisoluisen B-solulymfooman nykyhoito
Diffuusi suurisoluinen B-solulymfooma on yleisin imukudossyöpä. Se on kliinisesti
ja biologisesti monimuotoinen tauti, jonka alatyyppien ominaisuuksia pystytään toistaiseksi
huomioimaan hoitosuunnitelmissa vain rajoitetusti. Hoidon runko koostuu CD20-vasta-aineen
ja solunsalpaajien yhdistelmästä. Nykyhoitojen avulla paranee 75 % alle 65-vuotiaista
potilaista ja 46 % yli 65-vuotiaista. Ennustetta huonontavia riskitekijöitä ovat vanhuus,
laaja levinneisyys, huono yleistila, levinneisyys imusolmukealueiden ulkopuolella
ja seerumin suurentunut laktaattidehydrogenaasipitoisuus. Lymfoomat, joissa esiintyy
Bcl2-, Myc- ja Bcl6-geenien uudelleenjärjestymiä ja p53-geenin muutoksia ovat poikkeuksellisen
aggressiivisia ja huonoennusteisia. Haasteita ovat iäkkäiden potilaiden, suuren biologisen
riskin ja uusiutuneen taudin hoidot.</p
Diffuusin suurisoluisen B-solulymfooman nykyhoito
Teema : Hematologiset syövät. English summaryPeer reviewe
The DLBCL90 gene-expression assay identifies double-hit lymphomas with high sensitivity in patients from two phase II clinical trials with high-risk diffuse large B-cell lymphoma
Peer reviewe
Patients with high-risk DLBCL benefit from dose-dense immunochemotherapy combined with early systemic CNS prophylaxis
Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We conducted a phase 2 trial in 139 patients aged 18 to 64 years who had primary DLBCL with an age-adjusted International Prognostic Index (aaIPI) score of 2 to 3 or site-specific risk factors for CNS recurrence. The goal was to assess whether a dose-dense immunochemotherapy with early systemic CNS prophylaxis improves the outcome and reduces the incidence of CNS events. Treatment consisted of 2 courses of high-dose methotrexate in combination with biweekly rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14), followed by 4 courses of R-CHOP-14 with etoposide (R-CHOEP) and 1 course of high-dose cytarabine with R. In addition, liposomal cytarabine was administered intrathecally at courses 1, 3, and 5. Coprimary endpoints were failure-free survival and CNS progression rates. Thirty-six (26%) patients experienced treatment failure. Progression occurred in 23 (16%) patients, including three (2.2%) CNS events. At 5 years of median follow-up, failure-free survival, overall survival, and CNS progression rates were 74%, 83%, and 2.3%, respectively. Treatment reduced the risk of progression compared with our previous trial, in which systemic CNS prophylaxis was given after 6 courses of biweekly R-CHOEP (hazard ratio, 0.49; 95% CI, 0.31-0.77; P=.002) and overcame the adverse impact of an aaIPI score of 3 on survival. In addition, outcome of the patients with BCL2/MYC double-hit lymphomas was comparable to the patients without the rearrangements. The results are encouraging, with a low toxic death rate, low number of CNS events, and favorable survival rates.Peer reviewe
Patients with high-risk DLBCL benefit from dose-dense immunochemotherapy combined with early systemic CNS prophylaxis
Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We conducted a phase 2 trial in 139 patients aged 18 to 64 years who had primary DLBCL with an age-adjusted International Prognostic Index (aaIPI) score of 2 to 3 or site-specific risk factors for CNS recurrence. The goal was to assess whether a dose-dense immunochemotherapy with early systemic CNS prophylaxis improves the outcome and reduces the incidence of CNS events. Treatment consisted of 2 courses of high-dose methotrexate in combination with biweekly rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14), followed by 4 courses of R-CHOP-14 with etoposide (R-CHOEP) and 1 course of high-dose cytarabine with R. In addition, liposomal cytarabine was administered intrathecally at courses 1, 3, and 5. Coprimary endpoints were failure-free survival and CNS progression rates. Thirty-six (26%) patients experienced treatment failure. Progression occurred in 23 (16%) patients, including three (2.2%) CNS events. At 5 years of median follow-up, failure-free survival, overall survival, and CNS progression rates were 74%, 83%, and 2.3%, respectively. Treatment reduced the risk of progression compared with our previous trial, in which systemic CNS prophylaxis was given after 6 courses of biweekly R-CHOEP (hazard ratio, 0.49; 95% CI, 0.31-0.77; P=.002) and overcame the adverse impact of an aaIPI score of 3 on survival. In addition, outcome of the patients with BCL2/MYC double-hit lymphomas was comparable to the patients without the rearrangements. The results are encouraging, with a low toxic death rate, low number of CNS events, and favorable survival rates
Molecular background of double protein expressor B-cell lymphoma
Concomitant deregulation of MYC and BCL2, whether at the genomic or protein level, comprises a clinically significant poorly characterized biological high-risk feature in diffuse large B-cell lymphoma (DLBCL). To interrogate these lymphomas, we comprehensively characterized genomic alterations and protein expression of BCL2, BCL6 and MYC in the context of comprehensive mutational, transcriptomic and clinical data in 181 patients with primary DLBCL. While the structural variations of BCL2 were subtype-specific and specifically increased BCL2 expression, molecular dissection of MYC deregulation revealed associations with other lymphoma drivers, of which we highlight concurrent TP53 alterations. Double protein expression (DPE) arose from heterogeneous molecular backgrounds in a subtype-dependent manner. In GCB DLBCL, concurrent alterations of MYC and BCL2 loci gave rise to the majority of DPE DLBCLs, whereas in the ABC DLBCLs, concurrent alterations were infrequent. Clinically, DPE DLBCL defined a prognostic entity, which was independent of International Prognostic Index (IPI) and cell-of-origin, and together with TP53 alterations had synergistic dismal impact on survival. Importantly, BCL6 translocations identified non-GCB lymphomas with favorable BN2/C1 -like outcomes independent of IPI and concurrent DPE status. Our findings elucidate the pathogenesis and biological determinants of high-risk DLBCL and reveal subtype-specific and clinically feasible predictors of subtype and outcome
Distinct subtypes of diffuse large B-cell lymphoma defined by hypermutated genes
Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease whose personalized clinical management requires robust molecular stratification. Here, we show that somatic hypermutation (SHM) patterns constitute a marker for DLBCL molecular classification. The activity of SHM mutational processes delineated the cell of origin (COO) in DLBCL. Expression of the herein identified 36 SHM target genes stratified DLBCL into four novel SHM subtypes. In a meta-analysis of patients with DLBCL treated with immunochemotherapy, the SHM subtypes were significantly associated with overall survival (1642 patients) and progression-free survival (795 patients). Multivariate analysis of survival indicated that the prognostic impact of the SHM subtypes is independent from the COO classification and the International Prognostic Index. Furthermore, the SHM subtypes had a distinct clinical outcome within each of the COO subtypes, and strikingly, even within unclassified DLBCL. The genetic landscape of the four SHM subtypes indicated unique associations with driver alterations and oncogenic signaling in DLBCL, which suggests a possibility for therapeutic exploitation. These findings provide a biologically driven classification system in DLBCL with potential clinical applications.Peer reviewe