Targeted Sequencing Reveals Novel Gene Mutations Associated with Transformation and Early Progression in Follicular Lymphoma

Abstract Introduction : Follicular lymphoma (FL) remains an incurable malignancy as patients eventually experience progressive disease. A subset of patients is at risk of early lymphoma-related mortality due to histological transformation (TFL) to aggressive lymphoma (2-3% of patients per year) or early progression after immuno-chemotherapy, each of which leads to shortened survival. Mutations associated with transformation and/or early progression have been reported in the literature (e.g. CDKN2A, TP53, B2M) and the m7-FLIPI clinico-genetic risk model defines a high-risk patient group with poor failure-free survival after first-line treatment. However, the current knowledge of genetic alterations underlying transformation and/or early progression is inadequate to explain the majority of transformed cases and accurately predict early progressive disease. Materials and Methods: We performed targeted capture-based sequencing of 94 genes in a large cohort of fresh-frozen and formalin-fixed and paraffin-embedded patient specimens (402 samples in total). This cohort comprised 277 samples from 159 patients that experienced transformation (including 128 samples at T1 (the time of FL) and 149 samples at T2 (the time of transformation) with 118 paired biopsies) and 125 samples from 125 patients (pre-treatment samples only) presenting with either early progression within 2.5 years after starting immunochemotherapy (n=41) or late or never progression for at least 5 years after starting immunochemotherapy or observation (n=84). Mutations were called using MutationSeq and putative single nucleotide polymorphisms were filtered out using either matching germline samples (n=84) or dbSNP (v147). Bayesian proportion tests were used to compare the prevalence of gene mutations between groups. Results : We first compared T1 (n=128) and T2 (n=149) samples from 159 patients experiencing transformation. Eleven genes were more commonly altered in transformed lymphoma. These included genes that had previously been associated with transformation, such as TP53, B2M, MYC and EBF1, as well as genes that have not yet been implicated as contributing to this process, for example EZH2, CCND3, PIM1 and ITPKB. Moreover, mutations in GNA13, S1PR2 and P2RY8, that have been implicated in dissemination of germinal centre B cells, were enriched in T2 samples. In addition, cell-of-origin classification was available for 108 of the TFL cases with DLBCL histology, 18 and 90 of which were of the ABC and GCB subtype, respectively. Although the number of ABC-TFL cases was small, we observed higher percentages of BCL10 (16% versus 1%, Fisher P=0.004), CD79B (22% versus 4%, Fisher P=0.005) and MYD88 mutations (28% versus 9%, P=0.006) in ABC-TFL than in GCB-TFL, suggesting that B-cell receptor signaling and NF-κB signaling are important contributors to the ABC phenotype in TFL. Next, we assessed the association of gene mutations with patient outcomes contrasting early progressers (n=41) and late or non-progressers (n=84). Eleven genes were mutated more commonly in early progressers than in late progressers, including KMT2C, TP53, BTG1, MKI67, XBP1 and SOCS1. Overall, 32 out of 41 early progressers (78%) had mutations in at least one of the 11 early progression-associated genes, but none of the individual early progression-associated genes were mutated at a frequency > 22%. Thus, early progression appears to be related to relatively infrequent genetic alterations. None of the early progression-associated gene mutations form part of the m7-FLIPI outcome predictor. Furthermore, in our cohort that was enriched for clinical extremes, the m7-FLIPI was similarly associated with early progression when compared to the FLIPI but it was not superior, having higher specificity (89% versus 76%), but lower sensitivity (36% versus 63%). Conclusions: We found novel associations of gene mutations with transformation and showed that TFL is molecularly heterogeneous, with the ABC subtype being characterized by differential gene mutation when compared to the GCB subtype. With regards to progressive disease after immuno-chemotherapy, our approach identified early progression as a distinct clinico-genetic disease category that is imperfectly captured by traditional prognostic tools. Disclosures Connors: Seattle Genetics: Research Funding; Bristol Myers Squib: Research Funding; F Hoffmann-La Roche: Research Funding; NanoString Technologies: Research Funding; Millennium Takeda: Research Funding. Scott:NanoString Technologies: Patents & Royalties: named inventor on a patent for molecular subtyping of DLBCL that has been licensed to NanoString Technologies.

Download Full-text

Baseline Suvmax Did Not Predict Histological Transformation from Follicular Lymphoma to Aggressive Lymphoma in the Phase III GALLIUM Study

Blood ◽

10.1182/blood-2018-99-116686 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4160-4160 ◽

Cited By ~ 4

Author(s):

Farheen Mir ◽

Sally F Barrington ◽

Michel Meignan ◽

Helen Brown ◽

Tina Nielsen ◽

...

Keyword(s):

High Risk ◽

Follicular Lymphoma ◽

Research Funding ◽

Performance Status ◽

Bone Marrow Involvement ◽

International Prognostic Index ◽

B Cell Lymphoma ◽

Phase Iii ◽

Aggressive Lymphoma ◽

Histological Transformation

Abstract Introduction: Follicular lymphoma (FL) generally has an indolent clinical course, but there is a 1-2% annual rate of histological transformation (HT) into aggressive lymphoma. Nodal HT sites have a higher maximum standardized uptake value (SUVmax) than non-transformed sites, and patients with HT typically show greater variation in SUVmax between sites. Upfront identification of patients at high risk of HT would allow physicians to consider treatment intensification. The objective of this analysis was to assess the relationship between baseline SUVmax (bSUVmax) and HT in the GALLIUM study (NCT01332968). Methods In the randomized, phase III GALLIUM study, 1202 previously untreated patients with grade 1-3a FL were randomized to receive induction with either obinutuzumab (GA101; G)- or rituximab (R)-based immunochemotherapy. Patients who responded received maintenance therapy with the same antibody. The primary endpoint of investigator-assessed progression-free survival was significantly improved in the G arm relative to the R arm (hazard ratio 0.66; p=0.001). As an exploratory endpoint, the degree of 18-fluorodeoxyglucose (FDG)-avidity expressed by SUVmax was assessed in patients with baseline FDG positron emission tomography (FDG-PET) scans by an independent review committee. Results: Among 522 patients with available bSUVmax data, 13 (2.5%) experienced biopsy-confirmed HT to diffuse large B-cell lymphoma or Grade 3b FL after a median follow-up of 59 months. Patients with HT were older (median age 61 vs 56 years), and were more likely to have a poor performance status (Eastern Cooperative Oncology Group [ECOG] performance status 2: 15.4% vs 2.6%), present with high-risk Follicular Lymphoma International Prognostic Index (FLIPI; 61.5% vs 40.3%), and have bone marrow involvement (76.9% vs 52.9%) than those without. More than 65% of patients showed bSUVmax >10, but only a minority of these experienced HT. Median (range) bSUVmax in patients with versus without HT was 12.4 (8.14, 27.95) versus 11.8 (3.05, 64.43), respectively. Median (range) baseline SUVrange (bSUVrange), defined as the difference between bSUVmax of the most and least FDG-avid lymphoma sites, was 6.6 (1.08, 23.91) versus 7.14 (0.00, 59.81), respectively (Figure). Conclusions: bSUVmax >10 is common in patients with previously untreated FL and is rarely associated with early HT. Neither bSUVmax nor bSUVrange predicted HT in GALLIUM, suggesting there may be little benefit in re-biopsy of lesions to exclude HT before commencing therapy. Better markers for identification of FL patients at risk of transformation are needed. Disclosures Mir: F. Hoffmann-La Roche: Employment. Barrington:F.Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees; Department of Health (England): Research Funding; MRC: Research Funding; CRUK: Research Funding; EPSRC: Research Funding; National Institute of Health Research: Research Funding. Meignan:F. Hoffman-La Roche Ltd: Honoraria. Brown:PAREXEL, external business partner with Roche Products Ltd, Welwyn, UK: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Sahin:F. Hoffman-La Roche Ltd: Other: Ownership interests PLC. Trotman:F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; Janssen: Other: Unremunerated member of Ad Board, Research Funding; Beigene: Research Funding; Takeda: Other: Unremunerated member of Ad Board; Celgene: Other: Unremunerated member of Ad Board, Research Funding; PCYC: Research Funding.

Download Full-text

Clonal Evolution In Patients With Chronic Lymphocytic Leukemia (CLL) Developing Resistance To BTK Inhibition

Blood ◽

10.1182/blood.v122.21.866.866 ◽

2013 ◽

Vol 122 (21) ◽

pp. 866-866 ◽

Cited By ~ 15

Author(s):

Jan A. Burger ◽

Dan Landau ◽

Julia Hoellenriegel ◽

Carrie Sougnez ◽

Matthias Schlesner ◽

...

Keyword(s):

Signaling Pathway ◽

Copy Number ◽

Research Funding ◽

Progressive Disease ◽

Single Agent ◽

Disease Patient ◽

Genetic Alterations ◽

Bcr Signaling ◽

Trisomy 12 ◽

Pre Treatment

Abstract The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib thwarts B cell receptor (BCR) signaling via irreversible inhibition of BTK, and induces durable remissions in relapsed/refractory CLL with a progression-free survival rate of 75% after 26 months of therapy (Byrd JC et al., NEJM 2013). However, a small fraction of patients treated with this targeted therapy develop progressive disease after an initial response. Here, we describe a longitudinal genomic investigation, utilizing whole-exome sequencing (WES) and copy number information of 3 patients who, with daily exposure to ibrutinib, achieved partial remission and later experienced CLL progression, but not Richter’s transformation. All 3 patients had advanced stage CLL (Rai stage 3-4) and were enrolled on IRB-approved phase 1/2 trials of ibrutinib (420 mg) as a single agent (Patients 1 and 2) or combined with rituximab (Patient 3). Patients 1 and 3 had relapsed diseased after prior FCR frontline therapy, while Patient 2 had received 4 prior lines of therapy. At treatment initiation, Patients 1 and 2 had known acquired TP53 deletions. Patient 1 additionally had del(13q), and Patient 2 a subclone (11.5% by FISH) carrying trisomy 12 and del(13q). Patient 3 had complex cytogenetics which included del(11q). As the best response to ibrutinib-based therapy, all three experienced partial responses. Patient 1 demonstrated normalization of hematologic parameters but experienced persistent bone marrow disease. Patient 2 achieved a >10-fold reduction but persistently elevated absolute lymphocyte count, and resolution of anemia and thrombocytopenia. Patient 3 had resolution of anemia, thrombocytopenia, and splenomegaly. Progressive disease was observed at days 1022, 554 and 206 following ibrutinib initiation for Patients 1-3, respectively. DNA was extracted from CD19-purified CLL cells before ibrutinib therapy and at the time of disease progression. Matched germline and tumor DNA from 2 timepoints underwent WES (mean coverage depth 170X) and copy number analysis (by SNP 6.0 arrays). Somatic alterations were identified through comparison with germline DNA. To examine clonal populations, we measured the allelic fractions of somatic variants and integrated this information with local copy number and purity information to infer the fraction of cancer cells (CCF) affected by the mutation. Since ibrutinib targets BTK, we searched for resistance-conferring mutations in the BTK gene in the progressing leukemias, such as the previously described C481S BTK mutation in 4 of 13 patients with acquired resistance (Chang et al., ASCO 2013, Abstract 7014). We observed that all three patients lacked mutations in BTK and for the most part, in other genes in the BCR signaling pathway. In Patient 2, we did identify a single nucleotide variant in PLCg2, a substrate of BTK previously reported to be mutated in a patient with ibrutinub resistance. However, the CCF affected by this mutation was smaller than 0.15, and therefore it is unlikely to be the main driver of relapse in this patient. All three CLLs acquired new somatic mutations at the time of progression not observed in the pre-treatment samples, involving recurrent lesions in CLL associated with poor clinical outcome. Patient 1 acquired a new clonal (>0.95 CCF) mutation in SF3B1 (K666T). Patients 2 and 3 revealed clonal deletions in chromosome 8p. Patient 2 additionally demonstrated an increase in a subclone harboring trisomy 12 with an associated MLL2 missense substitution, with CCF rising from 0.12 pre-treatment to 0.5 upon relapse. Our results confirm that clinically evident ibrutinib resistance cannot be uniformly attributed to mutations in BTK or other genes of the BCR signaling pathway. In the 3 CLLs presented herein, progressive disease was associated with the emergence of leukemic populations harboring genetic alterations with putative driver characteristics (del(8p), SF3B1 mutation) arising from a background of pre-existing 17p or 11q deletions. Our findings support the concept that CLL clones persisting during continuous therapeutic pressure can adapt to bypass BTK-related survival signaling. Ongoing studies focus on finer kinetic analysis of clonal dynamics in these patients during the period leading up to progressive disease to elucidate whether these alterations were newly acquired following ibrutinib exposure or represent selective expansions of pre-existing small subclones. Disclosures: Burger: Pharmacyclics: Research Funding. O'Brien:Pharmacyclics: Research Funding. Neuberg:Synta Pharmaceuticals: Trust owns stock; I am a Trustee Other.

Download Full-text

IgM-Gammopathies Transformed into Aggressive Lymphoma: Incidence, Basal Clinical Features and Outcome of a Registry Based, Spanish Retrospective Series

Blood ◽

10.1182/blood-2019-123353 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4011-4011

Author(s):

Irene Dogliotti ◽

Cristina Jiménez ◽

Federica Cavallo ◽

Noemi Puig ◽

Gian Maria Zaccaria ◽

...

Keyword(s):

Flow Cytometry ◽

Board Of Directors ◽

B Lymphocytes ◽

Clinical Features ◽

Research Funding ◽

Initial Diagnosis ◽

Aggressive Lymphoma ◽

Advisory Committees ◽

Histological Transformation

Background Transformation into aggressive lymphoma (AL) is a rare complication of indolent lymphoproliferative disorders (LPDs) and is characterized by poor outcome. Immunoglobulin M (IgM) gammopathies are a spectrum of conditions, from monoclonal gammopathy of undetermined significance (MGUS) to Asymptomatic Waldenstroem Macroglobulinemia (AWM) and Symptomatic WM (SWM) that can eventually evolve to transformed WM (tWM). Actually, tWM represents a clinical challenge, mainly because of its poor characterization. Aims This registry study aims to better characterize tWM, focusing on prognostic factors heralding transformation to AL. Methods Two registries of IgM-MGUS, AWM and SWM [Owen, Semin Oncol 2003] based in Salamanca and in the region of Castilla and Leon (Spain) were investigated to identify cases with histological transformation. IgM-secreting patients with other LPDs (e.g. chronic lymphocytic leukemia, marginal zone lymphoma, IgM-multiple myeloma) were excluded from the analysis. All patients provided written informed consent in accordance to Helsinki's declaration. Statistical analysis was carried out using R v 3.3.3. tool; survival analyses were performed with Log-Rank method, while group comparison was performed with t-student for continuous variables and Chi-square tests for categorical variables. Results Data from 903 patients with IgM-secreting disorders diagnosed between 1976 and 2019 were analyzed; 587 cases with confirmed diagnosis of IgM-MGUS, AWM or SWM were selected. Out of 587 IgM-gammopathies, 22 cases with histological transformation to AL were identified. Cumulative incidence of tWM was: 1.4% at 5, 3.4% at 10 and 5.3% at 12 years, respectively (figure 1). Clinical features at first diagnosis of patients subsequently developing tWM where then analyzed: 3/22 tWM evolved from previous IgM-MGUS, while the remaining patients originally presented with AWM (6/22) or SWM (13/22). IPSS-WM prognostic score was LR for 5, IR for 12 and HR for 3/20 patients, respectively [Morel, Blood 2009]. Glancing on distributions between groups according to the outcome, tWM differed from not transformed (NT) cases for: lower median age at diagnosis (66 vs 72 years, p=0.018), lower platelets levels (median 188 vs 235 x 10^9/mmc, p=0.017), higher LDH ratio (0.8 vs 0.67, p=0.015), higher incidence of chromosome 6q deletion by FISH (40 vs 14%, p=0.021) and higher clonal B lymphocytes infiltration on marrow aspirate by flow cytometry (15 vs 4.5%, p= 0.022). Moreover, 13/22 patients received anti-WM treatment within 3 months from initial diagnosis, mainly chlorambucil-based; 5/22 patients received rituximab in first line and 13 in second line. From the whole series, after a median follow-up of 80 months, median transformation-free survival was 61 months from initial diagnosis (range: 0-228). Among these, Only 1/22 of tWM patient is still alive; 19/21 deaths were thus related to AL/WM, with a median survival after transformation of 12 months (0-53). In the whole series (n=587), median OS from initial diagnosis of IgM gammopathy was 76 months for the tWM group (6-225), that is shorter than the NT group (128 months, p=0.012, figure 2). Focusing only on patients treated at initial diagnosis, median survival after first treatment (SAFTI) was 62 vs 90 months for tWM vs NT (p=0.011, figure 3), and median time to next treatment was 28 vs 46 months, respectively (p=0.13). Overall, 10/22 tWM patients received ≥3 treatment lines, and median number of lines prior to transformation was 2 (0-3). Finally, in the whole series IPSS-WM score at diagnosis confirmed to impact on survival (median OS=151, 119 and 56 months for LR, IR and HR groups, respectively, p <0.001). However, this was not the case for tWM cases only, where OS was no longer different between groups. Conclusions In this retrospective study, we confirmed dismal outcome for tWM patients; incidence of transformation was comparable to expectations at 5 years, but higher at subsequent follow-up. At initial diagnosis of IgM gammopathy, younger age, low platelets level, high LDH ratio, high B lymphocytes infiltration by flow cytometry and presence of 6q deletion were significantly enriched among patients subsequently developing tWM. IPSS-WM score looked less predictive among tWM patients probably given to the limited numbers of tWM series. Novel prognostic tools are eagerly awaited for tWM patients. Figure Disclosures Cavallo: Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Puig:The Binding Site: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria. Ferrero:Gilead: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Speakers Bureau; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees. Boccadoro:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding.

Download Full-text

Prevalence, Predictive Factors Therapy and Outcome of Patients with Follicular Lymphoma Refractory to First Line Immunochemotherapy

Blood ◽

10.1182/blood.v126.23.1510.1510 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1510-1510 ◽

Cited By ~ 1

Author(s):

Marc Sorigue ◽

Juan-Manuel Sancho ◽

Santiago Mercadal ◽

Ruben Fernández-Álvarez ◽

Helena Pomares ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Follicular Lymphoma ◽

Research Funding ◽

Univariate Analysis ◽

High Serum ◽

Consolidation Therapy ◽

Second Line ◽

First Line ◽

Histological Transformation

Abstract Background: Follicular lymphoma (FL) is the most frequent indolent lymphoma and is characterized by a high response to immunochemotherapy (ICT). However, patients refractory to first-line ICT have a worse prognosis. The objective of this study was to determine the prevalence of refractory FL, the factors that predict refractoriness as well as the salvage treatment and outcome. Patients and methods: This is a retrospective analysis including stage II-IV FL patients treated with first-line ICT in 3 Spanish institutions. The cohort was divided into ICT-refractory patients (less than partial response after induction or maintenance/consolidation therapy, as well as relapse or progression within 6 months of the last dose of therapy) and ICT-sensitive. Baseline features, therapy received and outcome were analyzed. Results: 283 patients were included, the median age was 58 years-old (range 28 to 85) and 53% were female. 200/231 (87%) had a good performance status (ECOG < 2), 260/295 (88%) presented with stages III and IV and 163/284 (57%) had bone marrow involvement. High-risk FLIPI score was seen in 108/256 (42%), high serum LDH in 78/263 (28%) and high serum B2-microglobulin in 138/253 (54%). RCHOP was administered to 226 (80%), RCVP to 36 (13%) and rituximab in combination with fludarabine or bendamustine-based therapy to 21 (7%). Seventeen patients received consolidation with radioimmunotherapy and 140 received maintenance with rituximab (n=137) or interferon (n=3). Sixteen patients received complementary radiotherapy. Forty-three (16%) patients were ICT-refractory (37 within 6 months of the completion of induction and 6 during or within 6 months of the completion of maintenance/consolidation therapy). On univariate analysis, high-risk FLIPI (OR 5.4, [95% CI 2.3-12.6]), high-risk FLIPI2 (5.4, [2.4-12.4]), B symptoms (3.2, [1.6-6.6]), ECOG ≥ 2 (4.6, [2-10.9]), involvement of > 4 nodal regions (2.3, [1.02-5.3]), hepatomegaly (7.5, [2.6-21.5]), splenomegaly (2.8, [1.4-5.9]), high B2-microglobulin (4, [1.7-9.5]), high serum LDH (3.9, [1.8-8]) and treatment with RCVP (compared with RCHOP, 2.8, [1.2-6.2]) were correlated with refractoriness. On multivariate analysis, high-risk FLIPI score (4.9, [2.1-11.7]) and treatment with RCVP (3.4, [1.2-9.4]) were the only variables associated with refractoriness. After exclusion of FLIPI, ECOG ≥ 2 (3, [1.1-8.4]) and high serum LDH (4.7, [2-11]) were correlated with refractoriness, in addition to RCVP therapy (4.5, [1.5-13.2]). Ten-year OS probabilities in ICT-sensitive and ICT-refractory patients were 83% (95% CI 76%-90%) and 33% (12%-54%), respectively (p<0.001) (Figure 1). ICT-refractory patients were more likely to be also refractory to second-line therapies than ICT-sensitive patients (21/31 [68%] vs 10/58 [17%], p<0.001). In addition, histological transformation was suspected by clinical or biological features or confirmed by tissue biopsy in 11/43 ICT-refractory and 8/240 ICT-sensitive (p<0.0001). Death among ICT-refractory patients was more frequently due to lymphoma than in ICT-sensitive patients (19/23 [83%] vs 14/28 [50%], p=0.033). Conclusions: In this series of FL treated with first-line ICT, the prevalence of refractoriness was low and occurred most frequently during or within 6 months of induction rather than maintenance/consolidation therapy. FLIPI score and RCVP treatment (compared to RCHOP) were predictive of refractoriness. The response rate of ICT-refractory FL patients to second-line therapy is low and the prognosis is poor. Supported in part by RD12/0036/0029 del RTICC, Instituto Carlos III. Figure 1. Overall survival in immunochemotherapy (ICT)-sensitive and ICT-refractory patients (p<001) Figure 1. Overall survival in immunochemotherapy (ICT)-sensitive and ICT-refractory patients (p<001) Disclosures Sancho: CELLTRION, Inc.: Research Funding. Sureda:Seattle Genetics Inc.: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau.

Download Full-text

Genetic Alterations at Diagnosis Predict Outcome of AML Patients Age 60 or Older Undergoing Allogeneic Transplantation in First Remission

Blood ◽

10.1182/blood-2019-125967 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 48-48 ◽

Cited By ~ 1

Author(s):

H. Moses Murdock ◽

Haesook T. Kim ◽

Bryan Hambley ◽

Pankit Vachhani ◽

Nathan Denlinger ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Genetic Risk ◽

Research Funding ◽

Gene Mutations ◽

Genetic Alterations ◽

Advisory Committees ◽

Genetic Characteristics ◽

The Impact ◽

Advisory Role

Background: Older age is associated with inferior outcomes after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML). High risk genetic characteristics are common among older patients and linked to poor outcomes in the non-transplant setting. An enhanced understanding of genetic risk may thus provide a basis for improving transplant outcomes in these patients. We evaluated the impact of leukemia genetic characteristics at diagnosis on HSCT outcomes in a multi-center cohort of AML patients age 60 or older receiving HSCT in first complete remission (CR1). Methods: We performed targeted sequencing of 112 genes on diagnostic leukemia samples from 257 patients with AML age 60 or older who received allogeneic HSCT in CR1 at 5 US transplant centers. Median age at diagnosis and HSCT were 65 (range 59-76) and 66 (range 60-76), respectively. 31% had clinically defined secondary AML, 11% had therapy-related AML, and 23% had adverse cytogenetics by 2017 ELN classification. Most (84%) were treated with anthracycline-based induction chemotherapy, while 16% received non-intensive induction. Conditioning was either reduced-intensity or non-myeloablative in 94% of patients. Median follow-up for survivors was 3.7 years; 3-year overall survival (OS) and leukemia-free survival (LFS) were 48% and 44%, respectively. Results: All patients had recurrent genetic alterations at the time of diagnosis, including 251 (98%) with gene mutations and 6 with only cytogenetic abnormalities. The most frequent gene mutations were DNMT3A (25%), NPM1 (23%), FLT3-ITD (22%), ASXL1 (21%), TET2 (21%), RUNX1 (20%), and SRSF2 (18%). Secondary-type mutations associated with antecedent MDS occurred in 42%, and 10% had TP53 mutations. As expected, secondary-type and TP53 mutations were associated with clinically-defined secondary AML (p<0.001), need for reinduction (p=0.03), and CR with incomplete count recovery (p= 0.03). Despite the older age at leukemia diagnosis, putative germline pathogenic variants were identified in 22 (8.6%) patients, including 17 (6.6%) with DDX41 mutations (13/17 with somatic mutation of the second allele), and 5 with TERT or TERC variants not found in population databases. We evaluated the impact of gene mutations on LFS using univariable and multivariable Cox models and developed a hierarchical model of 3 molecular genetic risk groups according to the hazard ratios (Fig 1A): (1) patients with TP53 mutation or JAK2 mutation or FLT3-ITD/NPM1-WT (high risk), (2) patients without high risk mutations who have DNMT3A or GATA2 or DDX41 mutations (low risk) (3) patients without high- or low-risk mutations (intermediate risk), with 3-year LFS of 8%, 65%, and 47% (p<0.001), respectively. Next, we combined molecular genetic and cytogenetic risk to derive a final genetic model comprised of 4 groups with distinct 3-year LFS (69%, 50%, 27%, and 0%) (Fig 1B). Poor LFS in the very high-risk group was due almost entirely to relapse (3-year relapse rate > 90%), but was driven by a combination of relapse and non-relapse mortality in the intermediate and high-risk groups (Fig 2). Conclusion: Genetic characteristics at diagnosis are highly associated with OS and LFS in AML patients age 60 or older who undergo allogeneic transplantation in CR1. We identify patients with low genetic risk and remarkably good outcomes who may be candidates for strategies aimed at reducing toxicity, and those with very high-risk genetics who have limited benefit from current transplant approaches. Among intermediate and high-risk patients, the impact of disease genetics on LFS is mostly due to relapse, suggesting that a model incorporating measurement of residual disease in CR1 and after transplantation could enable a more dynamic estimation of risk. Disclosures Perales: Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding. Koreth:Equillium: Consultancy; Amgen: Consultancy; Cugene: Consultancy. Ho:Jazz Pharmaceuticals: Consultancy. Soiffer:Mana therapeutic: Consultancy; Kiadis: Other: supervisory board; Juno, kiadis: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Gilead, Mana therapeutic, Cugene, Jazz: Consultancy; Jazz: Consultancy; Cugene: Consultancy. Carroll:Astellas Pharmaceuticals: Research Funding; Incyte: Research Funding; Janssen Pharmaceuticals: Consultancy. Vasu:Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: Clinical trial support. Wang:Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Lindsley:Jazz Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy; Medlmmune: Research Funding.

Download Full-text

Lenalidomide Consolidation Added to Rituximab Maintenance Therapy in Patients Remaining PET Positive after Treatment for Relapsed Follicular Lymphoma: Phase 2 Australasian Leukaemia & Lymphoma Group NHL26 Study

Blood ◽

10.1182/blood-2021-146343 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2428-2428

Author(s):

Judith Trotman ◽

Peter Presgrave ◽

Duncan P. Carradice ◽

Douglas Stuart Lenton ◽

Maher Gandhi ◽

...

Keyword(s):

Follicular Lymphoma ◽

Primary Endpoint ◽

Conversion Rate ◽

Research Funding ◽

Type I ◽

Phase 2 ◽

Multicentre Phase ◽

Rituximab Maintenance ◽

Conversion Rates ◽

Histological Transformation

Abstract Introduction The combination of rituximab & lenalidomide (R 2) is an established regimen for treatment of follicular lymphoma (FL), with efficacy reported in the first line and relapsed setting (Morchhauser NEJM 2018, Leonard JCO 2019). The inferior OS of patients who remain post-induction PET-CT positive (PET+ve) has also been demonstrated in both settings (Trotman Lancet Haem 2014, Lancet Oncol 2018, Ysebaert, ASH 2011). We sought to study the effect of R 2 in relapsed FL by examining its ability to convert to PET-negative (PET-ve) those patients who remain PET+ve after reinduction rituximab-chemotherapy. Methods This was a prospective, multicentre, Phase 2 study of patients with bulky Stage II, or Stage III-IV relapsed FL. Eligibility criteria were: at least stable disease on CT within 4-6 weeks of last cycle of re-induction rituximab-chemotherapy; ECOG ≤2; CrCL ³30mL/min; haemoglobin >80g/L, neutrophils >1.0 & platelets >75 x 10 9/L. Exclusion criteria were: histological transformation ≤12 months (mo); any interim-PET that was negative, and other malignancy ≤5 years. After enrolment pts underwent a centrally-reviewed PET within 8 weeks of D1 last cycle of re-induction rituximab-chemotherapy. Given the higher probability of further progression in the relapsed setting PET+ve was defined as a Deauville score (DS) 3-5. PET-ve patients were assigned rituximab maintenance q2mo for 2 years, and those remaining PET+ve were assigned R 2 to commence within 12 weeks. Lenalidomide schedule for R 2 pts was 10mg/d x 21 q28d, with dose modifications for tolerance, over a planned 2 years. Repeat PET scans were scheduled at 6 & 12 mo after starting R 2. The primary endpoint was the rate of conversion from postinduction PET+ve to PET-ve in evaluable patients 6 mo after commencing lenalidomide. Evaluable patients were defined as those receiving >63 days of Lenalidomide. Sample size calculations used a one-sided exact test for proportions, assuming a conversion rate of ³50% as worthy of further evaluation and ≤20% as unacceptable. Thus 16 evaluable patients were required to have 80% power with type I error of 5%. Secondary endpoints were PET conversion rates by baseline DS in the PET+ve, the toxicity & deliverability of R 2, and PFS & OS in both the PET+ve & PET-ve populations. Results Thirty-seven patients (pts) were recruited from Nov 2013 to Jan 2021 when the study was closed due to poor recruitment attributed to competing studies. Median (med) age was 67yrs (36-83); 58% male, med 2 (range 2-11) prior therapies incl. the recent rituximab-chemotherapy; FLIPI low risk (21%), intermediate risk (12%) high risk (67%). Eighteen of 37 (48.6%) pts were postinduction PET+ve. Med follow-up was 38 mo (0.8 - 76.4): 32 mo (0.8 - 76.4) in PET+ve and 42 mo (6.7 - 73.8) in PET-neg. Of the 18 PET+ve pts one was ineligible for R 2 due to reactivation of hepatitis B; 3 were not evaluable having not received >63 doses of lenalidomide due to progressive disease (PD). Thus 14/18 (78%) PET+ve pts were evaluable, of whom 5/14 (36%; 95% CI 11% - 61%) became PET-ve at 6-mo, thus not excluding a PET conversion rate of <20%, (p=0.14). If we had obtained full recruitment both additional pts would have had to convert to PET-neg to meet the primary endpoint. PET conversion occurred in 4/6 evaluable pts with DS 3 and 1/8 with DS 5. PD occurred in 14 pts: 11/17 PET+ve and 3/19 PET-ve. Med PFS was 30.8 mo (5.7-37.6) in the PET+ve and NR (95% CI 42.3-NR) in the PET-ve, p = 0.0001. Death occurred in 11/37 (30%): 7 from lymphoma (5 PET+ve), 1 other malignancy, 2 pneumonia, 1 aspergillosis. Med OS was 68.1 mo (9.6 - NR) in PET+ve and NR (95% CI 42.3 - NR) in PET-ve (p 0.059). Of the 17 PET+ve pts starting lenalidomide, deliverability was limited by both disease progression and AEs: 3 failed to receive 3 cycles, 6 pts received 4-6, and 8 pts 7-24 cycles. Mean number of lenalidomide doses was 213 (SD 188). At least one AE was reported in 16/17 (94%), most commonly neutropenia (n=10, 59%, Gd4 24%). At least one SAE occurred in 9/17 (53%): infections 2, malignancy 2, cardiac disorders 2, musculoskeletal 2, other causes 3 pts. Conclusion The high PET+ve rate of 49% (DS 3-5) after rituximab-chemotherapy for relapsed FL suggests the need for consolidation therapy. However, R 2 did not achieve a sufficiently high PET-conversion rate to justify further study. The inferior outcome of patients who remain PET+ve after treatment of relapse highlights the importance of investigating novel approaches in this setting. Figure 1 Figure 1. Disclosures Trotman: TAKEDA: Research Funding; beigene: Research Funding; roche: Research Funding; BMS: Research Funding; PCYC: Research Funding; JANSSEN: Research Funding. Gandhi: janssen: Research Funding; novartis: Honoraria. Butcher: WriteSource: Current Employment, Other: Medical writing for Pharma companies. Not pertinent to this abstract for which author is study Statisticiam.

Download Full-text

Divergent Modes of Tumor Evolution Underlie Histological Transformation and Early Progression of Follicular Lymphoma

Blood ◽

10.1182/blood.v128.22.1091.1091 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1091-1091

Author(s):

Fong Chun Chan ◽

Robert Kridel ◽

Anja Mottok ◽

Merrill Boyle ◽

Pedro Farinha ◽

...

Keyword(s):

Treatment Failure ◽

Genetic Drift ◽

Early Treatment ◽

Research Funding ◽

Tumor Evolution ◽

Clinical Events ◽

Mutational Burden ◽

Histological Transformation ◽

Early Progression ◽

Evolution Modeling

Abstract Introduction: Follicular lymphoma (FL) remains a significant clinical burden as it is an incurable disease and most patients will eventually suffer from disease progression. Two clinical events are associated with poor outcomes for patients with FL: (1) histological transformation (TFL) of their original FL into a high-grade, aggressive lymphoma subtype (2-3% of patients per year) and (2) early disease progression (PFL) where patients experience treatment failure within 2 years of receiving therapy (20% of patients). Despite recent high-throughput sequencing studies, the nature of tumor clonal dynamics leading to TFL or PFL is poorly understood and it is unknown if similar, or contrasting, modes of selection underpin these FL clinical events. Materials & Methods:We assembled a study cohort consisting of 21 patients: 15 experiencing TFL and 6 PFL. For each TFL and PFL patient, we obtained primary biopsies (T1; taken at the time of the initial FL diagnosis), biopsies at transformation/progression (T2) and matched normal samples. We performed whole genome sequencing on each specimen and identified single point mutations and copy number alterations using MutationSeq and TITAN, respectively. We compared T1 to T2 somatic mutation profiles and identified mutations associated with extinction of T1 clones and expansion of T2 clones. To validate these patterns, we selected 192 positions from each patient for deep-targeted sequencing validation (~10733X) in their T1, T2, and normal samples. We applied a statistical model (PyClone) to estimate cancer cell fraction (CCF) of each validated mutation. These CCF estimates were used to construct clonal phylogenies (Citup) and infer clonal dynamic patterns during their evolutionary histories. The Wright-Fisher model of genetic drift was used to model tumor evolution. Results: Temporal analysis of mutational burden revealed that mutational burden was significantly higher in T2 (8162 mutations ± 2146) than in T1 (6373 ± 2630) tumors for both TFL and PFL patients (Wilcox P < 0.001). This was independent of time interval between sampling (Spearman R2 = 0.029, P = 0.456). Mutation variant allelic fraction (VAF) distributions revealed that all distributions showed evidence of shared clonal ancestry between T1 and T2 tumors accompanied by substantial numbers of T1 and T2-specific mutations. We selected ≥ 192 mutations per patient from these distributions and performed deep-targeted amplicon sequencing, validating 96.3% of mutations and acquiring precise VAFs to infer clonal dynamics. In 13 of 15 TFL patients (87%), we observed dramatic clonal dynamics, characteristic of T2 tumors dominated by clones (or phylogenetic lineages) that were absent or extremely rare in T1 tumors (< 1% CCF). Digital droplet PCR was used to confirm the existence of both scenarios (confirming a clone as rare as 2 out of approximately 105 cells). Tumor evolution modeling demonstrated that this mode of evolution was driven through positive selection for mutations that confer fitness advantages and not by genetic drift. In contrast, PFL patients exhibited markedly different patterns of clonal dynamics compared to TFL patients. 4 of 6 PFL patients (67%) harbored readily detectable clones at T1, which expanded to full clonal prevalence during treatment with immuno-chemotherapy. Tumor evolution modeling demonstrated that this mode of evolution could be explained under neutral evolutionary dynamics (drift). Conclusions: We have shown that histological transformation and early progression manifest through divergent modes of tumor evolution. As the transformation phenotype may arise after diagnosis, more frequent monitoring of these patients will be required to determine the exact timing of the evolutionary inflection point that elicits transformation. In comparison, prediction of early treatment resistance should be achievable through comprehensive characterization of the genetic and clonal composition at diagnosis; this would ultimately identify patients who may benefit from upfront alternative therapies without the need to first endure predictable early treatment failure. Disclosures Sehn: roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria. Connors:Millennium Takeda: Research Funding; Seattle Genetics: Research Funding; F Hoffmann-La Roche: Research Funding; Bristol Myers Squib: Research Funding; NanoString Technologies: Research Funding. Scott:Janssen: Consultancy; Celgene: Consultancy; Roche: Honoraria; BC Cancer Agency: Patents & Royalties: Inventor on a patent licensed to NanoString Technologies.

Download Full-text

Exome Sequencing of Relapsed Multiple Myeloma Combined with Pooled CRISPR/Cas9 Screens Identifies Gene Mutations Associated with Drug-Specific Resistance

Blood ◽

10.1182/blood-2019-131245 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 809-809

Author(s):

Stephan Bohl ◽

Laura K. Schmalbrock ◽

Imke Bauhuf ◽

Anna Dolnik ◽

Tamara J. Blätte ◽

...

Keyword(s):

Multiple Myeloma ◽

Exome Sequencing ◽

Cell Lines ◽

Research Funding ◽

Specific Resistance ◽

Gene Mutations ◽

Genetic Alterations ◽

Recurrent Mutations ◽

Pre Treatment ◽

Increased Susceptibility

Lenalidomide, bortezomib, melphalan and dexamethasone are standard drugs for the treatment of multiple myeloma (MM). Although many patients initially respond to treatment regimens including these drugs, the majority ultimately relapses due to the development of resistance of the MM cells, what may result from acquired genetic alterations. Here we performed fluorescence in situ hybridization (FISH) and whole exome sequencing (WES) on 16 paired pre-treatment/ progression MM samples followed by functional validation through CRISPR/Cas9-based screens to identify gene mutations that are associated with resistance. Treatment between two samples consisted of lenalidomide (n=16), bortezomib (n=14), dexamethasone (n=16) and melphalan (n=9). Cytogenetic analyses by FISH revealed that the majority of translocations (7 of 10) and chromosomal gains and deletions (22 of 28) were concordant between pre-treatment and relapse samples. In contrast, gene mutations assessed by WES were highly variable: of the total of 794 identified mutations 6% (n=46) were present only at diagnosis, 59% (n=474) at both time points and 35% (n=274) specifically at relapse with an increase of the median number of mutations from 29 (range 9-103) in pre-treatment to 47 (range 13-110) in progression samples (figure 1A). Recurrent mutations detected pretreatment were in general stable at progression: NRAS (3/3), KRAS (4/4), IGLL5 (3/3) and DIS3 (2/3). Only very few of the newly acquired gene mutations at progression were recurrent: TP53 (n=4), DNAH5 (n=4) and WSCD2 (n=3) while the remaining were non-recurrent. In order to investigate the functional impact of relapse-specific gene mutations on drug resistance we performed pooled CRISPR-Cas9-based knockout screens (figure 1B). We included 160 gene mutations that fulfilled the following criteria: 1) a variant allele fraction (VAF) of >20% at the time of progression, 2) found exclusively in progression samples or had a more than 2-fold increase in VAF at progression as compared to pre-treatment, 3) predicted to be loss-of-function. In addition, we included genes found recurrently mutated in relapsed MM in previously published studies. Resistance screens were performed in three different MM cell lines (MM1S, NCIH-929, KMS27) with 4 sgRNA per gene in the presence of lenalidomide, dexamethasone, melphalan, bortezomib or DMSO as a control. None of the sgRNAs included in the screen conferred resistance to all four drugs. In contrast, we identified several genes whose inactivation caused resistance to a specific drug. For lenalidomide, the top hits were members of the CRBN-CRL4 E3 ubiquitin ligase, the primary target of IMiDs, including CRBN, CUL4B and DDB1. CRISPR-mediated inactivation of these genes was specifically associated with lenalidomide resistance since sensitivity towards other drugs was not affected. In addition, we found sgRNAs targeting SYT5, a membrane protein involved in Ca2+-dependent exocytosis, to be enriched in lenalidomide-treated cells that so far has not been related to lenalidomide resistance. SgRNAs targeting TP53 were also weakly enriched after lenalidomide treatment in two of the three cell lines but conferred a high level of resistance to melphalan in all three cell lines (figure 1C). Consistently, three of the four TP53 mutations identified by WES were detected in samples obtained after cytotoxic chemotherapy and one after 3 years of treatment with lenalidomide/dexamethasone. Our screens also revealed an increased susceptibility to melphalan by inactivation of ATM, FANCA, BIRC3, and BRCC3, all involved in DNA damage repair. The top sgRNAs causing resistance to dexamethasone were directed against ANKMY2 and BIRC3 in two cell lines (MM1S and NCI-H929). For bortezomib, inactivation of only one gene, TMC2, encoding a transmembrane protein was associated with resistance in two cell lines whereas BIRC3 inactivation provided increased susceptibility to bortezomib. In conclusion, by combination of comprehensive genetic analyses of tumor samples before and after treatment with functional genetic screens we found mutations that are causally linked with drug-specific resistance and sensitivity. These results may help to personalize therapy in patients with multiple myeloma. Figure 1 Disclosures Bohl: Pfizer: Honoraria. Döhner:Celgene, Novartis, Sunesis: Honoraria, Research Funding; AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria; AROG, Bristol Myers Squibb, Pfizer: Research Funding. Bullinger:Astellas: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Daiichi Sankyo: Honoraria; Gilead: Honoraria; Hexal: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria; Menarini: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Seattle Genetics: Honoraria; Bayer: Other: Financing of scientific research; Abbvie: Honoraria; Amgen: Honoraria. Krönke:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Download Full-text

Follicular lymphoma t(14;18)-negative is genetically a heterogeneous disease

Blood Advances ◽

10.1182/bloodadvances.2020002944 ◽

2020 ◽

Vol 4 (22) ◽

pp. 5652-5665

Author(s):

Dominik Nann ◽

Joan Enric Ramis-Zaldivar ◽

Inga Müller ◽

Blanca Gonzalez-Farre ◽

Janine Schmidt ◽

...

Keyword(s):

Follicular Lymphoma ◽

Growth Pattern ◽

Marginal Zone ◽

Gene Mutations ◽

Genetic Alterations ◽

Molecular Clusters ◽

Diffuse Growth ◽

Frequent Mutations ◽

Nodal Marginal Zone Lymphoma ◽

Cd23 Expression

Abstract Fifty-five cases of t(14;18)− follicular lymphoma (FL) were genetically characterized by targeted sequencing and copy number (CN) arrays. t(14;18)− FL predominated in women (M/F 1:2); patients often presented during early clinical stages (71%), and had excellent prognoses. Overall, t(14;18)− FL displayed CN alterations (CNAs) and gene mutations carried by conventional t(14;18)+ FL (cFL), but with different frequencies. The most frequently mutated gene was STAT6 (57%) followed by CREBBP (49%), TNFRSF14 (39%), and KMT2D (27%). t(14;18)− FL showed significantly more STAT6 mutations and lacked MYD88, NOTCH2, MEF2B, and MAP2K1 mutations compared with cFL, nodal marginal zone lymphoma (NMZL), and pediatric-type FL (PTFL). We identified 2 molecular clusters. Cluster A was characterized by TNFRSF14 mutations/1p36 alterations (96%) and frequent mutations in epigenetic regulators, with recurrent loss of 6q21-24 sharing many features with cFL. Cluster B showed few genetic alterations; however, a subgroup with STAT6 mutations concurrent with CREBBP mutations/16p alterations without TNFRSF14 and EZH2 mutations was noted (65%). These 2 molecular clusters did not distinguish cases by inguinal localization, growth pattern, or presence of STAT6 mutations. BCL6 rearrangements were demonstrated in 10 of 45 (22%) cases and did not cluster together. Cases with predominantly inguinal presentation (20 of 50; 40%) had a higher frequency of diffuse growth pattern, STAT6 mutations, CD23 expression, and a lower number of CNAs, in comparison with noninguinal cases (5.1 vs 9.1 alterations per case; P < .05). STAT6 mutations showed a positive correlation with CD23 expression (P < .001). In summary, t(14;18)− FL is genetically a heterogeneous disorder with features that differ from cFL, NMZL, and PTFL.

Download Full-text

Risk of Histological Transformation in Patients with Primary Refractory Follicular Lymphoma

Blood ◽

10.1182/blood-2018-99-115956 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4145-4145

Author(s):

Sara Alonso ◽

Martina Manni ◽

Clementine Sarkozy ◽

Marielle Wondergem ◽

Attilio Guarini ◽

...

Keyword(s):

Follicular Lymphoma ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Advisory Board ◽

Critical Event ◽

P Value ◽

Advisory Committees ◽

Increased Risk ◽

Histological Transformation

Abstract INTRODUCTION There is a growing interest in analyzing the biological and clinical variables that might help in identifying patients at risk of histological transformation (HT), a critical event that can still lead to reduced survival in patients with follicular lymphoma (FL). As part of the Aristotle study, we have previously reported that the risk of HT as a first event has been significantly reduced by the use of rituximab (Federico et al, Lancet Hematology 2018). However, this incidence might still be unacceptable in some groups of patients. Thus, we investigated the risk of HT in patients with primary refractory FL, a subset of patients with poor prognosis. METHODS We carried out a retrospective analysis of cumulative incidence of HT in the 289 cases with primary refractory FL retrieved from the Aristotle Study, which included a total of 6970 FL cases (grade 1, 2 or 3a), diagnosed between 1997 and 2013 and treated with systemic therapy. Refractoriness was defined as progressive disease (PD) within the end of first-line therapy. Patients with PD were compared to patients with partial response (PR) or stable disease (SD) and to patients with complete response (CR) at the end of therapy. The cumulative incidence of HT was calculated using the Nelson-Aalen estimator, with a 95 confidence interval (CI). The estimate is in absolute value, and then multiplied by 100. The overall survival (OS) and survival after relapse/progression (SAR) were calculated using Kaplan-Meier estimation, with a 95% CI. RESULTS Six hundred and twenty-eight cases (9%) were excluded for incomplete data and 6,339 were considered for analysis. The five-year cumulative incidence of HT among patients with PD was 34.2% (95% CI: 26.9-43.4), whilst it was 7.1% (95% CI: 6.0-8.5) and 3.5% (95% CI: 3.0-4.2) in the 1,954 and 4,096 patients with PR+SD and CR at the end of induction therapy, respectively. The rate observed in PD group had a Hazard Ratio (HR) of 11.4 (95CI: 8.61-15.0) compared with CR patients, and 6.14 (95% CI: 4.6-8.2), when compared with PR+SD patients. All comparisons and estimations showed a p-value below 0.001. Cumulative incidences of HT according to response to initial therapy are represented in Figure 1. The five-year SAR was 33% (95% CI: 28-39) for the PD group, with a median SAR of 1.1 year (95% CI: 0.8-1.8). At the same time point, the SAR was 56% (95% CI: 53-60) in patients with initial PR/SD, with a median SAR of 6.3 years (95% CI: 5.7-8.6). Finally, in patients with initial CR who later relapsed, the 5 year SAR was 63% (95% CI: 66-72), with a median of 10.4 years (95% CI: 10-12.2). The difference among groups was statistically significant (p-value <0.001, Figure 2). HR for PD group was 3.39 (95% CI: 2.87-4.01) compared to CR, and 2.12 (95% CI: 1.8-2.5) compared to PR/SD group. CONCLUSIONS According to the results of the present study, primary refractory FL patients have not only an already known reduced SAR (Casulo et al, JCO 2015), but also a dramatically increased risk of HT, which probably contributes to patients' adverse outcome. These findings reinforce the need to develop combined diagnostic and therapeutic strategies aimed to eradicate the disease at the "first shot", reducing the risk of refractoriness and eventually further improving the outcome of FL patients. Disclosures Sarkozy: ROCHE: Consultancy. Wondergem:NOVARTIS: Other: advisory board, educational talk; SANOFI: Other: advisory board; GILEAD: Other: educational talk. Chamuleau:Genmab: Research Funding; BMS: Research Funding; celgene: Research Funding; Gilead: Research Funding. Gomes da Silva:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Institution's payment for consultancy, Travelling support; Celgene: Other: Travelling support; Roche: Other: Institution's payment for consultancy, Travelling support; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Research Funding. Holte:Roche, Norway: Research Funding; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Zucca:CELGENE: Other: Grant to the Institution + Advisory Board; Janssen: Other: Grant to the Institution; ROCHE: Other: Grant to the Institution + Advisory Board; Celltrion Healthcare + Mei Pharma + Astra Zeneca: Other: Advisory Board; AbbVie + Gilead: Other: Travel Expenses; Gilead + Bristol-Myers Squibb + MDS: Other: Expert Statement + Meetings. Aurer:Roche: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Marcheselli:Fondazione Italiana Linfomi (FIL) Onlus: Employment. Salles:Novartis: Consultancy, Honoraria; Acerta: Honoraria; Abbvie: Honoraria; Morphosys: Honoraria; Epizyme: Honoraria; Amgen: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Other: Advisory Board, Research Funding; Pfizer: Honoraria; Gilead: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Merck: Honoraria; Servier: Honoraria, Other: Advisory Board; Takeda: Honoraria; BMS: Honoraria, Other: Advisory Board; Servier: Honoraria.

Download Full-text