Clinical Features and Treatment Outcomes of Large Granular Lymphocytic Leukemia Coexisting with Autoimmune Diseases

Abstract Introduction: Large granular lymphocytic leukemia (LGLL) is a rare, indolent malignancy arising from cytotoxic T cells (T-LGLL, ~85%) or NK cells [chronic NK-cell lymphoproliferative disorder (CLPD-NK), ~15%]. When treatment is needed, single-agent immunosuppressive therapeutics are usually used, including low-doses of methotrexate (MTX), cyclophosphamide (Cy), and cyclosporine A (CSA). The coexistence of LGLL with autoimmune diseases (ADs) especially rheumatoid arthritis (RA) and Felty Syndrome (FS) has been reported in some patients (pts), suggesting a role of initial strong antigenic stimuli from autoantigens in the pathogenesis of LGLL. However, it remains unclear whether AD-associated LGLLs have unique clinical features or treatment outcomes. We have recently published the largest retrospective study of 319 LGLL cases (Dong et al. 2021). Here we report the outcomes of the LGLL pts with coexisting ADs. Methods: All patients who presented to Moffitt Cancer Center from 2001 to 2020 with a diagnosis of coexistence of T-LGLL or CLPD-NK and AD were included. Diagnostic criteria, treatment and response evaluation were reported elsewhere (Dong et al. 2021). Comparison of response rates was performed using Fisher's exact test or Chi-square test when appropriate. Median survival was estimated using Kaplan-Meier method and compared with log-rank test. Multivariate analysis was not done due to limitation of sample size. All analyses were done using SAS 9.4. Results: The patient characteristics are listed in Table 1. Among the 83 pts, 77 (92.8%) had T-LGLL and 6 (7.2%) had CLPD-NK. The most common ADs were RA [38 (45.8%)], followed by FS 13 (15.7%), and inflammatory bowel disease, polymyalgia rheumatica and vasculitis [5 (6%) each]. 33 (39.8%) pts needed treatment for LGLL. Three of the 5 pts who underwent NGS testing were positive for STAT3 mutation. In our practice, we favor MTX as the frontline therapy for LGLL with coexisting ADs such as RA. The treatments and responses are presented in Table 2. Among the 29 pts who received MTX, 24 (82.8%) had response, including 6 (20.7%) complete response (CR). Among the 11 pts treated with Cy, 9 (81.8%) had response and 5 (45.5%) had CR. CSA was used in 6 pts and had response in 3 (50.0%) and CR in 2 (33.3%). The response rates were not different between MTX, Cy and CSA, neither were the CR rates, although the statistical testing was limited by sample size. Consistent with our previous findings in LGLL, the response to growth factor (GCSF) was low and only 1 of 4 pts responded. Compared to the 131 LGLL pts without co-existing AD in our series, AD-associated LGLL had higher response rates to MTX, Cy or CSA (61.9% vs 78.3%, respectively, p=0.04). Interestingly, pts with CLPD-NK were less likely to respond to CSA, MTX or Cy compared to pts with T-LGLL [1/5 (20%) vs 35/41 (85.4%), p=0.006]. The type of AD, age, splenomegaly, anemia, neutropenia, thrombocytopenia or STAT3 mutation were not associated with response. With a median follow-up of 5.2 (IQR 2.0-9.5) years, the median survival was 10.9 (95% CI 8.1-not estimable) years. Anemia and thrombocytopenia were associated with worse survival (figures 1 and 2). The median survival for pts with vs without anemia was 8.1 (95% CI 3.9-not estimable) years vs not estimable (95% CI 8.7-not estimable), p=0.01. The median survival for pts with vs without thrombocytopenia was 8.4 (95% CI 3.8-10.1) years vs 13.3 (95% CI 8.1-not estimable) years, p=0.05. The type of LGLL, blood LGL count, splenomegaly, or neutropenia were not associated with survival. Conclusions: The majority (~80 %) of LGLL pts with AD responded to MTX, Cy or CSA, although CR rate was low (20-45%). Interestingly, CLPD-NK pts were less likely to respond compared to T-LGLL which could be attributed to a small sample size and warrants an expanded case study. Anemia and thrombocytopenia were associated with worse survival. Future studies will be of interest to evaluate the hematological responses of LGLL in patients with coexisting ADs treated with FDA-approved biological agents for AD such as TNF inhibitors, IL-6 antagonists and T-Cell co-stimulation blocker. Such studies may provide insights into LGLL treatment as both diseases may share some common pathogenic pathways. Figure 1 Figure 1. Disclosures Sokol: Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; Dren Bio: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Rituximab and alemtuzumab have not been approved by FDA for LGL leukemia.

Download Full-text

Large Granular Lymphocytic Leukemia with Coexisting Malignancies

Blood ◽

10.1182/blood-2020-136796 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 10-11

Author(s):

Ning Dong ◽

Leidy Isenalumhe ◽

Yumeng Zhang ◽

Franco Castillo Tokumori ◽

Todd C. Knepper ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Solid Tumors ◽

Clinical Features ◽

Nk Cell ◽

Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Exact Test ◽

Treatment Responses

Introduction: Large granular lymphocytic leukemia (LGLL) is a rare, indolent malignancy arising from cytotoxic T cells (~85%) or NK cells (~15%). The coexistence of LGLL with MDS, B cell neoplasms and plasma cell dyscrasias have been reported in case reports and two retrospective studies (Gayal et al 2018, Viny et al 2008). However, those studies were limited by sample size and a small number of coexisting malignancies. To our knowledge, there is no systematic study on coexisting solid tumors with LGLL in the literature. In present study, we systemically analyzed the coexisting malignancies (CMs) including solid tumors and hematological malignancies (liquid tumors) in our LGLL patients (pts). We compared the clinical features, immunophenotype, treatment responses and estimated outcomes of CM-associated LGLL and non-CM associated LGLL pts. Methods: Total 303 consecutive LGLL pts evaluated at Moffitt Cancer Center (MCC) between 2001 and 2017 were included in the study. Pts who did not meet the WHO diagnostic criteria of peripheral blood (PB) LGL count ≧ 2.0 k/μL but presented with persistent LGL clonal populations along with characteristic immunophenotype, matching clinical features and bone marrow involvement with clonal LGL population were considered to have LGLL. Results: Among the total 303 LGLL patients, 123 (40.6%) had at least 1 CM. The maximum number of coexisting malignancies were 3. 114 pts (37.6%) had invasive cancers (excluding non-melanomatous skin cancer), 83 (27.1%) had solid tumors and 60 (19.8%) had liquid tumors. The most frequent invasive solid tumors in our LGLL patients were: prostate cancer, breast cancer, lung cancer, colorectal cancer, and melanoma. The most frequent liquid tumors were: B-cell lymphoma, T-cell lymphoma, CLL/SLL, CML and MM (Table 1). The number of patients with CM diagnosed before, at the same time and after LGLL diagnosis were 103, 7, and 28, respectively. Table 2 compared the clinical features of LGLL pts with CM to those without CM separated into liquid and solid tumors. Compared to pts without CM, LGLL patients with liquid tumors were older, less likely to have B symptoms (49.2% vs 73.6%, respectively), less likely to be neutropenic (32.1% vs 53.4%), less likely to be pRBC transfusion dependent (7.3% vs 24.5%), and less likely to require treatment (33.3% vs 61.1%). LGLL pts with solid tumors compared to those without CM were older, more likely to be Caucasians, more likely to have NK-cell LGLL (13.3% vs 6.1%), and less likely to have B symptoms (59.5% vs 73.6%). NGS testing was performed in 25 patients. Activating STAT3 mutations were detected in 9/21 patients without CM and 1/4 patients with CM (p=0.63 by Fisher's exact test). None of tested pts demonstrated STAT5B mutation. An extensive 10-color flow cytometry panel was employed after year 2015 in 34 pts. The immunophenotype was similar between CM-associated T-LGLLs and non-CM associated T-LGLLs except that CM-associated T-LGLL pts were more likely to be CD56+ (6/11 vs 3/23, p=0.03 by Fish's exact test). CM-associated LGLLs and non-CM associated LGLLs had comparable response rates to treatments (Table 3). The median follow-up time for all patient population was 4.8 years. Pts with CM had worse overall survival (OS) (Figure 1). The survival difference was significant after adjusting for age, gender and race (data not shown). Conclusions: In the present study of 303 consecutive LGLL pts, 40.6% had CM, including 27.4% with solid tumors and 19.8% with liquid tumors. CM-associated LGLLs had similar clinical and pathologic features and treatment responses as non-CM associated LGLLs, except that LGLL pts with CM were less likely to be symptomatic and less likely required treatment. Earlier detection of LGLL in pts with liquid tumors may have contributed to those differences. Interestingly, T-cell LGLLs with CM were more likely to be CD56 positive and LGLLs associated with solid tumors were more likely to be derived from NK-cell lineage. The high incidence of CMs in LGLL can be explained by the following hypotheses: 1) CM provided an initial antigenic stimulus and contributed to the pathogenesis of LGLL or alternatively, 2) host immunosuppression due to clonal LGLL proliferation promoted development of CM. The findings in this study that a majority of CMs manifested prior to LGLL diagnosis favor the first hypothesis. Our results provide additional insights into the pathogenesis of LGLL. Disclosures Komrokji: BMS: Honoraria, Speakers Bureau; Agios: Speakers Bureau; Novartis: Honoraria; Acceleron: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Geron: Honoraria; Jazz: Honoraria, Speakers Bureau. Sokol:EUSA Pharma: Consultancy, Honoraria, Speakers Bureau; Kyowa/Kirin Inc.: Membership on an entity's Board of Directors or advisory committees; Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Systematic STAT3 Mutation Testing Identifies Patients with Unsuspected T-Cell Large Granular Lymphocytic Leukemia

Blood ◽

10.1182/blood.v128.22.919.919 ◽

2016 ◽

Vol 128 (22) ◽

pp. 919-919

Author(s):

Elizabeth A. Morgan ◽

Mark N. Lee ◽

Daniel J. DeAngelo ◽

David P. Steensma ◽

Richard M. Stone ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Peripheral Blood ◽

Hematologic Malignancies ◽

Sh2 Domain ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Stat3 Mutation ◽

Stat3 Mutations

Abstract The initial clinical presentation of T-cell large granular lymphocytic leukemia (T-LGL) and myelodysplastic syndromes (MDS) can be similar, each characterized by unexplained peripheral cytopenias. However, these diseases are pathobiologically distinct and associated with stark differences in prognosis and therapy. T-LGL is a clonal lymphoid disorder defined by phenotypically abnormal cytotoxic T cells and an indolent clinical course, while MDS is a clonal disorder of hematopoietic stem cells defined by ineffective hematopoiesis, morphologic dysplasia, and an elevated risk of acute leukemia. Despite these differences, distinction between T-LGL and MDS can be challenging and misdiagnosis can significantly delay initiation of appropriate therapy. The recent identification of STAT3 mutations in LGL may facilitate this distinction: activating STAT3 mutations occur in 40-70% of T-LGL cases, primarily within the SH2 domain, but have not been reported in patients with MDS without concomitant T-LGL. STAT3 is included within our clinical next generation sequencing (NGS) panel, which is used to evaluate patients with known or suspected hematologic malignancies, primarily acute myeloid leukemia, MDS and myeloproliferative neoplasms, as well as various lymphocytic leukemias. We report the frequency and type of STAT3 mutations within our patient population and assess the impact of this information on diagnosis. Between 1/1/2015 and 6/30/2016, 3414 samples (primarily peripheral blood (PB) or bone marrow (BM)) from 2530 unique patients evaluated at Brigham and Women's Hospital and/or Dana-Farber Cancer Institute underwent clinical NGS with a custom, 95-gene, amplicon-based panel (PMID: 27339098). Exons 2-17 and 21-23 of the STAT3 gene were analyzed in each sample using reference transcript 1 (NM_139276). We identified 40 patients with 40 candidate STAT3 mutations (Figure 1). Based on domain localization, variant allele fraction, and population allele frequency, we classified these sequence variants as somatic SH2 domain mutations (n = 21), somatic non-SH2 domain mutations of unknown significance (n = 5) or germline variants (n = 14). Of the 21 patients with somatic SH2 domain mutations, 9 carried a prior diagnosis of T-LGL and 8 were concurrently diagnosed with T-LGL by conventional diagnostic criteria (clonal aberrant T cells in the setting of neutropenia, anemia, or lymphocytosis). The final 4 patients with STAT3 SH2 domain mutations were unexpected diagnoses of T-LGL. These 4 patients were initially referred from outside institutions for MDS based on the reported presence of unilineage erythroid dysplasia (n=2), unquantified ring sideroblasts (n=1), or pancytopenia with unspecified marrow findings (n=1). In 3 of these cases, the STAT3 mutation discovery prompted T-cell flow cytometric analysis of peripheral blood, which revealed an aberrant immunophenotype, and T-cell receptor gamma gene rearrangement studies, which were clonal; these tests are pending in the 4th case. BM evaluation was performed in 12 of 21 patients, including the 4 with suspected MDS; in all cases, the findings did not meet diagnostic criteria for MDS by expert hematopathology review and all showed a normal karyotype. Five additional cases demonstrated somatic non-SH2 domain STAT3 mutations of unknown pathobiologic significance: 3 myeloid neoplasms, 1 chronic lymphocytic leukemia, and 1 autoimmune hemolytic anemia. Additional non-STAT3 mutations were also frequently identified in tumors other than T-LGL. Our experience demonstrates that STAT3 sequencing is a critical component of the evaluation of unexplained cytopenias, and identification of a mutation can clarify ambiguous phenotypes thus averting the consequences of misdiagnosis or diagnostic delay. Notably, several series have reported that MDS and T-LGL can infrequently occur concurrently and thus identification of a STAT3 mutation and a clonal T-LGL population does not exclude the possibility of concomitant MDS. In our cohort, however, no T-LGL patient with a STAT3 mutation demonstrated pathologic evidence of MDS and the majority (19 of 21) showed no other myeloid-associated somatic mutations. In addition, 5 cases in our cohort had likely somatic, non-SH2 domain STAT3 mutations in the context of disparate clinical scenarios, suggesting that these mutations may have a pathogenic role in other hematologic malignancies, a subject of future study. Disclosures DeAngelo: Ariad: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Baxter: Consultancy; Incyte: Consultancy; Celgene: Consultancy. Stone:Celator: Consultancy; Jansen: Consultancy; ONO: Consultancy; Agios: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Consultancy; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy. Lindsley:MedImmune: Research Funding; Takeda Pharmaceuticals: Consultancy.

Download Full-text

Prognostic Impact of Biallelic Versus Monoallelic Deletion 13q and the Proportion of Cells with Deletion 13q within the CLL8 Trial of the German CLL Study Group (GCLLSG)

Blood ◽

10.1182/blood.v118.21.2841.2841 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2841-2841

Author(s):

Dirk Winkler ◽

Raymonde Busch ◽

Andreas Buehler ◽

Michael K. Wenger ◽

Kirsten Fischer ◽

...

Keyword(s):

Board Of Directors ◽

Response Rates ◽

Continuous Variable ◽

Lymphocytic Leukemia ◽

Prognostic Impact ◽

Advisory Committees ◽

Clone Size ◽

Mutation Status ◽

Significant Difference ◽

Baseline Characteristics

Abstract Abstract 2841 Introduction: Genomic aberrations are widely used markers to predict survival of patients with chronic lymphocytic leukemia (CLL). Deletion of 13q as sole abnormality (del 13q) has been associated with a favorable prognosis. However, whether the clinical impact of monoallelic del 13q (mono-del 13q) is different as compared to biallelic del 13q (bi-del 13q), remains controversial. Similarly, it is unsettled, if there is an impact of clone size on outcome of patients with del 13q. Methods: The prognostic impact of mono-del 13q and bi-del 13q, as well as the proportion of cells with del 13q prior therapy was studied in the CLL8 trial of the GCLLSG (1st line FC vs FCR). Pretherapeutic variables, response rates (ORR, CR), progression free survival (PFS), and overall survival (OS) were compared between the groups. Results: 224 patients with del 13q as single aberration were analyzed. 189 patients (84%) had a mono-del 13q, and 35 (16%) a bi-del 13q. B-symptoms were observed more frequently in patients with bi-del 13q (63% vs. 38%, P<.01). No significant differences were seen when comparing all other baseline characteristics between the two groups (Binet/Rai stage, ECOG, leukocyte count, sex, levels of thymidine kinase and ß2-mikroglobuline, IGHV mutation status, usage of V3-21 genes and TP53 mutation) and there was no significant difference in ORR (87% vs 89%) and CR (34% vs 37%) rates. However, PFS was significantly longer in patients with bi-del 13q (median not reached vs. 52 months, P=.04; Fig. 1a). When treated with FCR, patients with bi-del 13q had significantly higher CR rates than those with mono-del 13q (60% vs 47%), while there was no significant difference when treated with FC (25% vs 22%). Similarly, FCR resulted in longer PFS in patients with bi-del 13q as compared to mono-del 13q patients (P=.06). Interestingly, this difference was not observed for FC therapy. Regarding OS, there was a trend towards better outcome in patients with bi-del 13q when combining both treatment arms (P=.18, Fig. 1b). Comparison of treatment arms regarding OS was limited due to few events. However, it was of note that not a single death was observed in the group with bi-del 13q when treated with FCR. Interestingly, among bi-del 13q cases, PFS and OS was independent of the IGHV mutation status (P=.78 for PFS, P=.42 for OS). In contrast, patients with mono-del 13q with mutated IGHV genes had a significantly longer PFS and OS than those with unmutated IGHV genes (P<.01 for PFS, P<.01 for OS). Regarding the clone size of del 13q, there were no significant differences in response rates, PFS and OS in relation to the % of cells with del 13q. This was irrespective of using clone size as a continuous variable, using the median value as cut-point, or separating clone size into quartiles (percentile 25: 42%, median: 76%, percentile 75: 88% del 13q). Median clone sizes in patients achieving a CR, PR, SD or PD were 74% (N=77), 78% (N=119), 74% (N=14) and 70% (N=1), respectively. Median PFS in months was 66, 59, 57 and 39 in quartiles 1–4 (P=.44) and median OS was not reached in either quartile. Conclusion: Although most baseline characteristics were not significantly different when comparing mono-del 13q and bi-del 13q, the presence of a bi-del 13q was associated with significantly longer PFS and a trend towards longer OS after FC-based 1st line treatment in CLL. Bi-del 13q appeared to predict for higher CR rates and longer PFS with FCR as compared to FC treatment. For patients with bi-del 13q, PFS and OS were independent of IGHV mutation status. The size of the aberrant del 13q clone did not impact response rate, PFS or OS. Disclosures: Fischer: Hoffmann La Roche:. Hallek:Hoffmann-la Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stilgenbauer:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants.

Download Full-text

Distinct Gene Expression Signatures in Patients with Richter's Syndrome and Chronic Lymphocytic Leukemia with Prior Exposure to Ibrutinib

Blood ◽

10.1182/blood-2020-136172 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 30-31

Author(s):

Hanyin Wang ◽

Shulan Tian ◽

Qing Zhao ◽

Wendy Blumenschein ◽

Jennifer H. Yearley ◽

...

Keyword(s):

Gene Expression ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Activation ◽

Expression Profiles ◽

Lymphocytic Leukemia ◽

B Cell Activation ◽

Advisory Committees ◽

Upregulated Genes

Introduction: Richter's syndrome (RS) represents transformation of chronic lymphocytic leukemia (CLL) into a highly aggressive lymphoma with dismal prognosis. Transcriptomic alterations have been described in CLL but most studies focused on peripheral blood samples with minimal data on RS-involved tissue. Moreover, transcriptomic features of RS have not been well defined in the era of CLL novel therapies. In this study we investigated transcriptomic profiles of CLL/RS-involved nodal tissue using samples from a clinical trial cohort of refractory CLL and RS patients treated with Pembrolizumab (NCT02332980). Methods: Nodal samples from 9 RS and 4 CLL patients in MC1485 trial cohort were reviewed and classified as previously published (Ding et al, Blood 2017). All samples were collected prior to Pembrolizumab treatment. Targeted gene expression profiling of 789 immune-related genes were performed on FFPE nodal samples using Nanostring nCounter® Analysis System (NanoString Technologies, Seattle, WA). Differential expression analysis was performed using NanoStringDiff. Genes with 2 fold-change in expression with a false-discovery rate less than 5% were considered differentially expressed. Results: The details for the therapy history of this cohort were illustrated in Figure 1a. All patients exposed to prior ibrutinib before the tissue biopsy had developed clinical progression while receiving ibrutinib. Unsupervised hierarchical clustering using the 300 most variable genes in expression revealed two clusters: C1 and C2 (Figure 1b). C1 included 4 RS and 3 CLL treated with prior chemotherapy without prior ibrutinib, and 1 RS treated with prior ibrutinib. C2 included 1 CLL and 3 RS received prior ibrutinib, and 1 RS treated with chemotherapy. The segregation of gene expression profiles in samples was largely driven by recent exposure to ibrutinib. In C1 cluster (majority had no prior ibrutinb), RS and CLL samples were clearly separated into two subgroups (Figure 1b). In C2 cluster, CLL 8 treated with ibrutinib showed more similarity in gene expression to RS, than to other CLL samples treated with chemotherapy. In comparison of C2 to C1, we identified 71 differentially expressed genes, of which 34 genes were downregulated and 37 were upregulated in C2. Among the upregulated genes in C2 (majority had prior ibrutinib) are known immune modulating genes including LILRA6, FCGR3A, IL-10, CD163, CD14, IL-2RB (figure 1c). Downregulated genes in C2 are involved in B cell activation including CD40LG, CD22, CD79A, MS4A1 (CD20), and LTB, reflecting the expected biological effect of ibrutinib in reducing B cell activation. Among the 9 RS samples, we compared gene profiles between the two groups of RS with or without prior ibrutinib therapy. 38 downregulated genes and 10 upregulated genes were found in the 4 RS treated with ibrutinib in comparison with 5 RS treated with chemotherapy. The top upregulated genes in the ibrutinib-exposed group included PTHLH, S100A8, IGSF3, TERT, and PRKCB, while the downregulated genes in these samples included MS4A1, LTB and CD38 (figure 1d). In order to delineate the differences of RS vs CLL, we compared gene expression profiles between 5 RS samples and 3 CLL samples that were treated with only chemotherapy. RS samples showed significant upregulation of 129 genes and downregulation of 7 genes. Among the most significantly upregulated genes are multiple genes involved in monocyte and myeloid lineage regulation including TNFSF13, S100A9, FCN1, LGALS2, CD14, FCGR2A, SERPINA1, and LILRB3. Conclusion: Our study indicates that ibrutinib-resistant, RS-involved tissues are characterized by downregulation of genes in B cell activation, but with PRKCB and TERT upregulation. Furthermore, RS-involved nodal tissues display the increased expression of genes involved in myeloid/monocytic regulation in comparison with CLL-involved nodal tissues. These findings implicate that differential therapies for RS and CLL patients need to be adopted based on their prior therapy and gene expression signatures. Studies using large sample size will be needed to verify this hypothesis. Figure Disclosures Zhao: Merck: Current Employment. Blumenschein:Merck: Current Employment. Yearley:Merck: Current Employment. Wang:Novartis: Research Funding; Incyte: Research Funding; Innocare: Research Funding. Parikh:Verastem Oncology: Honoraria; GlaxoSmithKline: Honoraria; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; AbbVie: Honoraria, Research Funding; Merck: Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Kenderian:Sunesis: Research Funding; MorphoSys: Research Funding; Humanigen: Consultancy, Patents & Royalties, Research Funding; Gilead: Research Funding; BMS: Research Funding; Tolero: Research Funding; Lentigen: Research Funding; Juno: Research Funding; Mettaforge: Patents & Royalties; Torque: Consultancy; Kite: Research Funding; Novartis: Patents & Royalties, Research Funding. Kay:Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; MEI Pharma: Research Funding; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Ding:DTRM: Research Funding; Astra Zeneca: Research Funding; Abbvie: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Impact of Idelalisib Treatment Interruption with or without Dose Reduction on Outcomes in Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2019-124541 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5468-5468

Author(s):

Shuo Ma ◽

Rebecca J Chan ◽

Lin Gu ◽

Guan Xing ◽

Nishan Rajakumaraswamy ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Dose Reduction ◽

Clinical Outcomes ◽

Research Funding ◽

Treatment Interruption ◽

Lymphocytic Leukemia ◽

Hodgkin's Lymphoma ◽

Advisory Committees

Introduction: Idelalisib (IDELA) is the first-in-class PI3Kδ inhibitor and is approved as a monotherapy for relapsed or refractory (R/R) follicular lymphoma and in combination with rituximab for R/R chronic lymphocytic leukemia (CLL). We previously evaluated IDELA treatment interruption as a mechanism to mitigate treatment-emergent adverse events (TEAEs) and found that limited interruption with clinically appropriate re-challenging resulted in superior clinical outcomes. These findings did not comprehensively address the potential confound of interruptions inherently being associated with longer duration of therapy (DoT). Furthermore, the compound effect of IDELA dose reduction together with treatment interruption on IDELA efficacy was not assessed. Objectives: 1) To evaluate whether the benefit of IDELA interruption is retained in patients on therapy >180 days, a duration previously found to be associated with longer overall survival among patients who discontinued IDELA due to an AE; and 2) To compare clinical outcomes of patients who reduced IDELA dosing in addition to interrupting IDELA with those of patients who interrupted IDELA without additional dose reduction. Methods: Using data from Gilead-sponsored trials of patients with R/R indolent non-Hodgkin's lymphoma (iNHL) treated with IDELA monotherapy (N=125, Gopal et al., N. Engl. J. Med., 2014) or with R/R CLL treated with IDELA + anti-CD20 (N=110, Furman et al., N. Engl. J. Med., 2014; and N=173, Jones et al., Lancet Haematol., 2017), DoT, progression-free survival (PFS), and overall survival (OS) were compared between patients on IDELA therapy >180 days with vs. without interruption and between patients who experienced Interruption and Dose Reduction (IDR) vs. patients who experienced Interruption but NoDose Reduction (INoDR) at any point during IDELA treatment. Interruption was defined as missing at least one IDELA treatment day due to an AE and dose reduction could have occurred before or after the first interruption. PFS and OS were estimated using the Kaplan-Meier method and were compared using a log-rank test. Results: Sixty-nine of 125 patients with R/R iNHL (55.2%) and 222 of 283 patients with R/R CLL (78.4%) remained on IDELA therapy >180 days with 29 (42.0%) and 103 (46.4%) of them, respectively, experiencing interruption on or after day 180 (Table 1). The proportions of patients with interruption before day 180 were similar within each of these populations. Among patients on therapy >180 days, those with treatment interruption on or after 180 days had a longer median (m) DOT than patients without interruption (Table 1). Both PFS and OS were longer in CLL patients who interrupted compared to those who did not interrupt (mPFS=28.9 mos. vs. 17.3 mos. and mOS=not reached [NR] vs. 40.4 mos. for with interruption vs. without interruption, respectively, Table 1 and Figure 1). In patients with iNHL, no difference was observed in PFS or OS between patients who interrupted vs. those who did not (Table 1). Of patients who experienced at least one AE-induced interruption at any point during IDELA therapy (n=63 iNHL and n=157 CLL), 47 iNHL patients (74.6%) and 84 CLL patients (53.5%) also had dose reduction. Two iNHL patients (1.6%) and 5 CLL patients (1.8%) had IDELA dose reduction but no interruption. Both iNHL and CLL patients with IDR experienced a similar PFS compared to patients with INoDR (mPFS=16.5 mos. vs. 14.2 mos. for iNHL and 21.8 mos. vs. 22.1 mos. for CLL with IDR vs. INoDR, respectively, Table 2). However, OS was longer in both iNHL and CLL patients with IDR compared to INoDR (mOS=61.2 mos. vs. 35.3 mos. for iNHL and NR vs. 42.4 mos. for CLL, respectively, Table 2; CLL patients shown in Figure 2). Discussion: IDELA treatment interruption is not associated with rapid clinical deterioration, as observed with some B-cell receptor signaling pathway inhibitors. No clear relationship between IDELA DoT and frequency of interruption was observed. When normalized for DoT >180 days, IDELA treatment interruption retained its clinical benefit in the CLL population. When utilized together with IDELA interruption, dose reduction did not lead to inferior clinical outcomes but instead extended OS in both iNHL and CLL populations. Adherence to treatment interruption and dose reduction guidance as outlined in the IDELA USPI may optimize IDELA tolerability and efficacy for patients with iNHL and CLL. Disclosures Ma: Janssen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Juno: Research Funding; Incyte: Research Funding; Xeme: Research Funding; Beigene: Research Funding; Novartis: Research Funding; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Acerta: Research Funding; Bioverativ: Consultancy; Genentech: Consultancy. Chan:Gilead Sciences, Inc.: Employment, Equity Ownership. Gu:Gilead Sciences, Inc.: Employment. Xing:Gilead Sciences, Inc.: Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Employment. Ruzicka:Gilead Sciences, Inc.: Employment. Wagner-Johnston:Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

BAX-Mutated Clonal Hematopoiesis in Patients on Long-Term Venetoclax for Relapsed/Refractory Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2020-137775 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 9-10

Author(s):

Piers Blombery ◽

Ella R Thompson ◽

Xiangting Chen ◽

Tamia Nguyen ◽

Mary Ann Anderson ◽

...

Keyword(s):

Advisory Committee ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Clonal Hematopoiesis ◽

Eliza Hall Institute ◽

Hall Institute ◽

Over Time

Venetoclax (Ven) is an effective element of treatments for chronic lymphocytic leukemia (CLL) with high response rates observed in the upfront and relapsed/refractory (R/R) settings. In addition to inducing apoptosis in CLL cells, Ven also induces apoptosis within normal and malignant myeloid lineage populations (accounting for its efficacy in the treatment of acute myeloid leukemia). We investigated the effects of Ven outside the target tumor compartment in patients (pts) with CLL receiving long-term continuous Ven and make the novel observation of the development of BAX-mutated clonal hematopoiesis in this heavily pre-treated patient group. 92 pts with CLL receiving continuous non time-limited Ven have been treated at our institutions on clinical trials. Of these, 41 had sufficient (>6 mo) follow up (median 70; range 14-95 mo) and suitable samples available for further analysis. 38/41 (93%) pts had received previous treatment with alkylators and/or fludarabine. In order to assess the non-CLL compartment in these 41 pts we identified those with peripheral blood or bone marrow aspirate samples taken during deep response to Ven demonstrating either minimal (<5%) or no CLL involvement by flow cytometry (sensitivity 10-4). We initially performed unique molecular index (UMI)-based targeted next generation sequencing of apoptosis pathway genes as well a panel of 60 genes recurrently mutated in lymphoid and myeloid malignancy. From these 41 pts we identified mutations in the apoptosis effector BAX in samples from 12 (29%). 20 different BAX mutations were observed across these 12 pts at variant allele frequencies (VAF) consistent with their occurrence in the non-CLL compartment. Mutations included frameshift, nonsense, canonical splice site and missense mutations occurring in key structural elements of BAX consistent with a loss-of-function mechanism (Fig 1A). Interestingly, an enrichment of missense and truncating mutations predicted to escape nonsense mediated decay were observed at the C-terminus of the BAX protein affecting the critical α9 helix. Mutations in this region have previously been shown in cell lines to cause aberrant intracellular BAX localization and abrogation of normal BAX function in apoptosis (Fresquet Blood 2014; Kuwana J Biol Chem 2020). For comparison, NGS targeted sequencing for BAX mutations was performed on samples from cohorts of pts with (i) myeloid or lymphoid malignancy (n=80) or (ii) R/R CLL treated with BTK inhibitors (n=15) after a similar extent of preceding chemotherapy. Neither of these cohorts had previous exposure to Ven. BAX mutations were not detected in any samples from these pts. Longitudinal sampling from pts on Ven harboring BAX mutations in the non-CLL compartment was performed to further understand compartment dynamics over time (in 9 pts over 21-93 months of follow up). Multiple pts demonstrated a progressive increase in VAF of single BAX mutations over time to become clonally dominant within the non-CLL compartment and with observed VAFs consistent with their presence in the myeloid compartment. Mutations in other genes implicated in clonal hematopoiesis and myeloid malignancy including ASXL1, DNMT3A, TET2, U2AF1 and ZRSR2 were also detected in these pts samples. Targeted amplicon single cell sequencing (Mission Bio) demonstrated the co-occurrence of clonally progressive BAX mutations within the same clones as mutations in DNMT3A and ASXL1 as well as the existence of further BAX mutations at low VAF outside these dominant clones which remained non-progressive over time (Fig 1B). In addition, fluctuations in the presence and VAF of myeloid-disease associated mutations was noted with Ven exposure. In aggregate these data are consistent with the existence of a selective pressure within the myeloid compartment of these pts and an interplay of BAX with other mutations in determining survival and enrichment of these clones over time with ongoing Ven therapy. In summary, we have observed the development of BAX-mutated clonal hematopoiesis specifically in pts with CLL treated with long-term Ven. These data are consistent with a multi-lineage pharmacological effect of Ven leading to a survival advantage for clones harboring BAX mutations within the myeloid compartment during chronic Ven exposure. Finally, our data support the further investigation of BAX mutations as a potential resistance mechanism in myeloid malignancies treated with Ven. Disclosures Blombery: Invivoscribe: Honoraria; Amgen: Consultancy; Janssen: Honoraria; Novartis: Consultancy. Anderson:Walter and Eliza Hall Institute: Patents & Royalties: milestone and royalty payments related to venetoclax.. Seymour:Celgene: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Mei Pharma: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Nurix: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Tam:Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BeiGene: Honoraria. Huang:Servier: Research Funding; Walter and Eliza Hall Institute: Patents & Royalties: milestone and royalty payments related to venetoclax.; Genentech: Research Funding. Wei:Janssen: Honoraria, Other; Walter and Eliza Hall Institute: Patents & Royalties; AMGEN: Honoraria, Other: Advisory committee, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Astellas: Honoraria, Other: Advisory committee; Pfizer: Honoraria, Other: Advisory committee; Macrogenics: Honoraria, Other: Advisory committee; Abbvie: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau; Genentech: Honoraria, Other: Advisory committee; Servier: Consultancy, Honoraria, Other: Advisory committee; Celgene: Honoraria, Other: Advisory committee, Speakers Bureau; Astra-Zeneca: Honoraria, Other: Advisory committee, Research Funding. Roberts:Janssen: Research Funding; Servier: Research Funding; AbbVie: Research Funding; Genentech: Patents & Royalties: for venetoclax to one of my employers (Walter & Eliza Hall Institute); I receive a share of these royalties.

Download Full-text

Chronic Lymphocytic Leukemia in Kuwait

Blood ◽

10.1182/blood-2019-127234 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5467-5467

Author(s):

Salem Alshemmari ◽

Ramesh Pandita ◽

Abdulaziz Hamadah ◽

Ahmad Alhuraiji

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Mutational Analysis ◽

Staging System ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Western Countries ◽

Mutational Status ◽

Study Results ◽

History Of

Background :Chronic lymphocytic leukemia (CLL) is common malignancy in Western countries. However, little known about this disease entity in our area. This study exploring the biology in out patients' population. Method:Patients with confirmed CLL under IGHV and TP53 mutational analysis at presentation or during follow up. We also integrated other clinical and biological parameter in this study. Results: A total of 137 cases were analyzed, median age 61 years (range:34-89); 30% of the cases age was<55 years at presentation. There was 108 males vs. 29 females M:F ratio 3.7. Two patients gave a family history of CLL, while 1 patient gave a history of other lymphoproliferative disorders. Binet staging system available in 134 cases, A: 109 (81.3%), B: 12 (9%), C:13 (9.7%). B2 macroglobulin elevated in 40/112 (36%) cases and 10/103 (10%) had M-spike. CD38 positivity reported in 37/112 (33%) of cases. Cytogenetics data evaluable in 85 cases: isolated del(13q): 35%, isolated trisomy 12 (16.5%), del(11q) (4.5%), del(17p)(2.4%). IGHV mutational status mutated vs unmutated: 40% vs 60%. Cases with available treatment information on 132 cases. Fifty cases required treatment due to disease progression. First line treatment Bendamustine-Rituximab (BR) 3 cases, Fludarabine Cyclophosphamide Rituximab (FCR) 30 cases and Chlorambucil with anti-CD 20 antibody 6 cases. At the time of review, 3 cases on ibrutinib (2 in 3rdline and 1 case in the 4thline). Conclusion: This is the first study to shed light on CLL in our area. There are biological differences between our patients' population and the western countries. Disclosures Pandita: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

The Broad Spectrum of TP53 Variants in CLL: NGS Analysis of 573 Pathogenic TP53 Variants

Blood ◽

10.1182/blood-2019-130907 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3021-3021

Author(s):

Gregory Lazarian ◽

Floriane Theves ◽

Myriam Hormi ◽

Virginie Eclache ◽

Stéphanie Poulain ◽

...

Keyword(s):

Tumor Progression ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Fish Analysis ◽

Snp Analysis ◽

Advisory Committees ◽

Exon 2 ◽

Tp53 Mutations ◽

Mutational Status

TP53 aberrations, including somatic mutations of TP53 gene or 17p deletion leading to the loss of the TP53 locus, are a major predictive factor of resistance to fludarabin based chemotherapy in chronic lymphocytic leukemia (CLL) and remain an adverse prognostic factor in the chemofree era. Therefore, detection of TP53 alteration before each new line of treatment is required for theranostic stratification. In order to better characterize the distribution and combination of the TP53 variants in CLL, we collected the TP53 sequencing data of 343 patients harboring TP53 mutations from centers of the French Innovative Leukemia Organization-CLL (FILO) and established a large data base of 573 TP53 mutations. Mutations were identified through NGS sequencing (covering exon 2 to 11) allowing the detection of low frequency variants down to 1% VAF. Several distinct low VAF mutations were orthogonally confirmed by digital PCR. TP53 variants were analyzed through UMD_TP53 data gathering 90 000 TP53 mutations from all type of cancers. IGHV mutational status and FISH analysis were available for 224 and 176 patients respectively. Using ACMG criteria from the UMD_TP53 database, we confirmed that 523 could be classified as pathogenic, 42 were likely pathogenic and 8 were VUS (Variants of Unknown Significance). As expected, the mutation distribution along the p53 protein exhibited a clustering of variants in the DNA binding domain of the protein. We also confirmed the presence of a specific hotspot at codon 234 (6%) which is noticeable in other CLL cohorts but absent in solid tumors. 431 TP53 variants led to the expression of a mutant protein whereas the remaining 142 led a TP53 null phenotype. For 8 patients without 17p deletion and a mutation VAF larger than 50%, SNP analysis indicate that these tumors had a copy number neutral loss of heterozygosis at 17p with a duplication of the mutant allele leading to homozygous mutations of TP53. When focusing on the allele burden of TP53 mutations, 264/573 (46%) variants had an allele frequency <10%. Even if they were predominantly found in polymutated cases, presence of only low VAF (<10%) mutations was evidenced in 74 (21%) patients (50 patients with a single TP53 mutation and 24 patients with more than one). All these cases would have been missed by conventional sequencing. Among the 343 patients, 113 (33%) were poly-mutated and harbored more than one pathogenic TP53 variants (2 to 11 variants per patient): 57 (16,7 %) had 2 variants, 32 (9,3%) had 3, 10 had 4 (3%) and 14 patients (4%) had 5 to 11 variants. Using both long range sequencing and in silico analysis, we could show that all these variants were distributed in different alleles supporting an important intratumoral heterogeneity and a strong selection for TP53 loss of function during tumor progression in these patients. Null variants were rarely found as single alteration: only 46 patients (13,4%) patients harbored a single null mutation. Null mutations were predominantly found in patients with multiclonal mutations (87% with 4 or more). Median size of variants significantly decreased with the number of mutations and most of low VAF (less than 10%) variants were found in multiclonal combinations. Multiclonal mutations were predominantly found in previously treated patients (41% treated versus 10 % untreated) but whether all these variants preceded treatment and were further selected is currently unknown. We observed that 71,5 % of patients were IGHV unmutated and multiclonal mutations were surprisingly more frequent in mutated IGHV cases than in unmutated ones. Only 50% of cases carried a 17p deletion, highlighting again the importance of testing for TP53 mutations in addition to FISH analysis. Presence or absence of 17p deletion was unrelated to the number of TP53 mutations. Taken together these observations suggest that the TP53 mutational landscape in CLL is very complex and can involve multiple mechanisms, converging to a total loss of TP53 function and tumor progression. NGS provides a powerful tool for detecting all these alterations including variants with low VAF and should become a standard for CLL screening prior to each line of treatment. Disclosures Leblond: Amgen: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Letestu:Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Roche: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Alexion: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts. Cymbalista:Abbvie: Honoraria; Roche: Research Funding; Sunesis: Research Funding; Gilead: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria.

Download Full-text

Clinical Characteristics and Outcome of Young Chronic Lymphocytic Leukemia Patients: A Single Institution Study of 204 Cases

Blood ◽

10.1182/blood.v94.2.448 ◽

1999 ◽

Vol 94 (2) ◽

pp. 448-454 ◽

Cited By ~ 147

Author(s):

Francesca R. Mauro ◽

Robert Foa ◽

Diana Giannarelli ◽

Iole Cordone ◽

Sabrina Crescenzi ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Clinical Features ◽

Median Survival ◽

Survival Probability ◽

Older Patients ◽

Lymphocytic Leukemia ◽

Second Primary ◽

Age Group ◽

Single Institution ◽

Younger Patients

Abstract A retrospective analysis on chronic lymphocytic leukemia (CLL) patients ≤55 years observed at a single institution was performed with the purpose of characterizing the clinical features and outcome of young CLL and of identifying patients with different prognostic features. Over the period from 1984 to 1994, 1,011 CLL patients (204 [20%] ≤55 years of age and 807 [80%] >55 years of age) were observed. At diagnosis, younger and older patients displayed a similar distribution of clinical features, except for a significantly higher male/female ratio in younger patients (2.85 v 1.29;P < .0001). Both groups showed an elevated rate of second primary cancers (8.3% v 10.7%), whereas the occurrence of Richter’s syndrome was significantly higher in younger patients (5.9% v 1.2%; P < .00001). Younger and older patients showed a similar overall median survival probability (10 years) but were characterized by a different distribution of causes of deaths: CLL unrelated deaths and second primary malignancies predominated in the older age group, whereas the direct effects of leukemia were prevalent in the younger age group. Although younger and older patients displayed a similar survival, the evaluation of the relative survival rates showed that the disease had a greater adverse effect on the expected survival probability of the younger population. Multivariate analysis showed that for young CLL patients only dynamic parameters, such as lymphocyte doubling time and other signs of active disease, were the independent factors that significantly influenced survival probability (P = .00001). A prolonged clinico-hematologic follow-up allowed us to identify two subsets of young CLL patients with a different prognostic outcome: a group of patients (40%) with long-lasting stable disease without treatment and an actuarial survival probability of 94% at 12 years from diagnosis and another group (60%) with progressive disease and a median survival probability of 5 years after therapy. For the latter patients, the therapeutic effect of innovative therapies with curative intents needs to be investigated in prospective, comparative clinical trials.

Download Full-text

Acute Myeloid Leukemia (AML) Treated with Azacitidine: Survival Outcomes for Patients Who Complete More Than Six Cycles Are Similar to High-Risk Myelodysplastic Syndrome/Low Blast Count AML

Blood ◽

10.1182/blood-2019-122122 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5156-5156

Author(s):

Jill Fulcher ◽

Zahra Abdrabalamir Alshammasi ◽

Nathan Cantor ◽

Christopher Bredeson ◽

Grace Christou ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Median Survival ◽

Research Funding ◽

Survival Outcomes ◽

Advisory Committees ◽

Ottawa Hospital ◽

Funding Agencies ◽

Progression Of Disease ◽

Refractory Aml

INTRODUCTION: Despite accumulating evidence supporting the efficacy of hypomethylating agents in patients with AML and > 30% bone marrow blasts as well as in relapsed/refractory AML, this therapy is not yet funded by National Health Plans / Healthcare Funding Agencies in a number of countries including Canada. The assistance of an industry-sponsored compassionate program has enabled provision of azacitidine for this group of patients at The Ottawa Hospital. We report here our local "real-world" experience of azacitidine efficacy in this diverse group of AML patients and identify a sub-group whose outcomes are equivalent to that of patients with higher-risk Myelodysplastic Syndrome (MDS) and AML with 20-30% blasts for whom azacitidine therapy has funding approval in Canada. METHODS: All patients who received azacitidine at The Ottawa Hospital between 2009 and 2016 were included in this single-center, retrospective analysis. Azacitidine was administered at a dose of 75mg/m2 subcutaneously daily for 7 consecutive days every 28 days. Response was evaluated with a repeat bone marrow aspirate and trephine biopsy after the 6th cycle. In those patients confirmed to have stable or responsive disease, azacitidine was continued until progression of disease, intolerable side-effects of the drug or the patient chose to discontinue therapy. Overall survival curves were generated using the Kaplan-Meier method and log-rank tests were used to compare subgroups of patients. Actuarial median survival months were calculated with 95% confidence intervals (CI). P-values less than 0.05 were considered statistically significant. RESULTS: During the study period, 109 patients received azacitidine: 54 had MDS /AML with 20-30% blasts (the 'funded' group) and 55 had either AML with > 30 % blasts (n=23), AML relapsed post-intensive chemotherapy (n=14), AML relapsed post-allogeneic stem cell transplant (n=10) or primary refractory AML (n=8) (the 'unfunded' group). Median survival of the 'funded' group was 12.2 months while median survival of the 'unfunded' group was 5.6 months (95% CI 3.3-7.7; p=0.0058). Of the AML patients in the 'unfunded' group, 24% completed more than 6 cycles of azacitidine compared to 52% of patients in the 'funded' group. In both the 'funded' and 'unfunded' groups, patients who completed more than 6 cycles of azacitidine had similar survival outcomes (p=0.7277): the 'funded' group had a median survival of 19 months (95% CI 14.4-25.3) while the median survival of this sub-population of the 'unfunded' AML group was 22 months (95% CI 11.7-24.9). Patients in both groups who failed to complete more than 6 cycles of azacitidine also had a similar outcome (p=0.39), with a median survival of 5.7 months (95% CI 4.0-6.3) for patients with MDS/AML 20-30% blasts and 3.6 months (95% CI 2.2-5.1) for AML patients with > 30% blasts or relapsed/refractory disease. Reasons for patients not completing at least 6 cycles of azacitidine included progression of disease (25%), bacterial infections most commonly pneumonia (53%) and patient preference (7%). CONCLUSION: A significant sub-population of AML patients with > 30% blasts or refractory/relapsed AML can achieve a meaningful survival benefit with the hypomethylating agent, azacitidine. A higher proportion of this AML patient population discontinued azacitidine as a result of infective complications. The provision of routine prophylactic antibiotics may enable more patients with AML to receive an adequate amount of azacitidine to achieve therapeutic benefit and warrants further investigation. Our results add to the growing body of 'real-world' evidence that supports healthcare funding agencies to provide coverage of azacitidine for patients with AML who in some countries at present do not fulfill government funding criteria. Disclosures Bredeson: Otsuka: Research Funding. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sabloff:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Research Funding.

Download Full-text