scholarly journals A Phase II Trial of Ibrutinib and PD-1 Blockade in Asymptomatic High Risk Chronic Lymphocytic Leukemia to Improve Immune Function

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5483-5483
Author(s):  
Julio C. Chavez ◽  
Ariel F Grajales-Cruz ◽  
Virginia Olivia Volpe ◽  
Elyce P. Turba ◽  
Lisa Nodzon ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Immune Responses ◽  
Board Of Directors ◽  
Unmet Need ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Background: Chronic lymphocytic leukemia (CLL) is the most common chronic leukemia. Patients in active surveillance with untreated high-risk CLL (defined as presence of del17p or TP53, del11q or ATM mutation or unmutated IGVH) have an unmet need as they tend to progress rapidly and develop resistance to standard therapies. There is evidence that deferring treatment in high-risk patients may be detrimental due to a more aggressive course of disease and that patients with clonal evolution into high-risk features may fare even worse prognosis (Shanafelt et al, JCO 2006). The CLL12 trial (ibrutinib for asymptomatic high risk CLL patients, Langerbeins et al ICML2019) showed event (EFS) and progression (PFS) free survival benefit when compared to placebo. In addition, T-cell dysfunction and immunosuppressive environment have been shown in CLL. The rationale of the trial is that the combination of PD1:PDL1 Blockade (PDB) and ibrutinib will reverse T cell dysfunction commonly seen in CLL patients, potentiating more robust anti-infective and anti-tumor immune responses. Methods: This is a phase 2 clinical trial. Enrollment goal: 25. Treatment will consist of the combination of pembrolizumab (Pem) 200 mg IV every 3 weeks and ibrutinib 420 mg daily orally (to be started after 2nd infusion of PDB) for up to 51 weeks, as depicted in Figure 1. Eligibility criteria includes: Age > 18, confirmed diagnosis of CLL, presence of at least 1 high risk factor for CLL (Del17p, Del11q and or unmutated IGVH), and not meeting iwCLL criteria to start treatment. Primary endpoints are incidence of complete remission (CR) and time to CLL response. Secondary endpoints: overall response rate (ORR), restoration of immune response (decreased markers of T-cell exhaustion and improvement in quantitative immunoglobulins), safety, PFS. Exploratory biomarkers include evaluation of T-cell and B-cell function and cytokine profile at different time points through therapy. Disclosures Chavez: Karyopharm: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Nodzon:Pfizer: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy, Other: Speaker Fees; Abbvie: Other: Speaker Fees. Pinilla Ibarz:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy; TG Therapeutics: Consultancy; Bayer: Speakers Bureau; Sanofi: Speakers Bureau. OffLabel Disclosure: The combination of PD1:PDL1 Blockade (PDB) and ibrutinib will reverse T cell dysfunction commonly seen in CLL patients, potentiating more robust anti-infective and anti-tumor immune responses

scholarly journals Size Matters: Identification of Larger Size CD19 Positive Extracellular Vesicles in Chronic Lymphocytic Leukemia That Inhibit Chimeric Antigen Receptor T Cell Functions

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1865-1865
Author(s):  
Cynthia L. Forsman ◽  
Reona Sakemura ◽  
Fabrice Lucien-Matteoni ◽  
Elizabeth Juarez-Diaz ◽  
Nan Yang ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Risk Profile ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Effector Functions ◽  
Cell Functions ◽  
Cd19 Expression

Abstract Introduction: Unprecedented clinical outcomes were reported after CD19 chimeric antigen receptor T cell (CART19) therapy and led to their FDA approval in diffuse large B cell lymphoma and in acute lymphoblastic leukemia. However, the complete response rate in chronic lymphocytic leukemia (CLL) after CART19 therapy is much lower, at approximately 20-30%, and the mechanism(s) for this relative lack of success is unclear. The dominant known mechanism(s) that prevent successful CART cell therapy in CLL have been limited to CART expansion and poor persistence. However, potential mechanisms are not limited to the CLL T-cell. Several immune defects have been identified in CLL that result from the complex bi-directional interaction between B-CLL cells and their microenvironment. In CLL the leukemic microenvironment is rich with extracellular vesicles (EVs) secreted by B-CLL cells. There is growing evidence that these vesicles play an important role in intracellular communication by the delivery of growth factors, genetic material and microenvironmentally relevant molecules. Therefore, we aimed to investigate the role and interactions of EVs in the diminished or absent CART response seen in some CLL patients. Methods: EVs were isolated from peripheral blood of 16 patients with untreated CLL at different Rai stages (8 patients had early and 8 had advanced stage disease) and risk profile by FISH (8 patients had low risk and 8 patients had high risk disease, based on the presence of 17p deletion). Cytometry was used to determine size, number of particles per µl, Annexin V and CD19 expression. These variables were correlated to the Rai stage and risk category of the disease. To investigate the impact of EVs on CART cell functions, CART19 cells were stimulated with either CLL EVs alone or in combination with the CD19 positive cell line JeKo1. After coincubation different effector functions were analysed. Results: Two patterns of EVs in CLL patients were identified; a single versus two distinct EV size populations (small [EVssmall]; 50-240nm, median=110nm) and large [EVslarge]; 180-560nm, median = 360nm Fig 1.A). In 25% of patients, EVs were CD19 positive (EVCD19+). CD19 positivity was detected only in patients with the EVslarge (Fig 1.B). The EVs concentration, CD19 expression (EVsCD19+ vs EVsCD19-), or the size (EVssmall vs EVslarge) did not correlate with disease stage (early vs advanced Rai stage) or risk profile of CLL (low vs high risk) although some variation could be seen (Fig 1.C). To investigate our hypothesis that EVs could modulate CART19 function, CART19 cell effector functions were examined in the presence of EVsCD19+, EVsCD19-, EVssmall, or EVslarge. EVs, 1.5x10e5 particles, alone were insufficient to stimulate CART19 cells. However when CART19 cells were stimulated with the CD19 positive cell line JeKo1, their effector functions were reduced only in the presence of EVsCD19+, 50,000 particles, 2.5 x 10e3/ µl, but not EVsCD19- at the same concentration. This included a significant reduction in CART specific killing (Fig 1.D) and a reduction in cytokine production. The impairment of CART cell functions was independent of the size of EVs, i.e. there was no impairment of CART functions with large or small size EVCD19- in co-culture. Summary: We identify CD19 positive large size EVs from patients with CLL and demonstrate that these EVs play a role in the leukemic microenvironment by reducing CART cell activity. Studies are ongoing to define the mechanism(s). Disclosures Parikh: Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Gilead: Honoraria; MorphoSys: Research Funding; Abbvie: Honoraria, Research Funding. Kay:Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Kenderian:Tolero Pharmaceuticals: Research Funding; Humanigen: Research Funding; Novartis: Patents & Royalties.

scholarly journals T-cell dysfunction in chronic lymphocytic leukemia from an epigenetic perspective

Haematologica ◽  
2021 ◽  
Author(s):  
Fleur S. Peters ◽  
Jonathan C. Strefford ◽  
Eric Eldering ◽  
Arnon P. Kater
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Immune Cell ◽  
Lymphocytic Leukemia ◽  
T Cell Therapy ◽  
High Expectations ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Cellular immunotherapeutic approaches such as chimeric antigen receptor (CAR) T-cell therapy in chronic lymphocytic leukemia (CLL) thus far have not met the high expectations. Therefore it is essential to better understand the molecular mechanisms of CLLinduced T-cell dysfunction. Even though a significant number of studies are available on T-cell function and dysfunction in CLL patients, none examine dysfunction at the epigenomic level. In non-malignant T-cell research, epigenomics is widely employed to define the differentiation pathway into T-cell exhaustion. Additionally, metabolic restrictions in the tumor microenvironment that cause T-cell dysfunction are often mediated by epigenetic changes. With this review paper we argue that understanding the epigenetic (dys)regulation in T cells of CLL patients should be leveled to the knowledge we currently have of the neoplastic B cells themselves. This will permit a complete understanding of how these immune cell interactions regulate T- and B-cell function. Here we relate the cellular and phenotypic characteristics of CLL-induced T-cell dysfunction to epigenetic studies of T-cell regulation emerging from chronic viral infection and tumor models. This paper proposes a framework for future studies into the epigenetic regulation of CLL-induced Tcell dysfunction, knowledge that will help to guide improvements in the utility of autologous T-cell based therapies in CLL.

scholarly journals The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia

Haematologica ◽  
2013 ◽  
Vol 98 (6) ◽  
pp. 953-963 ◽  
Author(s):  
D. Brusa ◽  
S. Serra ◽  
M. Coscia ◽  
D. Rossi ◽  
G. D'Arena ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

scholarly journals CD3xCD19 Dart Treatment Is Efficient in Venetoclax Resistant CLL and Reverses T Cell Dysfunction

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3043-3043
Author(s):  
Anne W. J. Martens ◽  
Susanne R. Janssen ◽  
Ingrid A.M. Derks ◽  
Sanne Tonino ◽  
Eric Eldering ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Board Of Directors ◽  
Cd8 T Cells ◽  
Research Funding ◽  
Cell Killing ◽  
Advisory Committees ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Intro - Agents targeting the apoptosis pathway, like the Bcl-2 inhibitor venetoclax, are highly effective in chronic lymphocytic leukemia (CLL). However, not all patients experience deep responses and acquired resistance has already been described. T cell mediated lysis is another tool currently exploited in hematologic malignancies. In contrast to acute lymphoblastic leukemia (ALL) however, efficacy of autologous based T cell therapy, such as CAR T cells, in CLL has been low. This is linked to a CLL mediated acquired T cell dysfunction. Bispecific T cell engagers targeting CD19 are successfully applied in ALL, but whether it overcomes the acquired T cell dysfunction in CLL is unknown. We therefore tested efficacy of a CD3xCD19 Dual Affinity Re-Targeting molecule (DART) in CLL. Since it has been observed that bispecific antibodies can overcome deficient synapse formation in CLL (Robinson et al, 2018) and based on our assumption that T cell mediated lysis differs from venetoclax-mediated killing, we hypothesized that usage of a CD3xCD19 DART in CLL overcomes T cell dysfunction and will be effective against venetoclax resistant CLL. Methods - Co-culture of CLL derived or aged-matched healthy donor (HD) CD4+ and/or CD8+ T cells with (CD40 activated) primary CLL or CD19+ cell lines JeKo-1 or Ramos in presence of CD3xCD19 (JNJ-64052781), CD3xFITC, anti-CD3/28 antibodies was performed. R esults - JeKo-1 cells were highly sensitive to CD3xCD19 mediated HD T cell killing with close to 70% of lysis in a concentration of 10ng/mL using an E:T ratio of 4:1. In the same conditions, primary CLL cells proved sensitive for CD3xCD19 mediated HD T cell killing with 50% of lysis. Killing was observed irrespective of IGHV mutation or chemorefractory status. We next compared HD with CLL-derived T cells by measuring activation levels between direct TCR (anti-CD3/CD28) and CD3xCD19 stimulation. As described, TCR stimulation resulted in impaired CLL CD4+ and CD8+ T cell activation and proliferation when compared to HD. In contrast, treatment of CLL derived PBMCs with CD3xCD19 did not resulted in dysfunctional CLL-derived T cell responses (Fig 1A-C). Consistently, co-culture of CLL derived CD4+, CD8+ or a combination with either JeKo-1 or allogeneic CLL cells in the presence of CD3xCD19 resulted in significant cytotoxicity (Fig. 1D). In the allogeneic setting, cytotoxic capacity of CD4+ T cells was similar to their CD8+ counterparts. When targeting autologous CLL, a benefit was observed when both CD4+ and CD8+ T cells were present (Fig. 1D). We then studied whether venetoclax resistant CLL cells could be targeted by CD3xCD19 mediated T cell killing. Bcl-2 overexpressing Ramos were equally lysed in presence of the CD3xCD19 DART as their wildtype counterpart, indicating that Bcl-2 expression does not inhibit CD3xCD19 mediated cell death. Following CLL cell stimulation by CD40 ligation, anti-apoptotic Bcl-XL, Bfl-1 and Mcl-1 are highly induced (Thijssen et al., 2015) resulting in venetoclax resistance (Fig 1E). Nevertheless, CD40L stimulated CLL cells were as efficiently lysed upon CD3xCD19 treatment as unstimulated CLL. (Fig 1F). This indicates that an augmented apoptotic threshold does not impact efficacy of CD3xCD19. Further examination of the mechanism of CD3xCD19 mediated killing showed that lysis depended on granzymes, as blocking granule exocytosis prevented cell death. Independence of the mitochondrial apoptotic pathway was shown by equal sensitivity to CD3xCD19 mediated T cell lysis comparing BAX/BAK knockout Jeko-1 cells to the parental cell line. Also, caspase blockage did not inhibit cell death, pointing to apoptosis independent killing. In concordance, PARP cleavage could only be detected when caspase activity was not blocked. Conclusion - This is the first report describing reversal of CLL mediated T cell dysfunction by applying a CD3xCD19 DART. Furthermore, it shows that venetoclax resistant CLL can still be efficiently targeted by T cells, in a non-apoptotic fashion. These results imply that T cell mediated therapy could be used alongside venetoclax. Figure 1 Disclosures Eldering: Celgene: Research Funding; Roche: Research Funding; Janssen Pharmaceutical Companies: Research Funding. van der Windt:Genmab: Employment. Kater:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding.

High Expression Of Cereblon (CRBN) Is Associated With Achievement Of Complete Response To Thalidomide Plus Fludarabine Regimen In Chronic Lymphocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4934-4934
Author(s):  
Krzysztof Jamroziak ◽  
Janusz Szemraj ◽  
Tadeusz Robak ◽  
Krzysztof Giannopoulos
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Receptor Expression ◽  
Cell Populations ◽  
Advisory Committees ◽  
Pre Treatment

Abstract Cereblon (CRBN) has recently been identified as a target for immunomodulatory drugs (IMiDs), thalidomide, lenalidomide and pomalidomide, and its downregulation has been linked to resistance to IMiDs in multiple myeloma (MM). However, little is known on the role of CRBN as a resistance/response biomarker in other diseases in which treatment with IMiDs is investigated, such as chronic lymphocytic leukemia (CLL). Although lenalidomide has recently proven to be more promising drug in CLL, we had previously performed a clinical trial that assessed efficacy of thalidomide (100mg p.o on days 1-28) combined with fludarabine (25mg/m2 i.v. on days 7–11) given for six 4-week cycles in patients with CLL. The objective of the present study was to correlate retrospectively pre-treatment CRBN expression in CLL cells with response to thalidomide/fludarabine regimen as well as to cellular and molecular changes that were monitored in vivo after initial 7-day thalidomide monotherapy. CRBN and interferon regulatory factor 4 (IRF4) expressions were studied by quantitative RT-PCR using mRNA extracted from frozen pre-treatment CLL cells. Tumor necrosis factor (TNF) and TNF receptor expression were analyzed by ELISA. T-cell populations were estimated using flow cytometry during the clinical part of the study. Frozen biological pre-treatment samples were available for 27 out of 40 patients included to the thalidomide/fludarabine clinical trial. First, we verified that CRBN expression was independent from all established prognostic parameters in CLL including IGVH mutational status, high-risk FISH, ZAP-70 and CD38 expression and beta-2 microglobulin level (p>0.05 for all parameters). Subsequently, we analyzed the CRBN expression in regard to response and CLL prognosis. Interestingly, we found that patients with CRBN expression in the highest quartile tended to have significantly higher probability of complete response (CR) (50% vs. 10%, Fisher exact test p=0.56). However, although median CRBN expression was highest in patients with CR (median=0.80), it was lower in patients achieving partial remission (PR) (0.24) than in patients who did not responded (0.50), and the response categories did not correlate directly with CRBN expression in CLL cells, (r=0.07, p=0.71). Furthermore, no significant association was found between CRBN expression above and below median and duration of response after thalidomide/fludarabine treatment (28 vs. 29 month, p=0.88). Interestingly, in contrast to previous data in MM, we found that CRBN expression did not correlate with IRF4 expression (r=0.25, p=0.22). Furthermore, analysis of molecular and cellular parameters assessed after initial 7-day thalidomide monotherapy including the changes in TNF levels and regulatory T-cell populations did not reveal any significant relation to basal CRBN levels. In conclusion, we found that high pre-treatment CRBN expression in CLL cells is associated with CR achievement on thalidomide-containing chemotherapy. However, in contrast to published data on MM, CRBN expression in CLL cells does not correlate directly with CLL prognosis or molecular and cytological effects caused by thalidomide. Our results may indicate complex mechanisms of IMiDs activity in CLL and that basal CRBN levels in CLL microenvironment and immune effector T and NK cells may be more important for CLL outcome. Disclosures: Off Label Use: The presentation is a retrospective analysis of a clinical trial on thalidomide that is not approved in CLL. Currently, another IMiD, lenalidomid, is being investigated in CLL with promising activity,and the data from this retrospective study may add to understanding on its action. Robak:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

scholarly journals E -TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction

2009 ◽  
Vol 106 (15) ◽  
pp. 6250-6255 ◽  
Author(s):  
G. Gorgun ◽  
A. G. Ramsay ◽  
T. A. W. Holderried ◽  
D. Zahrieh ◽  
R. Le Dieu ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Identification by Serological Proteome Analysis (SERPA) of Tumor-Associated Antigens Eliciting Antibody Responses In Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 917-917
Author(s):  
Marta Coscia ◽  
Michela Capello ◽  
Valentina Griggio ◽  
Federica Linty ◽  
Candida Vitale ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Immune Responses ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Ifn Gamma ◽  
Tumor Associated Antigens ◽  
Pulsed Dc

Abstract Abstract 917 In this study we applied the serological proteomics-based approach (SERPA) to identify novel tumor associated antigens (TAA) capable of inducing humoral immune responses in patients with chronic lymphocytic leukemia (CLL). Proteins extracted from the leukemic cells isolated from the peripheral blood of 21 untreated CLL patients were separated by 2-DE electrophoresis and transferred onto membranes by electroblotting to obtain 21 2-DE proteomic maps. Each map was subsequently probed with the corresponding autologous serum collected from the same patient. To verify the CLL-specificity of antibodies (Ab) recognition, 7 out of 21 maps obtained from CLL patients were also probed with sera collected from 7 healthy donors (HD). The Western Blot (WB) performed with sera of CLL patients displayed a total of 45 immunoreactive spots. Only 3 antigen spots were detected in HD sera. For identification, antigen spots in WB were aligned with proteins in 2-DE. The protein spots corresponding to the assigned antigens were excised from the gel, destained and subjected to trypsin digestion. The resulting tryptic fragments were analyzed by peptide mass fingerprint by MALDITOF-MS with MASCOT. All the 45 antigen spots were characterized and consisted of 16 different antigens. Sixteen out of 21 CLL sera (76%) showed immunoreactivity against at least 1 of the 16 identified TAA and 69% of these reactive sera recognized from 2 to 6 different antigens. The IGHV mutational status was available in 20 CLL patients and 12 patients were M, while 8 patients were UM. The reactivity rate and number of WB spots were similar in M and UM patients and did not correlate with other parameters of clinical outcome. Sera from 46% CLL patients exhibited immunoreactivity against a protein which was identified by mass spectrometry as α-Enolase (ENOA). Interestingly, ENOA recognition was CLL specific since none of the sera from HD showed reactivity against this protein. The frequency of ENOA recognition was particularly high in M patients. Indeed, ENOA was recognized from sera of 7 out of 12 M patients (59%), but only from sera of 2 out of 8 UM patients (25%). The ability of ENOA to induce antigen-specific T cell responses was assessed. T cells isolated from the PB of a CLL patient with Ab-based ENOA reactivity were stimulated with autologous monocytes-derived ENOA-pulsed dendritic cells (DC). The results showed that CLL-derived ENOA-pulsed DC stimulated autologous T cells to secrete IFN-gamma. This response was ENOA-specific because it was not induced by unpulsed DC or DC pulsed with an irrelevant protein, and also CLL-specific because IFN-gamma release was not induced when T cells from a HD were stimulated with autologous ENOA-pulsed DC. Altogether, these results indicate that ENOA is capable of eliciting CLL-specific humoral and cellular immune responses. Therefore, ENOA can be considered as an alternative and promising biomarker in CLL, as well as a potential target candidate for immunotherapeutic approaches. Disclosures: Boccadoro: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Massaia:Novartis: Honoraria, Research Funding.

scholarly journals Identification of Baseline Characteristics That Predict Good Outcome of Allogeneic Hematopoietic Cell Transplantation in Young Chronic Lymphocytic Leukemia Patients - a Retrospective Analysis from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 522-522
Author(s):  
Michel van Gelder ◽  
Dimitris Ziagkos ◽  
Liesbeth C de Wreede ◽  
Anja van Biezen ◽  
Peter Dreger ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Lymphocytic Leukemia ◽  
Unrelated Donor ◽  
Advisory Committees ◽  
Matched Sibling

Abstract Patients with relapsed/refractory chronic lymphocytic leukemia (CLL) have excellent responses with kinase or BCL2 inhibitors, but patients with high risk cytogenetics (del(17p) and/or del(11q)) do not seem to achieve long-term disease control. Allogeneic hematopoietic stem cell transplantation (alloHCT) can result in sustained progression-free survival. As non-relapse mortality (NRM) after alloHCT is partly age-dependent, alloHCT is preferably considered in younger high cytogenetic risk CLL patients, but data of early NRM and longer-term PFS lack for this age group. We focused in this study on younger allo-transplanted CLL patients (<50 years) in an EBMT registry cohort with additional data collection (n=197, median follow-up 90.4 months). The most important prognostic factor for 2-year NRM in multivariate analysis was the donor HLA match: HR 2.5, 95% CI: 1.1-5.4 for an HLA-matched unrelated donor, and HR 4.0, 95% CI: 1.4-11.6 for an HLA-mismatched unrelated donor, both versus a matched sibling (Table 1). Predictors for poor 8-year PFS were "no remission at the time of alloHCT" (HR 1.7 (95% CI: 1.1-2.5)) and partially HLA-mismatched unrelated donor (HR 2.8 (95% CI: 1.5-5.2))(Table 2). High risk cytogenetics did not have a significant impact on 8-year PFS. Based on the regression model, a reference patient was created with high risk cytogenetics (del(17p) and/or del(11q)) and "good transplant" characteristics (remission at the time of alloHCT and HLA- and sex-matched sibling donor). The predicted two-year NRM for this patient was 12.1% (95% CI: 2.5%-21.7%)(Figure A) and 8-year PFS 53.5% (95% CI: 38.0%-69.0%)(Figure B). Such a low predicted NRM may keep up with the 9% "real-world" reported 1-year NRM of ibrutinib and the 8-year PFS compares favorably to outcomes after using kinase inhibitors or venetoclax. Taking into account the amount of uncertainty for predicting survival after alloHCT but also for the sequential administration of kinase inhibitors and venetoclax, alloHCT still remains a valid option for younger high cytogenetic risk refractory/relapsed CLL patients with a 10/10 HLA-allele matched donor. Figure. Figure. Disclosures Dreger: Novartis: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy; Gilead: Consultancy; Roche: Consultancy. Gramatzki:Janssen: Other: Travel/Accommodation/Expenses, Research Funding. Delgado:Janssen: Consultancy, Honoraria; Novartis/GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Infinity: Research Funding. Schoenland:Jansen: Honoraria, Other: financial support of conference participation, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schetelig:Sanofi: Honoraria.

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