scholarly journals Artificial Intelligence-Assisted Mapping of Proliferation Centers in Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma Identifies Patterns That Reliably Distinguish Accelerated Phase and Large Cell Transformation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1558-1558
Author(s):  
Siba El Hussein ◽  
Pingjun Chen ◽  
L. Jeffrey Medeiros ◽  
Jia Wu ◽  
Joseph D. Khoury
Keyword(s):  
Artificial Intelligence ◽  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Nuclear Size ◽  
Predictive Values ◽  
Mean Intensity ◽  
Heat Value ◽  
Disease Entities ◽  
The Mean

Abstract Background Chronic lymphocytic leukemia (CLL) involving tissues is characterized by sheets of small lymphocytes and vague nodules of larger cells, known as proliferation centers (PCs). CLL can undergo progression to accelerated CLL (aCLL) or further progress to diffuse large B-cell lymphoma, also known as Richter transformation (RT). Distinguishing CLL with many PCs from aCLL or RT can be challenging, particularly in small needle-biopsy specimens. In this study, we sought to design an artificial intelligence (AI)-based tool to automate and enhance the delineation of PCs and provide an objective approach to CLL/SLL acceleration/transformation. Material & Methods We manually annotated 25, 28 and 21 regions of interest (ROIs) encompassing small round PCs and confluent/ expanded PCs of 10 CLL, 12 aCLL, and 8 RT digitized hematoxylin & eosin stained slides, respectively (Figure A1). We analyzed the ROIs with both length and width larger than 2,000 pixels and set the tile length and stride as 1,000 and 100 pixels, respectively (Figure A1), and were able to extract sufficient tiles from each ROI (Figure A2). To recreate PCs, after performing nuclear segmentation via convolutional neural network and quality control, we quantified the nuclear size/intensity of cells occupying each tile (Figure A3). Nuclear size varied from 8 to 108 square micrometers, and nuclear mean intensity varied from 0 to 255. We normalized both the values of nuclear size and mean intensity to 0.0 and 1.0, by subtracting the minimum value and dividing it by the value range length. Nuclear size and mean intensity were represented as S(celli) and Imean(celli), respectively. We estimated the heat value of one tile integrating nuclear and mean intensity using the equationin Figure A2. Results We generated heatmaps based on the heat values per tile inside each ROI from the 3 disease entities (CLL, aCLL and RT), as illustrated in Figures B1-4. Areas with high heat values (in the yellow spectrum) correspond to tiles harboring cells with increased nuclear size and mean intensity (PCs in CLL cases and expanded/ confluent PCs in aCLL and RT cases). In contrast, areas with low heat values (in the blue spectrum) correspond to tiles with decreased nuclear size and mean intensity (small neoplastic lymphocytes surrounding PCs) (Figure B4).We then generated a heat value histogram per tile for each ROI (Figure B5).Based on these results, the two optimal thresholds isolated to obtain the highest separation value among the three disease entities based on the optimal F-score were: 0.228, below which the case was most likely to be CLL, and 0.288, above which the case was most likely to be RT. Cases with heat values ranging between 0.228 and 0.288 were most likely aCLL cases. We then plotted the mean heat value frequencies of the 3 entities: There was a significant difference in the ranges of mean heat value frequencies for CLL, aCLL, and RT, which were 0.168 to 0.233, 0.212 to 0.307, and 0.261 to 0.353, respectively (Figure C). The accuracy and area under the curve diagnostic predictive values using data from nuclear size alone were 0.658 (+/-0.115) and 0.771 (+/-0.096), respectively; and using mean nuclear intensity, 0.679 (+/-0.094) and 0.841 (+/-0.052), respectively; with a noticeable increase using heat value frequencies (integrating the nuclear size and mean nuclear intensity) reaching 0.813 (+/-0.0630) and 0.885 (+/-0.109), respectively. Conclusion We describe a novel AI-based heatmap technique to objectively assess the extent of PCs in CLL, based on the integrative analysis of cell nuclear size and mean nuclear intensity. We suggest that an ROI mean heat value less than 0.228 is predictive of CLL, and more than 0.288 is predictive of RT. aCLL cases demonstrate a mean heat value ranging from 0.228 to 0.288. Using the mean heat value of all cases, we were able to reliably separate the three entities in question with robust diagnostic predictive values. Figure 1 Figure 1. Disclosures Khoury: Stemline Therapeutics: Research Funding; Kiromic: Research Funding; Angle: Research Funding.

Costs to Medicare of Treating Chronic Lymphocytic Leukemia Patients with Alemtuzumab.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2477-2477
Author(s):  
Marie-Hélène Lafeuille ◽  
Francis Vekeman ◽  
Matthew Kerrigan ◽  
Si-Tien Wang ◽  
Mei Duh
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cardiac Dysfunction ◽  
Healthcare Costs ◽  
Research Funding ◽  
Care Service ◽  
Lymphocytic Leukemia ◽  
Western World ◽  
Diagnostic Code ◽  
Diagnostic Codes ◽  
The Mean

Abstract Abstract 2477 Poster Board II-454 Background: Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the Western world, comprising over one-third of all new leukemia cases. Alemtuzumab is a humanized monoclonal antibody targeted to lymphocytes through the CD52 receptor that has been demonstrated to reduce the amount of malignant lymphocytes in patients with CLL. Alemtuzumab is, however, associated with various adverse events (AEs) including cytopenia, infections, and cardiac dysfunction. The current study aimed to quantify the incremental cost to Medicare of treating CLL patients with alemtuzumab. Methods: An analysis of patients' electronic health insurance claims records (1999-2007) from the Medicare 5% national sample was conducted. Patients with continuous enrollment for 3 or more months prior to their first observed claim with a CLL diagnosis, no more than two malignancies (by ICD-9 diagnostic codes associated with claims), and 1 or more claim for alemtuzumab were included in the analysis. Patients who had HMO coverage under Medicare were excluded from the analysis to ensure data completeness. A pre-post design was used to quantify the incremental costs associated with alemtuzumab by calculating health care costs within 6 months after alemtuzumab initiation relative to the 6-month period before alemtuzumab initiation. Mean monthly (per-patient per-month, PPPM) costs were calculated and were grouped by sites of care, service type, tests and procedures, treatment and drugs, and by AEs. To estimate the costs of AEs, claims with ICD-9 diagnostic codes for the AE of interest were grouped and mean PPPM costs were calculated for those groups. These groups were not mutually exclusive: claims could be associated with more than one diagnostic code. Statistical comparisons between the pre- and post-treatment periods were based on paired Student t-tests. Results: A total of 81 CLL patients treated with alemtuzumab formed the study population. The mean age (SD) was 75.2 (7.5) years and females represented 38.3% of the cohort. Patients were observed for an average of 50 months and mean time between the first observed CLL diagnosis and initiation of alemtuzumab treatment was 36 months. After alemtuzumab initiation, mean total healthcare costs increased from $4,272 to $10,385 PPPM (cost difference: $6,113, P<0.0001). Patients had a mean of 11.8 claims for alemtuzumab and the mean cost (SD) for alemtuzumab was $4,006 ($3,277) PPPM in the post-alemtuzumab period or 39% of total costs. Costs associated with diagnostic codes for cytopenia were $1,658 pre-alemtuzumab compared with $4,114 post-alemtuzumab (P<0.0001). In the pre- alemtuzumab period, costs with infection-related diagnostic codes were $107 PPPM compared with $841 in the post-alemtuzumab period (P=0.0005). Costs associated with cardiac dysfunction diagnostic codes were $766 PPPM in the pre-alemtuzumab period and $1,692 in the post-alemtuzumab period (P=0.0172) (Table 1). Note that these cost categories are not mutually exclusive. Conclusions: Amongst a cohort of Medicare fee-for-service patients with CLL, alemtuzumab was associated with a significant increase in healthcare costs in the 6 months after initiation of therapy of which the costs of alemtuzumab, oncology services, cytopenias, infections, and cardiac dysfunctions were large components. Disclosures: Lafeuille: Groupe d'analyse: Employment; GlaxoSmithKline: Research Funding. Vekeman:Groupe d'analyse: Employment; GlaxoSmithKline: Research Funding. Kerrigan:GlaxoSmithKline: Employment. Wang:Analysis Group: Employment; GlaxoSmithKline: Research Funding. Duh:GlaxoSmithKline: Research Funding; Analysis Group: Employment.

scholarly journals Mechanisms of Adaptation to Ibrutinib in High Risk Chronic Lymphocytic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 585-585 ◽  
Author(s):  
Valeria Spina ◽  
Gabriela Forestieri ◽  
Antonella Zucchetto ◽  
Alessio Bruscaggin ◽  
Tamara Bittolo ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Nuclear Localization ◽  
Peripheral Blood ◽  
Research Funding ◽  
Clonal Evolution ◽  
Lymphocytic Leukemia ◽  
Adaptation Process ◽  
Over Time ◽  
Stimulation Of

Abstract Introduction. Ibrutinib inhibits the BTK molecule downstream the B-cell receptor (BCR). Though highly active in high risk chronic lymphocytic leukemia (CLL), the most typical response achievable in patients is a minimal residual disease (MRD) positive partial remission (PR) which is maintained until the development of genetically driven resistance caused by the acquisition of mutations in the BTK or PLCG2 genes. The study aims at characterizing the adaptation process allowing residual CLL cells to persist despite BTK inhibition. Methods. The IOSI-EMA-001 study (NCT02827617) is an observational study consisting in the prospective and longitudinal collection of peripheral blood samples and clinical data from high risk CLL patients treated with ibrutinib. Peripheral blood CLL cells longitudinally drawn from patients before treatment start and at fixed timepoints under ibrutinib were monitored by: i) next generation flow cytometry approaches for changes in proliferation rate, surfaceome, and pathway activation; and ii) CAPP-seq targeted deep next generation (sensitivity ~10-3) for clonal evolution. Results. The study cohort comprised 31 high risk CLL patients, including 15 treatment naïve, 16 relapsed, 80% IGHV unmutated, 42% 17p deleted and 55% TP53 mutated. Median duration of ibrutinib treatment was 45 weeks (24-72 weeks). All patients obtained a MRD positive PR that was maintained in all but one who progressed with a PLCG2 mutation (VAF 3%). Compared to baseline, under ibrutinib therapy CLL cells slowed down their proliferation, as suggested by the decreased expression of Ki-67, the reduction of the proliferating fraction (CXCR4dimCD5bright), and the increase of the resting fraction (CXCR4brightCD5dim). Compared to baseline, under ibrutinib therapy CLL cells also upregulated BCR and adhesion/homing proteins, and decreased the expression of BCR inhibitor proteins. Upon stimulation of the BCR with anti-IgM, the downstream path through pBTK and pPLCG2 was inhibited by ibrutinib, while conversely the downstream path through pAKT and pERK was still inducible throughout all the assessed timepoints. The proportion of CLL cells harboring nuclear localization of NF-kB progressively increased over time under ibrutinib. NF-kB nuclear localization was inducible throughout all the assessed timepoints by CD40L stimulation of the non-canonical NF-kB pathway, but not by anti-IgM stimulation of the BCR/canonical NF-kB pathway. Overall, 880 individual mutations were longitudinally discovered and monitored across a total of 121 sequential timepoints collected during ibrutinib treatment. Clonal evolution was observed in (67.7%) cases, a proportion rate previously documented in CLL treated with chemoimmunotherapy. Clonal evolution appeared to be heterogeneous involving different genes without a stereotypic targeting. Consistently, none of the main driver gene mutations was homogeneously selected or suppressed by ibrutinib suggesting that the biological adaptation of CLL cells under ibrutinib is not genetically driven. Clonal evolution propensity was not associated with any of the biomarkers of the disease, and it did not decrease over time under ibrutinib. Conclusions. Taken together these results suggest that residual CLL cells persisting under ibrutinib therapy adapt their phenotype by upregulating adhesion molecules, chemokine receptors and BCR molecules, and by maintaining a competence of BCR signaling through the PI3K/AKT/ERK pathway. The progressive selection of CLL cells having NF-kB in the nucleus, likely due to the BTK independent non-canonical NF-kB pathway, might explain their survival despite ibrutinib therapy. Finally, clonal evolution is not suppressed by ibrutinib chemotherapy, and despite does not seem to be directly involved in such adaptation process, may ultimately favor the acquisition of BTK and PLCG2 ibrutinib resistance mutations. Disclosures Zucca: Celltrion: Consultancy; AstraZeneca: Consultancy. Ghia:Sunesis: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie, Inc: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding. Montillo:Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding. Tedeschi:Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy; AbbVie: Consultancy. Gaidano:AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Morphosys: Honoraria; Roche: Consultancy, Honoraria.

scholarly journals Lenalidomide and Rituximab Maintenance Therapy after Front-Line Induction Chemoimmunotherapy in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5470-5470
Author(s):  
Julie E Chang ◽  
Vaishalee P. Kenkre ◽  
Christopher D. Fletcher ◽  
Aric C. Hall ◽  
Natalie Scott Callander ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Second Malignancies ◽  
Front Line ◽  
First Line ◽  
11Q Deletion ◽  
Line Chemotherapy

Introduction: Chronic lymphocytic leukemia (CLL) is incurable with standard therapy. With first-line chemotherapy, some patients (pts) may achieve durable remissions of many months/years. Lenalidomide (LEN) has improved progression-free survival (PFS) when given as maintenance (MNT) therapy after front-line chemotherapy (CALGB10404, CLLM1). The combination of LEN + rituximab (LR) has activity in relapsed CLL, hypothesizing benefit as MNT therapy after first-line chemotherapy. Methods: Adult pts ≥18 years with previously untreated CLL received induction bendamustine (B) 90 mg/m2 IV days 1 & 2 and rituximab (R) IV day 1 (375 mg/m2 cycle 1, then 500 mg/m2 cycles 2-6) for 6 treatment cycles (as few as 4 cycles allowed). MNT therapy with LR was initiated within 12 weeks after cycle 6, day 1 of BR. Criteria to start LR MNT included: neutrophils ≥1000/microliter (uL), platelets ≥75 K/uL, and creatinine clearance ≥40 mL/min. LEN was administered in 28-day cycles for 24 cycles, initially 5-10 mg daily continuous dosing, later modified to 5-10 mg on days 1-21 of each 28-day cycle in 6/2018 due to neutropenia and second malignancy risk. LEN was reduced to 5 mg every other day for toxicities at 5 mg/day. R 375 mg/m2 IV was given every odd cycle (total of 12 doses). Patients discontinuing LEN for any reason were allowed to continue R MNT per protocol. The primary endpoint is PFS with LR MNT therapy, calculated from the first day of MNT therapy until progressive disease (PD), death, or start of a new therapy. Secondary endpoints are response rate and overall survival. Results: Thirty-four pts have enrolled beginning 11/2013, with follow-up through 6/2019. Median age is 64 years, with 8 pts ≥70 years; 8 women and 26 men. CLL FISH panel is available on all pts: 14 with 13q (as sole abnormality), 9 with 11q deletion, 6 with trisomy 12, 4 with normal FISH panel and 1 with 17p deletion. Heavy chain mutation analysis is available on 11 pts: 8 unmutated, 2 mutated, 1 indeterminate. Thirty-one pts completed 4 (n=2) or 6 cycles of induction BR; 3 pts are receiving induction BR. Twenty-four pts have received MNT LR; 7 did not receive LR for reasons of PD during induction (n=2), infection (n=1), pt preference (n=2), renal insufficiency (n=1), and new carcinoma (n=1). MNT LR was completed in 7 pts; 9 pts are still receiving LR. Fourteen subjects have discontinued protocol therapy, 3 during induction due to PD (n=2) and infection (n=1), and 8 during MNT. Toxicities that led to discontinuation of LR were recurrent infections in 7 pts, including 2 events of PJP pneumonia; 4 pts had recurrent neutropenia with infections; 1 pt had neutropenia without infections. Response is assessable in 31 patients using the International Working Group Consensus Criteria. Best responses to treatment were: partial response 65% (22/34), complete response (CR)/unconfirmed CR 24% (8/34). The median number of MNT cycles received is 16. The dose intensity of LEN across total cycles received (n=278): 5 mg every other day (52.5%), 5 mg/day (43.9%), and 10 mg/day (3.6%). The most common reason for dose reduction or dose holding was neutropenia. Most common Gr 3/4 toxicities (reported as events Gr3/Gr4) during MNT therapy were: neutropenia (20/20), leukopenia (19/4), febrile neutropenia (3/1), and infections (11/-). The majority of Gr3 infections were pneumonia/respiratory (n=5). One event of disseminated herpes zoster occurred. Second malignancies during MNT included: basal cell CA (n=1), squamous cell carcinoma (n=5), and colon cancer (n=1). No unexpected second malignancies were observed in pts receiving LR. Two-year PFS (defined from day 1 of MNT therapy) is 90% (95% confidence interval [CI] 0.78-1), and the median follow-up for 24 patient who started maintenance therapy is 1.79 years (95% CI 1.53-2.7). There have been no deaths. Conclusion: The combination of LR is effective in sustaining remissions after a BR induction in previously untreated CLL, but with frequent neutropenia and infections even at low doses of LEN. Most patients discontinuing MNT did so due to neutropenia and/or infections. A shorter planned interval of MNT LR (i.e., 6-12 months) may confer similar benefit to extended dosing that is more tolerable. Pts at high risk for short remissions after front-line chemotherapy (e.g., unmutated heavy chain status, 11q deletion and/or failure to achieve minimal residual disease after induction) may be the populations for which LR MNT therapy is most appropriate. Disclosures Chang: Genentech: Research Funding; Adaptive Biotechnologies: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Lenalidomide administered as maintenance therapy for first treatment of CLL/SLL.

scholarly journals 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 ◽  
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.

scholarly journals Long-Term Sustained Responses Following Ibrutinib Discontinuation after Frontline Therapy with Obinutuzumab Plus Ibrutinib in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Paula A. Lengerke Diaz ◽  
Michael Y. Choi ◽  
Eider F. Moreno Cortes ◽  
Jose V. Forero ◽  
Juliana Velez-Lujan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Side Effects ◽  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Combination Regimen ◽  
Grade 3

Single oral targeted therapies have emerged as a standard of care in chronic lymphocytic leukemia (CLL). However, accessibility, side effects, and financial burden associated with long term administration limit their clinical use. Mainly, it is unclear in what clinical situation discontinuation of oral therapy can be recommended. The combination of type II anti-CD20 antibody obinutuzumab-Gazyva® with ibrutinib (GI) has shown a significant progression-free survival benefit in patients (pts) with CLL, including those with high-risk genomic aberrations. We conducted a phase 1b/2, single-arm, open-label trial to evaluate the safety and efficacy of GI as first-line treatment in 32 CLL pts. We report the outcome in pts that discontinued ibrutinib (either after 3 years of sustained complete response (CR) as stipulated in the clinical protocol, or due to other reasons). CLL pts enrolled in this protocol were ≥65 years old, or unfit/unwilling to receive chemotherapy. Pts received GI for six cycles, followed by daily single-agent ibrutinib. The protocol was designed to ensure that pts with a sustained CR after 36 months were allowed to discontinue ibrutinib. The median age was 66 years (IQR 59-73), and 6% of the evaluated pts had 17p deletion. All pts were able to complete the six planned cycles of obinutuzumab. The combination regimen was well-tolerated, and the most common adverse events (&gt;5% CTCAE grade 3-4) were neutropenia, thrombocytopenia, and hyperglycemia. The rate and severity of infusion-related reactions (IRR) were much lower than expected (Grade≥ 3, 3%), and pts without IRR had lower serum levels of cytokines/chemokines CCL3 (P=0.0460), IFN-γ (P=0.0457), and TNF-α (P=0.0032) after infusion. The overall response rate was 100%, with nine pts (28%) achieving a CR, and four pts (12.5%) with undetectable minimal residual disease (uMRD) in the bone marrow, defined as &lt;10-4 CLL cells on multicolor flow cytometry. At a median follow-up of 35.5 months (IQR 24.5-42.7) after starting treatment, 91% of the enrolled pts remain in remission with a 100% overall survival. Sixteen pts have completed a long-term follow-up of 36 months. Six pts showed CR, with three of them achieving uMRD in the bone marrow. Ten of these pts were in PR, and only one had disease progression and started treatment for symptomatic stage I disease with obinutuzumab plus venetoclax. In total, thirteen pts (41%) have stopped ibrutinib, with a median time on treatment prior to discontinuation of 35 months. Five (16%) of these pts had CRs and discontinued after 36 months. Eight additional pts (25%) had PRs and discontinued ibrutinib without being eligible: three pts discontinued prior to 36 months due to toxicities, and five pts discontinued after 36 months (3 due to side effects, and 2 due to financially driven decision). One patient eligible to discontinue ibrutinib, decided to remain on treatment despite sustained CR. After a median follow up time following ibrutinib discontinuation of 8 months (IQR 3.5-17), only two out of 13 pts have progressed (10 and 17 months after Ibrutinib discontinuation). None of the pts that stopped ibrutinib after achieving a CR have shown signs of disease progression. Of note, the pharmaceutical sponsor provided ibrutinib for the first 36 months, after which pts or their insurer became financially responsible. This particular scenario could bias the discontinuation pattern compared to a real world experience. It also provided us with a perspective about diverse factors affecting the treatment choices of pts. In summary, the obinutuzumab plus ibrutinib combination therapy was well-tolerated, with a much lower IRR rate. Efficacy compares favorably with historical controls with all pts responding to therapy, no deaths associated with treatment or disease progression, and a longer than expected time-to-progression after discontinuation of ibrutinib. The rate of ibrutinib discontinuation was higher than reported in the literature, most likely influenced by the protocol design and financial decisions driven by the switch from sponsor-provided ibrutinib to insurance or self-paid medication. Our observations regarding safety, efficacy and lack of disease progression after ibrutinib discontinuation are encouraging, and warrant confirmation in long-term prospective studies. Clinicaltrials.gov Identifier NCT02315768. Funding: Pharmacyclics LLC. Disclosures Choi: AbbVie: Consultancy, Speakers Bureau. Amaya-Chanaga:AbbVie: Ended employment in the past 24 months, Other: Research performed while employed as an investigator of this study at UCSD.. Kipps:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Castro:Kite Pharma: Research Funding; Pharmacyclics: Research Funding; Fate Therapeutics: Research Funding.

scholarly journals Improvements in Health-Related Quality of Life and Symptoms in Patients with Previously Untreated Chronic Lymphocytic Leukemia: Final Results from the Phase II GIBB Study of the Combination of Obinutuzumab and Bendamustine

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3491-3491 ◽  
Author(s):  
Alexey Danilov ◽  
Habte A Yimer ◽  
Michael Boxer ◽  
John M Burke ◽  
Sunil Babu ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Health Status ◽  
Chronic Lymphocytic Leukemia ◽  
Global Health ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Future Health ◽  
Equity Ownership

Introduction: Longitudinal changes in health-related quality of life (HRQoL) are important in patients with chronic lymphocytic leukemia (CLL). GIBB (NCT02320487) is an open-label, single-arm phase II study of obinutuzumab (GA101; G) in combination with bendamustine (G-Benda) in patients with previously untreated CLL. A previous report from the GIBB study demonstrated an investigator-assessed objective response rate of 89.2%, a complete response rate of 49.0%, and no unexpected safety signals with G-Benda (Sharman et al. J Clin Oncol 2017). Here we report the final HRQoL data over 3 years from the GIBB study. Methods: Enrolled patients received G-Benda by intravenous infusion over six 28-day cycles: G 100mg on Day (D)1, 900mg on D2, and 1000mg on D8 and D15 of Cycle (C)1, then 1000mg on D1 of C2-6; benda 90mg/m2 on D2-3 of C1, and on D1-2 of C2-6. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) includes a global health status measure, 5 functional scales (physical, emotional, cognitive, social, and role functioning), 8 symptom scales/items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea), and an item on financial difficulties (Aaronson et al. J Natl Cancer Inst 1993). The EORTC Quality of Life Questionnaire-Chronic Lymphocytic Leukemia 16 (QLQ-CLL16) is a 16-item module, specific to CLL, containing 4 multi-item scales (fatigue, treatment side effects, disease symptoms, and infection) and 2 single items (social activities and future health worries). Both questionnaires were completed by patients on C1D1 (baseline), C3D1, and C6D1, at the end of induction (EOI) treatment (defined as +28 days from C6D1 or early treatment termination visit), at the response visit (defined as 2-3 months after the EOI treatment for all patients who received study treatment and had not experienced disease progression), and every 3 months thereafter at follow-up visits for up to 2 years. In total, there were 14 timepoints where data were collected. HRQoL scores were linear transformed to a 0-100-point scale. Mean baseline scores and mean score changes from baseline at each visit were evaluated. A threshold of ≥10-point change in score represents a clinically meaningful difference. For symptoms, negative change scores from baseline reflect an improvement in symptom burden. For global health status and functioning, positive change scores from baseline reflect improvements. Results: The trial enrolled 102 patients. Median age was 61 years and 68.4% of patients were male. Ninety-eight patients (96%) completed a questionnaire at baseline and at least 1 other questionnaire during a follow-up visit. Questionnaire completion rates at 14 time points ranged from 96% at baseline to 66% at 27 months follow-up (Table 1). According to the EORTC QLQ-C30 (Figure 1), improvements were observed for global health status at all follow-up visits, and clinically meaningful improvements were observed at the response visit, 3 months follow-up, and 27 months follow-up. Clinically meaningful improvements in role functioning were observed at EOI and persisted throughout the 27-month follow-up. For fatigue, clinically meaningful improvements were observed at every visit starting from the end of treatment (EOT) visit. Improvements were also observed for insomnia with mean reductions from baseline ≥10 points at various time points during follow-up. There was no worsening in other patient-reported symptoms or functional status over time. Similarly, with the EORTC QLQ-CLL16 (Figure 2), clinically meaningful improvements in symptoms were observed for fatigue, disease symptoms, and future health worries during treatment, at the EOT and/or throughout the follow-up. The largest improvement was observed for fatigue (-24.7) at the 24-month follow-up and future health worries (-25.4) at the 27-month follow-up. Conclusions: We previously reported that G-Benda is an effective regimen for first-line treatment of CLL with no unexpected safety signals. The HRQoL data from the GIBB trial suggest that G-Benda treatment consistently improved patient HRQoL over time. Several clinically meaningful improvements were observed in HRQoL, including global health status, functioning, symptoms, and future health worries. Disclosures Danilov: AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; MEI: Research Funding; Bristol-Meyers Squibb: Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Research Funding; Bristol-Meyers Squibb: Research Funding; Takeda Oncology: Research Funding; Aptose Biosciences: Research Funding; Aptose Biosciences: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Gilead Sciences: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Curis: Consultancy; Seattle Genetics: Consultancy; MEI: Research Funding; TG Therapeutics: Consultancy; Celgene: Consultancy; Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Abbvie: Consultancy; Abbvie: Consultancy. Yimer:AstraZeneca: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Honoraria; Celgene: Honoraria; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership; Amgen: Consultancy. Boxer:Gerson Lerman: Consultancy; Best Doctors: Consultancy; Takeda: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau. Burke:Celgene: Consultancy; Gilead: Consultancy; Roche/Genentech: Consultancy. Babu:Genentech: Research Funding. Li:Genentech: Employment; Roche: Equity Ownership. Mun:Genentech: Employment, Equity Ownership. Trask:Genentech: Employment, Equity Ownership. Masaquel:Roche: Equity Ownership; Genentech: Employment. Sharman:Acerta: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated: in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia; in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen

scholarly journals Recent progress of prognostic biomarkers and risk scoring systems in chronic lymphocytic leukemia

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Xiaoya Yun ◽  
Ya Zhang ◽  
Xin Wang
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tp53 Mutation ◽  
Scoring Systems ◽  
Lymphocytic Leukemia ◽  
Prognostic Biomarkers ◽  
Novel Agents ◽  
Prognostic Models ◽  
Predictive Values ◽  
Mutation Status ◽  
Staging Systems

Abstract Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia with high heterogeneity in the western world. Thus, investigators identified a number of prognostic biomarkers and scoring systems to guide treatment decisions and validated them in the context of immunochemotherapy. A better understanding of prognostic biomarkers, including serum markers, flow cytometry outcomes, IGHV mutation status, microRNAs, chromosome aberrations and gene mutations, have contributed to prognosis in CLL. Del17p/ TP53 mutation, NOTCH1 mutation, CD49d, IGHV mutation status, complex karyotypes and microRNAs were reported to be of predictive values to guide clinical decisions. Based on the biomarkers above, classic prognostic models, such as the Rai and Binet staging systems, MDACC nomogram, GCLLSG model and CLL-IPI, were developed to improve risk stratification and tailor treatment intensity. Considering the presence of novel agents, many investigators validated the conventional prognostic biomarkers in the setting of novel agents and only TP53 mutation status/del 17p and CD49d expression were reported to be of prognostic value. Whether other prognostic indicators and models can be used in the context of novel agents, further studies are required.

IKZF3 Overexpression Phenocopies Gain-of-Function Mutation in Chronic Lymphocytic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-9
Author(s):  
Shanye Yin ◽  
Gregory Lazarian ◽  
Elisa Ten Hacken ◽  
Tomasz Sewastianik ◽  
Satyen Gohil ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
Dna Binding ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Bcr Signaling ◽  
Experimental Group

A hotspot mutation within the DNA-binding domain of IKZF3 (IKZF3-L162R) has been identified as a putative driver in chronic lymphocytic leukemia (CLL); however, its functional effects are unknown. We recently confirmed its role as a CLL driver in a B cell-restricted conditional knock-in model. IKZF3 mutation altered mature B cell development and signaling capacity, and induced CLL-like disease in elderly mice (~40% penetrance). Moreover, we found IKZF3-L162R acts as a gain-of-function mutation, altering DNA binding specificity and target selection of IKZF3, and resulting in overexpression of multiple B-cell receptor (BCR) genes. Consistent with the murine data, RNA-sequencing analysis showed that human CLL cells with mut-IKZF3 [n=4] have an enhanced signature of BCR-signaling gene expression compared to WT-IKZF3 [n=6, all IGHV unmutated] (p&lt;0.001), and also exhibited general upregulation of key BCR-signaling regulators. These results confirm the role of IKZF3 as a master regulator of BCR-signaling gene expression, with the mutation contributing to overexpression of these genes. While mutation in IKZF3 has a clear functional impact on a cardinal CLL-associated pathway, such as BCR signaling, we note that this driver occurs only at low frequency in patients (~3%). Because somatic mutation represents but one mechanism by which a driver can alter a cellular pathway, we examined whether aberrant expression of IKZF3 could also yield differences in BCR-signaling gene expression. We have observed expression of the IKZF3 gene to be variably dysregulated amongst CLL patients through re-analysis of transcriptomic data from two independent cohorts of human CLL (DFCI, Landau et al., 2014; ICGC, Ferreira et al., 2014). We thus examined IKZF3 expression and BCR-signaling gene expression, or the 'BCR score' (calculated as the mean expression of 75 BCR signaling-associate genes) in those cohorts (DFCI cohort, n=107; ICGC cohort, n=274). Strikingly, CLL cells with higher IKZF3 expression (defined as greater than median expression) had higher BCR scores than those with lower IKZF3 expression (&lt;median) (p=0.0015 and p&lt;0.0001, respectively). These findings were consistent with the notion that IKZF3 may act as a broad regulator of BCR signaling genes, and that IKZF3 overexpression, like IKZF3 mutation, may provide fitness advantage. In support of this notion, our re-analysis of a gene expression dataset of 107 CLL samples (Herold Leukemia 2011) revealed that higher IKZF3 expression associated with poorer prognosis and worse overall survival (P=0.035). We previously reported that CLL cells with IKZF3 mutation appeared to increase in cancer cell fraction (CCF) with resistance to fludarabine-based chemotherapy (Landau Nature 2015). Instances of increase in mut-IKZF3 CCF upon treatment with the BCR-signaling inhibitor ibrutinib have been reported (Ahn ASH 2019). These studies together suggest an association of IKZF3 mutation with increased cellular survival following either chemotherapy or targeted treatment. To examine whether higher expression of IKZF3 was associated with altered sensitivity to ibrutinib, we performed scRNA-seq analysis (10x Genomics) of two previously treatment-naïve patients undergoing ibrutinib therapy (paired samples, baseline vs. Day 220). We analyzed an average of 11,080 cells per patient (2000 genes/cell). Of note, following ibrutinib treatment, remaining CLL cells expressed higher levels of IKZF3 transcript compared to pretreatment baseline (both p&lt;0.0001), whereas no such change was observed in matched T cells (n ranging between 62 to 652 per experimental group, p&gt;0.05), suggesting that cells with high expression of IKZF3 were selected by ibrutinib treatment. Moreover, we showed that ibrutinib treatment resulted in consistent upregulation of BCR-signaling genes (e.g., CD79B, LYN, GRB2, FOS, RAC1, PRKCB and NFKBIA) (n ranging between 362 to 1374 per experimental group, all p&lt;0.0001), which were likewise activated by mutant IKZF3. Altogether, these data imply that IKZF3 mutation or overexpression may influence upregulation of BCR-signaling genes and enhance cellular fitness even during treatment with BCR-signaling inhibitors. We highlight our observation that IKZF3 mutation appears to be phenocopied by elevated IKZF3 expression, and suggest that alterations in mRNA or protein level that mimic genetic mutations could be widespread in human cancers. Disclosures Kipps: Pharmacyclics/ AbbVie, Breast Cancer Research Foundation, MD Anderson Cancer Center, Oncternal Therapeutics, Inc., Specialized Center of Research (SCOR) - The Leukemia and Lymphoma Society (LLS), California Institute for Regenerative Medicine (CIRM): Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; VelosBio: Research Funding; Oncternal Therapeutics, Inc.: Other: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory, Research Funding; Ascerta/AstraZeneca, Celgene, Genentech/F. Hoffmann-La Roche, Gilead, Janssen, Loxo Oncology, Octernal Therapeutics, Pharmacyclics/AbbVie, TG Therapeutics, VelosBio, and Verastem: Membership on an entity's Board of Directors or advisory committees. Wu:BionTech: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding.

Prior Treatment with Alemtuzumab Interferes with T-Cell Engraftment After Allogeneic Stem Cell Transplantation in Patients with Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3351-3351
Author(s):  
Johannes Schetelig ◽  
Christian Thiede ◽  
Alexander Kiani ◽  
Uwe Platzbecker ◽  
Uta Oelschlaegel ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Washout Period ◽  
Research Funding ◽  
Limit Of Detection ◽  
Lymphocytic Leukemia ◽  
Cell Engraftment ◽  
Median Level ◽  
Antibody Levels ◽  
Donor Lymphocyte Infusions

Abstract Abstract 3351 Poster Board III-239 Objectives: The majority of patients with chronic lymphocytic leukemia (CLL) who receive allogeneic hematopoietic cell transplantation (HCT) have fludarabine-refractory disease. The most active single agent in this disease stage is alemtuzumab. Alemtuzumab has a long half-life and induces profound T-cell depletion (TCD). Since TCD may mitigate graft-versus leukemia effects we evaluated „pre-conditioning“ with alemtuzumab followed by a washout period in order to minimize in vivo T-cell depletion of the graft in a phase II study (NCT 00337519). Methods: Patients received cytoreductive treatment with 3 × 30 mg alemtuzumab weekly prior to HCT. The scheduled interval between last dose of alemtuzumab and HCT was increased from two weeks to one month during the study. The antibody level at the day of HCT was measured with an ELISA with a lower limit of detection of 31.25 ng/mL (BioAnaLab lim., Oxford, UK). The conditioning regimen contained fludarabine (150 mg/m2) and busulfan (8 mg/kg). Cyclosporine (CSA) and methotrexate (MTX) were applied as GVHD-prophylaxis. Medically fit patients with relapsed CLL were elible. Results: 62 patients with a median age of 57 years were included between April, 2004 and October, 2008. A median of 3 prior regimens had been given. 55% of the patients had fludarabine-resistant disease. Two patients failed to reach HCT due to progressive disease during alemtuzumab therapy. Donors were matched siblings for 26 and matched unrelated donors for 34 patients. The median level of alemtuzumab in peripheral blood after a washout period of two weeks was 62 ng/mL (interquartile range, 45 to 196 ng/mL; minimum below the limit of detection; maximum 490 ng/mL) compared to a median level below the limit of detection after a delay of four weeks (interquartile range, between the limit of detection and 77 ng/mL, maximum 256 ng/mL) (p=0.005). Despite one month time between the last dose of alemtuzumab and HCT 4 out of 30 patients (13%) had alemtuzumab levels greater than 200 ng/mL. No primary or secondary graft failure occurred. A linear relationship between the alemtuzumab level at HCT and the time to complete CD4-T-cell chimerism (TCC) was observed (p=0.003). At day +100 a CD4 positive T-cell-chimerism (TCC) >95% had been achieved by 84% of patients with alemtuzumab levels <100 ng/mL, 83% of patients with antibody levels between 100 and 200 ng/mL and 25% of patients with antibody levels >200 ng/mL (p=0.006). All patients had a complete neutrophil-chimerism at day +100. After early taper of immunosuppression (N=2) or the application of donor lymphocyte infusions in incremental doses (N=5) mixed TCC has been converted to complete TCC in all patients. The median follow-up is 17 months (1 to 61 months). Day +100 non-relapse mortality was 2%. At two years non-relapse mortality and relapse incidence were 21% and 29%, respectively. Two-year overall survival and progression-free survival were 67% (95% CI, 51% to 83%) and 50% (95% CI, 31% to 69%). Conclusions: In patients who received alemtuzumab prior to HCT, residual drug levels may interfere with T-cell engraftment. Lineage specific T-cell chimerism should therefore be assessed prospectively in this group of patients. Persistent mixed T-cell chimerism can be converted by an early taper of immunosuppression and incremental doses of donor lymphocyte infusions. Disclosures: Schetelig: Bayer Schering: Research Funding. Platzbecker:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document