Disability Associated with Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation

Abstract Chronic graft-versus-host disease (cGVHD) is the leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT) and is associated with poor quality of life (QoL) and functional status among long-term HCT survivors. Disability is defined as any physical or mental impairment that limits a person's ability to do certain activities or interact with their environment. There are limited data regarding the association of cGVHD and disability. The aim of this study is to define disability and further understand contributing factors in patients with cGVHD. The Living With cGVHD Patient Survey was a cross-sectional online survey administered from May to August 2020 to US adult patients who reported a cGVHD diagnosis within the previous 5 years. Participants were recruited through patient advocacy groups and online patient panels. Respondents reported demographics, disease diagnosis, work status, cGVHD symptoms per Lee Symptom Scale (LSS), and impact on activities of daily living. Descriptive and correlational analyses were used to inform 3 composite definitions of disability: (1) severe cognitive disability (any report of severe limitation [>7 on a 0-10 scale] concerning managing personal finances, social interaction, or computer use); (2) severe physical disability (any report of severe limitation concerning personal hygiene; dressing; eating; or ability to use the restroom, move around the house, prepare meals, shop, do housework, or get around outside the home); and (3) work disability (any report of taking disability leave or leaving a job because of cGVHD). Out of 165 total survey respondents, 28 reported being retired, self-employed, or a homemaker and were excluded from the analysis as they were not considered part of the potentially employable general workforce (N=137). There were no demographic or cGVHD differences between respondents included in the study cohort vs those who were excluded. Nearly half of respondents (47%) reported severe cognitive limitations in at least 1 of the activities of the composite score (Figure 1). Univariable analyses demonstrated that cGVHD severity/duration (P=0.0056); LSS eye (P=0.0266), mouth (P=0.0132), lung (P=0.0002), skin, nutrition, energy, and psychological symptoms (P<0.0001 for all); and number of treatments (P=0.0210) and specialists seen (P=0.0030) were all associated with self-reported severe cognitive disability. Skin and psychological symptoms and number of specialists seen remained significant in a multivariable analysis (Table 1). Two-thirds (67%) of respondents reported severe physical disability associated with cGVHD (Figure 1). In univariable analyses, cGVHD severity/duration (P=0.0003); LSS skin (P=0.0112), eyes (P=0.0107), psychological (P=0.0003), mouth, lungs, nutrition, energy symptoms (P<0.0001 for all); and number of treatments (P=0.0323) and specialists seen (P=0.0275) were associated with physical disability. In a multivariable analysis, female sex and energy, mouth, and nutrition symptoms were found to be significant (Table 1). Nearly two-thirds of respondents (63%) reported work disability (Figure 1). In univariable analyses, non-White race (P=0.0248); cGVHD severity/duration (P=0.0220); LSS skin (P=0.005), eyes (P=0.0239), mouth (P=0.0222), lungs (P=0.0011), nutrition (P=0.0010), energy (P<0.0001), and psychological symptoms (P=0.0014); and number of specialists seen (P=0.0495) were associated with work disability. Results from a multivariable analysis confirmed race and energy to be factors significantly associated with work disability (Table 1). A substantial proportion of survey respondents reported severe cognitive and physical disability, as well as work-related disability, associated with cGVHD, highlighting the importance of defining and better understanding cGVHD-associated disability. Additional investigations of the impact of work type, sex and racial disparities, and specific cGVHD symptoms are needed to further understand this relationship and improve the overall health-related QoL of long-term HCT survivors. Figure 1 Figure 1. Disclosures Hamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Williams: Incyte Corporation: Other: Employee of IQVIA, the company commissioned by Incyte Corporation to conduct this study. Flore: Incyte Corporation: Other: Employee of IQVIA, the company commissioned by Incyte Corporation to conduct this study. Galvin: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Turnbull: Incyte Corporation: Other: Employee of IQVIA, the company commissioned by Incyte Corporation to conduct this study. Yu: Incyte Corporation: Current Employment, Current holder of individual stocks in a privately-held company.

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Prediction of Graft-Versus-Host Disease in Recipients of Single Mismatched Unrelated Hematopoietic Cell Transplantation Donor Using a Highly Multiplexed Proteomic Assay, MHC-Pepseq

Blood ◽

10.1182/blood-2021-153597 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1808-1808

Author(s):

Karamjeet S. Sandhu ◽

Ketevan Gendzekhadze ◽

Dongyun Yang ◽

Ryotaro Nakamura ◽

Sally Mokhtari ◽

...

Keyword(s):

Board Of Directors ◽

Cell Transplantation ◽

Graft Versus Host Disease ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Advisory Committees ◽

Graft Versus Host ◽

Mismatched Donor

Abstract Graft-versus-host disease (GVHD) remains a major cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). In HLA-mismatched donor setting, indirect presentation of allogeneic peptides from recipient's mismatched HLA class I or II proteins by donor or recipient antigen presenting cells can be an immunogenic driver of GVHD. However, the potential diversity of such antigens is large, and predicting them in a systematic manner has proven challenging. Using a novel, highly-multiplexed peptide-MHC binding assay (MHC-PepSeq) we sought to 1) identify allogeneic peptides derived from mismatched HLA protein that can be efficiently presented by HLA-DR, and 2) explore the possibility that the frequency of these HLA-DRB1 binding allopeptides may be predictive of clinical GVHD in HLA-DPB1 mismatched donor/recipient pairs. Using publicly-available population allele frequency data (allelefrequencies.net), we identified a set of class I and II sequences that cover >95% of alleles at each of 9 human HLA-loci (-A, -B, -C, -DRA1,-DRB1, -DQA1, -DQB1, -DPA1, -DPB1) in 3 major US populations (European Caucasian, African American, Mexican Chicano). When represented in the form of densely overlapping tiled 15-mer peptides, 7,744 unique 15mers were identified. We encoded these peptides into DNA oligonucleotides and used the PepSeq parallel synthesis protocol to generate a library of the corresponding DNA-barcoded peptides. The library was incubated with recombinantly-expressed full-length HLA proteins, washed, eluted, amplified, and sequenced to identify the various HLA-derived peptides that bind to the assayed HLA proteins (Figure 1). In the current study, DPB1-derived allopeptides in the setting of HLA-A, B, C, DRB1, and DQB1 (10/10) matched unrelated (MUD) HCT donors with a mismatch in DPB1 were investigated. The peptide library was assayed for binding to the DRB1*07:01 protein, selected since it was the common allele in this cohort. We identified 327 patients who were transplanted at our center and met these criteria. For each case, we used comprehensive in silico tiling to identify HLA-DPA and DPB-derived peptides present in the recipient but absent in the donor. This set was intersected with the peptides identified as binders to HLA-DRB1*07:01 in the 7,744-plex MHC-PepSeq assay, to arrive at a donor-recipient pair-specific set of 'allopeptides' Overall, we identified such allopeptide at the median of 0 (range: 0-8) across the 327 cases. Next, we examined an association between the number of allopeptides and acute GVHD in the cohort of 94 patients with positive HLA-DRB1*07:01. Median age at alloHCT was 60 years (range: 19-78), 53% males, 1.% bone marrow graft and only 7% female to male donors. Ablative (TBI) conditioning was delivered to 34%) pts. 83% received Tacrolimus/Sirolimus-based, and 9% received post-transplant cyclophosphamide-based GVHD prophylaxis. Patient/HCT characteristics are summarized in Table 1. In this cohort, 18% had no DPB1 mismatch, 54% had a single and 28% had double mismatches, with 21% pts carrying non-permissive DPB1 mismatches. Allopeptide score was 0 in 75% of pts. Non-permissive mismatch 9 (39%) vs. 11 (16%) were more likely to have allopeptide score ≥1 and similarly double mismatches 11 (48%) vs. 15 (21%) were more likely to have allopeptide score of ≥1. Among pts with ≥1 allopeptide score 14 (61%) had DPB1 matched or permissive mismatch. The cumulative incidence of grade 2-4 acute GVHD was 40.8% (range: 29-52) in pts with no allopeptides from DPB1 compared with 56% (range: 34-74) in those with ≥1 allopeptides (p=0.259) (Figure 2). The cumulative incidence of grade 3-4 acute GVHD and chronic GVHD were similar between allopeptide 0 vs. ≥1. Together, we show that the "MHC-PepSeq" assay can identify novel candidate HLA-derived allopeptides in 10/10 MUD HCTs. The number of such peptides are relatively low - with a majority having no allopeptide. In an exploratory analysis in a selected cohort of patients with HLA-DRB1*0701 in the setting of 10/10 MUD HCT, the number of allopeptides in our assay may be predictive of GVHD. The expanded analyses on other HLA-DRB1 restriction elements are underway. Figure 1 Figure 1. Disclosures Al Malki: CareDx: Consultancy; Hansa Biopharma: Consultancy; Neximmune: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; Rigel Pharma: Consultancy. Ali: BMS: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy.

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Clinical Impact of Cytokine Release Syndrome on Outcomes of Peripheral Blood Stem Cell Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide

Blood ◽

10.1182/blood-2020-143166 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 10-11

Author(s):

Salman Otoukesh ◽

Hany Elmariah ◽

Dongyun Yang ◽

Sally Mokhtari ◽

Madiha Siraj ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Multivariable Analysis ◽

Advisory Board ◽

Board Meeting ◽

Advisory Committees ◽

Gvhd Prophylaxis ◽

Haploidentical Hematopoietic Cell Transplantation ◽

Grade 3

Peripheral blood stem cell (PBSC) as a graft source compared to bone marrow has been reported to result in lower risk of relapse after haploidentical hematopoietic cell transplantation (haplo-HCT) with use of post-transplant cyclophosphamide (PTCy) as a graft-versus-host-disease (GvHD) prophylaxis. However, cytokine release syndrome (CRS) is a common complication of this platform that can affect the outcomes of patients after PBSC haplo-HCT. CRS occurs due to rapid activation and proliferation of alloreactive donor T cells resulting in the elevated secretion of inflammatory cytokines. In this study, we sought to examine the risk factors for CRS and the effect of CRS severity on outcomes of PBSC haplo-HCT. We identified total of 271 consecutive patients with hematological malignancies who received their first PBSC haplo-HCT with PTCy-based GVHD prophylaxis at City of Hope (n=157) or Moffitt (n=114) Cancer Centers between 2014 and 2019. The median patient age at HCT was 54 years (INQ range, 37-64) for the entire cohort and 48% of the patients had HCT-CI ³3. Close to 70% of the study cohort had acute leukemia and 33% of all patients had high/very high-risk disease risk index. Myeloablative conditioning was used in 52% of the cases and 81% of all HCT recipients were CMV seropositive. The median donor age at HCT was 33 years (INQ range, 26-43). The HLA -A, -B, -C, -DRB1, -DQB1, or -DPB1 mismatch between the recipient and the donor in the GVH direction was 5/10 in 51%, 4/10 in 29% and £3/10 in 20% of cases. Offspring donors were used in 54% of the patients, sibling donors in 35%, and parent/other relative donors in 11%. Female donors to male recipients were used in only 22% of patients. The median infused CD34 dose was 5.25 x106 cells/kg (range, 2.3-22.4x106) and the CD3 dose was 2.48x108 cells/kg (range, 0.002-8.88 x108). CRS of any grade by ASTCT criteria was observed in 92% of study patients within first 7 days of HCT: 54% had grade 1, 39% grade 2, and 5.2% grade 3-4. Infused cell doses of CD34 >5x106 cells/kg and of CD3 >2.5x108 cells/kg had no significant effect on grade 3-4 CRS. On multivariable analysis, the use of reduced-intensity conditioning (RIC) was associated with increased grade 2-4 CRS (HR = 1.6, 95% CI: 1.11.-2.33, p=0.01) and grade 3-4 CRS (HR = 14.7, 95% CI: 1.97-109.5, p=0.009) compared with the myeloablative conditioning. Donor 5/10 HLA-mismatch was also associated with increased grade 2-4 CRS (HR = 1.5, 95% CI: 1.05-2.18; p=0.03) and grade 3-4 CRS (HR = 3.50, 95% CI: 1.00-12.32; p=0.05) compared with £4/10 HLA-mismatch. Non-relapse mortality (NRM) at day 100, and 1-year overall survival (OS) by CRS severity is shown in Figure. Comparing with the grade 0-1 CRS in multivariable analysis (Table), increase in CRS severity was associated with lower probability of neutrophil engraftment (HR = 0.9 for grade 2 and HR = 0.4 for grade 3-4; p=0.03). Increased CRS severity as compared to the grade 0-1 was also predictive of higher risks of NRM (HR = 1.6, 95% CI: 0.95-2.79 for grade 2 and HR = 6.6, 95% CI: 3.12-13.78 for grade 3-4; p<0.001), lower disease-free survival (DFS; HR = 1.3 for grade 2 and HR = 4.5 for grade 3-4; p<0.001) and lower OS (HR = 1.2 for grade 2 and HR = 4.1 for grade 3-4; p<0.001) after HCT. We observed no association between CRS severity and risk of relapse or the incidence and severity of acute GvHD after transplant. We conclude that CRS is a common complication after PB haplo-HCT/PTCy. CRS severity is associated with post-HCT outcomes with grade 3-4 CRS associated with the highest risk of NRM and overall mortality after HCT. Infused CD34 or CD3 cell doses effect on CRS is unclear. RIC and higher degree of HLA-mismatch are predictive of higher-grade CRS. Identification of modifiable risk factors can help to mitigate the risk for serious CRS and subsequent mortality after PB haplo-HCT/PTCy. Figure 1 Disclosures Nishihori: Karyopharm: Other: Research support to institution; Novartis: Other: Research support to institution. Pidala:CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Johnson and Johnson: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nakamura:Merck: Other: advisory board meeting; Alexion: Other: Support on a meeting presentation; Kyowa-Kirin: Other: Support on a meeting presentation; Celgene: Other: Support on seminar; Magenta Therapeutics: Other: Advisory board meeting; Viracor: Consultancy; Kadmon Corporation: Other: Advisory board meeting; NapaJen Pharma: Consultancy. Al Malki:Rigel Pharma: Consultancy; Jazz Pharmacuticals, Inc: Consultancy; Neximmune: Consultancy. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees.

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Incidence and Risk Factors of CMV Reactivation after Haploidentical Hematopoietic Cell Transplantation Using High-Dose Post-Transplant Cyclophosphamide - Possible Role of Donor KIR Genotypes

Blood ◽

10.1182/blood-2018-99-113514 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3416-3416

Author(s):

Monzr Al Malki ◽

Sanjeet Dadwal ◽

Dongyun Yang ◽

Sally Mokhtari ◽

Thai Cao ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Univariate Analysis ◽

Multivariable Analysis ◽

High Dose ◽

Advisory Committees ◽

Post Transplant ◽

Haploidentical Hematopoietic Cell Transplantation ◽

Cmv Reactivation

Abstract Haploidentical hematopoietic cell transplantation (HaploHCT) using high-dose post-transplant cyclophosphamide (PTCy) has been increasingly used in patients with hematologic disorders with promising results. However, limited data are available on the incidence, pattern, and risk factors including donor/recipient KIR genotypes for cytomegalovirus (CMV) reactivation after HaploHCT with PTCy. Furthermore, the impact of CMV reactivation on HaploHCT outcomes is not yet well-described. In this retrospective study, we evaluated a series of 119 consecutive patients who underwent HaploHCT with PTCy at City of Hope for hematological diseases, between January 2009 and December 2016. CMV reactivation was monitored by our institutional PCR assay (quantitative detection limit: 500 gc/ml, qualitative limit: 250 gc/ml) at least once a week for 100 days post-transplant, with preemptive anti-CMV therapy for positive PCR according to our institutional guidelines. The median age of the cohort was 43 years (range: 2 to 71 years); with 47 female and 72 male patients. CMV serostatus of donor/recipient was Donor−/Recipient− (D−/R−) in 7, D+/R− in 6, D−/R+ in 23, and D+R+ in 82 patients. Patients received fully ablative (n=46) or reduced intensity/non-myeloablative conditioning (n=73) followed by peripheral blood stem cell (n=81) or bone marrow (n=38) graft from sibling (n=42) or non-sibling haploidentical donors (n=77). Graft-versus-host disease (GVHD) prophylaxis was PTCy plus tacrolimus/mycophenolate mofetil. Diagnoses of these patients were acute leukemia (n=80), bone marrow failure (n=15), lymphoma (n=11), chronic leukemia (n=6), hemoglobinopathies (n=5), and multiple myeloma (n=2), and the HCT-comorbidity index was more than 2 in 42% (n=50) of patients. Cumulative incidence (CI) of CMV reactivation for the entire cohort was 68.1% (95%CI: 58.8-75.7%) at 100-days, with the median time to reactivation at 35 days (95%CI: 33-40); 76.2% in seropositive recipients and 7.7% in seronegative recipients (p<0.001). (Figure 1) Among 81 patients with any CMV reactivation; median initial viral load was 624 copies/mL (range: <500- 9930) and peak viral load was 2601 copies/mL (range: <500-166,865) with median CMV area under the curve (AUC) of 28,002 (range: 1671.0-2,149,929.5). In seropositive recipients (n=105), CI of CMV reactivation was 76.5% (95%CI: 66.9-83.6%) with the median onset of CMV reactivation at 33 days (95%CI: 30-36). Majority of patients (n=62) experienced only one reactivation episode with the median duration of 17 days (range=1-62) while 16 patients experienced more than one reactivation episodes with the median duration of 63.5 days (range: 33-78). Prolonged CMV exposure (>17days of CMV viremia) was seen in 47 patients. In univariate analysis; recipient CMV serostatus, recipient sex, and stem cell source were statistical significant factors, affecting CI of CMV reactivation, but only recipient CMV serostatus stood as an independent factor on multivariable analysis (HR=15.5, 95%CI: 2.3-106.3 for R+ compared to R−, p=0.005) (Figure 1). We also evaluated the effect of KIR status on the CI of CMV reactivation. Multivariable analysis indicated a trend towards decreased incidence of CMV reactivation in donors with 2DS5 and 3DS1 (HR= 0.71 for both donors; p value= 0.1). Donor-recipient KIR mismatch was also associated with a trend towards increased incidence of CMV reactivation (p=0.1) and statistically significant prolonged CMV reactivation (OR=2.48, 95%CI: 1.12-5.47, p=.025). With median follow up duration of 24.3 months (range: 10.3 to 99.2) and in univariate analysis, CMV reactivation, higher peak CMV PCR, time to CMV reactivation, or prolonged exposure to CMV were not associated with worse overall survival (OS), relapse-free survival (RFS), relapse incidence, or non-relapse mortality (NRM). Interestingly, the risk of extensive chronic GVHD was greater in patients who had no CMV reactivation than those who developed prolonged/recurrent CMV reactivations (41.9% vs. 26.2%, p= 0.046) In conclusion, recipient and not donor serostatus is predictive of CMV reactivation in HaploHCT with PTCy. With the current pre-emptive therapy approach, CMV reactivation did not translate into higher rate of CMV disease or worse survival outcome. Donor-recipient KIR match (KIR licensing) and donor activating KIR genes (2DS5 and 3DS1) may be involved with CMV control after HaploHCT. Figure 1. Figure 1. Disclosures Dadwal: MERK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Research Funding; AiCuris: Research Funding; Gilead: Research Funding. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Salhotra:Kadmon Corporation, LLC: Consultancy. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

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A Refined Model of HLA-DP Permissiveness Improves Stratification of Acute Graft-Versus-Host Disease Risks after Unrelated Hematopoietic Cell Transplantation: A Retrospective Study from the CIBMTR

Blood ◽

10.1182/blood-2021-146957 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2890-2890

Author(s):

Esteban Arrieta-Bolanos ◽

Pietro Crivello ◽

Meilun He ◽

Tao Wang ◽

Shahinaz M. Gadalla ◽

...

Keyword(s):

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Patent Application ◽

Multivariable Analysis ◽

Significant Proportion ◽

Cell Epitope ◽

Hematopoietic Cell ◽

Advisory Committees

Abstract Introduction: Permissive HLA-DPB1 mismatches defined by the T-cell epitope (TCE) model are an established selection criterion for unrelated donors in allogeneic hematopoietic cell transplantation (alloHCT) (Dehn et al. Blood 2019). Based on biological evidence, the TCE model has classified HLA-DPB1 alleles into at least three functional groups, one of which (TCE group 3; TCE3) houses a large number of alleles with different structural and functional characteristics. We have recently shown that structurally close HLA-DP allotypes have similar peptide-binding motifs and share a significant proportion of their immunopeptidomes, the latter being fundamental for permissiveness (Meurer & Crivello et al. Blood 2021). Hence, we hypothesized that HLA-DPB1 mismatches involving alleles that encode structurally distant allotypes within TCE3 could be less permissive than those involving alleles that encode structurally closer allotypes, and thus have a differential impact on clinical outcomes. Methods: Multidimensional scaling techniques were used to compare 28 polymorphic positions (amino acids 8-215) among 51 alleles present in a cohort of 5,140 10/10 matched patient-donor pairs who received a first alloHCT for AML, ALL, or MDS between 2008-2017. Based on these analyses, TCE3-permissive mismatches (N=2,216) were further stratified into those involving structurally close or more distant combinations and compared with HLA-DPB1-matched (N=785) and non-permissively mismatched (N=2,023) pairs. These models were tested in parallel to the "classical" TCE model considering permissive mismatches (N=2,332) as a whole, to determine their association with overall survival (OS), disease-free survival (DFS), treatment-related mortality (TRM), primary disease relapse, and acute (a) and chronic (c)GVHD. Kaplan-Meier analysis and log-rank testing were used to compare the median OS and DFS. The incidences of GVHD, relapse and TRM were compared using competing risks and Gray's test. The effect of HLA-DPB1 mismatch on time-to-event outcomes was modelled by Cox regression after adjusting for confounders and testing for the proportional hazards assumption. Results: Within TCE3, we identified a subgroup of 4 frequent and structurally as well as functionally closely related alleles (i.e. DPB1*02:01, 04:01, 04:02, 23:01) that form a separate cluster (Figure 1A). These "core" alleles have similar bound-peptide motifs (van Balen et al. J Immunol 2020) and can be distinguished from other alleles in TCE3 in terms of the strength of in vitro alloreactive responses elicited from permissive responders (Meurer et al. Front Immunol 2018). Moreover, principal component analysis identified the HLA-DP 84-87 DEAV/GGMP motif as a major factor driving structural variability among TCE3 alleles (not shown). We used these observations to stratify TCE3 permissive mismatches in the allo-HCT cohort into "core" (N=930) and "non-core" (N=1,286) or into DEAV/GGPM-matched (N=1,209) and mismatched (N=1,007) pairs (Figure 1B). Multivariable analysis confirmed the association of aGVHD2-4 for the classical TCE model of non-permissive mismatching (p<.0001) and revealed a trend in DEAV/GGPM and "core"/"non-core" TCE3-permissive models. When compared to HLA-DPB1 allele matched pairs the risks of aGVHD2-4 increased progressively with "core" TCE3-permissive (HR 1.12 [0.98-1.28]; p=0.1012), "non-core" TCE3-permissive (HR 1.24 [1.06-1.46]; p= 0.0082), and non-permissive mismatches (HR 1.32 [1.16-1.50]; p<.0001) (Figure 1C, "core" vs. "non-core" HR 0.90 [0.80-1.01]; p=0.062). Similar albeit less significant results were obtained with the DEAV/GGPM model. The "core"/"non-core" TCE3 model was also associated with TRM with alloHCT from "core" TCE3-permissive donors showing lower risks of TRM than "non-core" TCE3-permissive (HR 0.82 [0.70-0.96]; p=0.0118) and non-permissive donors (HR 0.78 [0.68-0.88]; p=0.0002). Conclusion: Our results suggest that structural differences within TCE3 that reflect functional divergence and differential immunogenicity of alleles in this group associate with the risks of aGVHD and TRM after alloHCT. Hence, within the population of 10/10 matched donors, selection of "core" TCE3-permissive donors might reduce patient morbidity after transplantation. Figure 1 Figure 1. Disclosures Paczesny: Medical University of South Carolina: Patents & Royalties: inventor on the ST2 bispecific antibody patent application. Lee: AstraZeneca: Research Funding; Incyte: Research Funding; Janssen: Other; Kadmon: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Syndax: Research Funding; Takeda: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding.

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Treatment of Corticosteroid-Refractory Graft-Versus-Host Disease with Ruxolitinib in 95 Patients

Blood ◽

10.1182/blood.v126.23.858.858 ◽

2015 ◽

Vol 126 (23) ◽

pp. 858-858 ◽

Cited By ~ 1

Author(s):

Robert Zeiser ◽

Andreas Burchert ◽

Claudia Lengerke ◽

Mareike Verbeek ◽

Kristina Maas-Bauer ◽

...

Keyword(s):

Board Of Directors ◽

Graft Versus Host Disease ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

The United States ◽

Outcome Data ◽

Cell Transplant ◽

Advisory Committees ◽

Host Disease ◽

Graft Versus Host

Abstract Background: Allogeneic hematopoietic cell transplantation is a potentially curative therapy for patients with hematological malignancies. However a fraction of patients will develop corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) which both cause a high mortality and impaired quality of life. Pre-clinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib by modification of T cells and dendritic cells. Methods: In this retrospective analysis, 19 stem cell transplant centers in Europe and the United States reported clinical outcome data from 95 patients who had received ruxolitinib as salvage-therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grade III or IV) or SR-cGvHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGvHD (1-10). The median follow-up times were 26.5 (3-106) for SR-aGVHD and 22.4 (3-135) weeks for SR-cGVHD-patients. Results: The ORR was 81.5% (44/54) in SR-aGVHD including 25 CRs (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). The median time to response was 1.5 (1-11) and 3 (1-25) weeks after initiation of ruxolitinib treatment in SR-aGVHD and SR-cGVHD, respectively. Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3%-90.7%,95% CI) and 97.4% (92.3%-100%,95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and CMV reactivation were observed during ruxolitinib-treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Relapse of the underlying malignancy occurred in 9.3% (5/54) and 2.4% (1/41) of the patients with SR-aGVHD or SR-cGVHD, respectively. Conclusion: Ruxolitinib constitutes a promising new treatment option for SR-aGVHD and SR-cGVHD. Its activity in SR-aGVHD and SR-cGVHD should be validated in a prospective trials in both, SR-aGvHD and cGvHD. Disclosures Bertz: GILEAD Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Scheid:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bug:TEVA Oncology, Astellas: Other: Travel Grant; NordMedica, Boehringer Ingelheim, Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene, Novartis: Research Funding.

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Pre-Transplant Serum Claudin-3 Predicts Intestinal Graft-Versus-Host Disease and Non-Relapse Mortality Risk after Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood-2019-129236 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 39-39

Author(s):

Shernan Holtan ◽

Todd E. DeFor ◽

Armin Rashidi ◽

Alexander Khoruts ◽

Christopher Staley ◽

...

Keyword(s):

Cord Blood ◽

Board Of Directors ◽

Graft Versus Host Disease ◽

Umbilical Cord Blood ◽

Hematopoietic Cell Transplantation ◽

Disease Risk ◽

Intestinal Damage ◽

Serum Samples ◽

Advisory Committees ◽

Graft Versus Host

Intestinal damage from prior chemotherapy or infections can contribute to the risk of gastrointestinal acute graft-versus-host disease (GI GVHD) and non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT). However, identifying patients who appear healthy but are at increased risk of GI GVHD and NRM due to pre-transplant intestinal tissue damage is challenging. The primary objective of this study was to determine the independent association of serum pre-transplant biomarkers associated with intestinal damage and GI GVHD on the incidence of GI GVHD and 1-year NRM. Specifically, we analyzed amphiregulin (AREG), epidermal growth factor (EGF), ratio of AREG/EGF, regenerating islet-derived 3a (REG3a), suppressor of tumorigenicity 2 (ST2), claudin-3, citrulline, and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) in pre-transplant serum samples from 528 unique pediatric and adult (median age 41, range <1-75 years) patients undergoing first allogeneic HCT at the University of Minnesota between 2010 - 2018. To identify the most influential predictors, we performed lasso (least absolute shrinkage and selection operator) regression (logistic for GI aGVHD and Cox for NRM), rather than standard regression, which too often results in model overfitting. We included standard clinical factors as potential confounders, including patient age (per increase by decade), donor type (matched sibling vs. haploidentical/mismatch related, unrelated donor [URD] vs. single umbilical cord blood [sUCB] vs. double umbilical cord blood [dUCB]), underlying disease risk (low disease risk vs. intermediate disease risk vs. high disease risk vs. non-malignancy), GVHD prophylaxis (CsA or TAC/MTX or Prednisone vs. CsA or TAC/MMF vs. Sirolimus/MMF) and comorbidity (HCT-CI; low risk vs. intermediate risk vs. high risk). In pre-transplant serum samples, only claudin-3 was associated with a risk of subsequent GI GVHD (odds ratio [OR] 1.16). In this cohort, the median pre-transplant claudin-3 was 29.4 pg/ml (range 5.1 - 120.6 pg/ml). The optimal cutpoint for subsequent GI GVHD was 24.5 pg/ml. Nearly one-third of patients with claudin-3 at or above this level developed GI GVHD (31%, 95% CI 13-26%), compared to 19% of patients with a claudin-3 <24.5 pg/ml developing GI GVHD (95% CI 13-26%). Pre-transplant claudin-3 was also associated with NRM, with an optimal cutpoint of 27.1 pg/ml and twice the proportion of 1-year NRM above that cutpoint (24%, 95% CI 19-28% vs 12%, 95% CI 8-17%). Higher REG3a (OR 1.04) and TIM-3 (OR 1.59) were also associated with NRM, whereas higher pre-transplant EGF was protective against NRM (OR 0.99) and AREG protective against GI GVHD (OR 0.99). Claudin-3 was not strongly correlated with the other biomarkers and was lower in patients with non-malignant disease compared to patients undergoing transplant hematologic malignancies (median 26.3 vs 30.4-32 pg/ml, p<0.01). We conclude that claudin-3, a major component of tight junctions between epithelial and endothelial cells, is the most promising pre-transplant biomarker of increased GI GVHD and NRM risk among those tested. Patients with elevated pre-transplant claudin-3 serum levels may have organ tissues less resilient to damage from chemotherapy, radiation, and infections and could thus be appropriate for studies of novel toxicity-sparing approaches. Table Disclosures Holtan: Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Janssen: Consultancy; CSL Behring: Consultancy. Weisdorf:Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy; Incyte: Research Funding. MacMillan:Angiocrine: Membership on an entity's Board of Directors or advisory committees; Equillium: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Alpine Immune Sciences: Consultancy.

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An International Multicenter Comparative Analysis of Tacrolimus Plus Sirolimus with or without Antithymocyte Globulin As Graft-Versus-Host Disease Prophylaxis in HLA-Mismatched Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood.v126.23.3142.3142 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3142-3142

Author(s):

Mohamed A. Kharfan-Dabaja ◽

Rocio Parody ◽

Janelle Perkins ◽

Oriana Lopez-Godino ◽

Lucia Lopez-Corral ◽

...

Keyword(s):

Board Of Directors ◽

Lower Incidence ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Infectious Complications ◽

Unrelated Donor ◽

Advisory Committees ◽

Graft Versus Host ◽

Allogeneic Hct ◽

Gvhd Prophylaxis

Abstract Background: There is lack of consensus in regards to the optimal regimen for graft-versus-host disease (GVHD) prophylaxis in patients undergoing HLA-mismatched unrelated donor (MMUD) allografting. A regimen combining tacrolimus plus sirolimus (TAC-SIR) has been shown to be effective as GVHD prophylaxis in HLA-matched related (MRD) or matched-unrelated donor (MUD) allogeneic hematopoietic cell transplantation (HCT). Addition of antithymocyte globulin (ATG) has been shown to reduce incidence of acute GVHD but it is associated with a high rate of infectious complications. Here, we retrospectively compare post-transplant outcomes using TAC-SIR or TAC-SIR-ATG in 104 patients who underwent a MMUD allogeneic HCT between June 2008 and December 2014 at 5 Spanish and 1 transplant center (MCC) in the United States. Patients and methods: Forty-three (MCC=5, Spanish Centers=38) patients received TAC-SIR whereas 61(MCC=41, Spanish Centers=20) received TAC-SIR-ATG as GVHD prophylaxis for MMUD allogeneic HCT. Patient-, disease-, and transplant characteristics are summarized in Table 1. Results: The median follow-up (months) for all, TAC-SIR, and TAC-SIR-ATG patients were 29 (5-83), 27 (5-64), and 30 (6-83) months, respectively. Patients receiving TAC-SIR had faster platelets (12 vs. 15 days, p=0.005) but slightly slower neutrophil engraftment (16 vs. 15 days, p=0.037). Addition of ATG resulted in a lower incidence of acute GVHD (grade 2-4) (44% (95%CI=33-59%) vs. 67% (95%CI=55-83%), p=0.055) and over two-fold lower incidence, albeit not statistically significant, of moderate/severe chronic GVHD (17% (95%CI=10-30%) vs. 38% (95%CI=25-60%), p=0.086). Non-relapse mortality (NRM) (2-year) was two-fold higher, but not statistically significant, in the TAC-SIR-ATG group (TAC-SIR-ATG=35% (95%CI=24-50%) vs. TAC-SIR=17% (95%CI=10-35%), p=0.078) mainly attributable to a 3-fold higher number of non-relapse deaths attributed to infections (9 vs. 3). There was no difference in cumulative incidence of relapse (2-year) (TAC-SIR=28% (95%CI=17-46%) vs. TAC-SIR-ATG=26% (95%CI=17-41%), p=0.858) or in 2-year OS (TAC-SIR=56% (95%CI=40-72%) vs. TAC-SIR-ATG=47% (95%CI=34-60%), p=0.244) between the groups. These and other outcomes are summarized in Table 2. Conclusion: In MMUD allogeneic HCT, addition of ATG to TAC-SIR results in a lower incidence of grade 2-4 acute GVHD but does not improve OS. The two-fold higher 2-year NRM with addition of ATG is probably explained by a higher incidence of resulting infectious complications with in vivo T-cell depletion. While these results are intriguing, a prospective randomized study is certainly needed to confirm these findings.Table 1.Patient-, disease-, and transplant-related characteristics.VariablesCategoriesTAC-SIRTAC-SIR-ATGMCC (N=5)Spanish Centers (N=38)MCC (N=41)Spanish Centers (N=20)Median age (range), years53 (25-64)51 (17-69)52 (24-67)55 (30-68)Gender mismatch(Donor→recipient)F→M F→F M→M,F Missing1 1 3 07 5 25 110 13 18 02 0 10 8 HLA-mismatchA B C DRB1 Missing1 1 3 0 010 14 8 6 024 13 4 0 08 3 3 5 1DiagnosesALL AML CLL CML HL MDS MF MM NHL Other1 2 0 0 0 1 0 0 1 03 10 3 1 3 7 1 1 10 04 18 3 2 1 5 1 0 7 01 6 1 0 1 3 0 1 5 2Preparative regimenFLU-BU FLU-MEL3 218 2035 611 7CIBMTR riskNone Low Intermediate High0 2 1 20 24 2 121 13 15 120 18 2 0Cell sourceBM PBSC0 58 300 411 19Median CD34 cells (range) x106/recipient Kg body weight7.99 (4.08-10.0)6 (1.2-11.0)8.57 (2.81-23.01)6.08 (0.67-9.5)Recipient/donor CMV serologic status+/+ +/- -/- -/+ Missing1 2 2 0 018 16 2 2 018 14 7 2 07 6 0 0 7 Table 2. Post-transplant outcomes. Outcomes TAC-SIR TAC-SIR-ATG P-value Median days (range) to ANC>500/µL 16 (10-29) 15 (9-24) 0.037 Median days (range) to platelets engraftment 12 (6-26) 15 (0-50) 0.005 Cum incidence acute GVHD (grade 2-4) (at 100 day) 67% (55-83%) 44% (33-59%) 0.055 Cum incidence acute GVHD (grade 3-4) (at 100-day) 16% (8-32%) 10% (5-21%) 0.347 Chronic moderate or severe (at 2-year) 38% (25-60%) 17% (10-30%) 0.086 Cum incidence of NRM (at 100-day) 12% (5-27%) 13% (7-25%) 0.078 Cum incidence of NRM(2-year) 17% (10-35%) 35% (24-50%) 0.078 Cum Incidence of relapse (2-year) 28% (17-46%) 26% (17-41%) 0.858 EFS (2-year) 54% (38-69%) 38% (26-52%) 0.191 OS (2-year) 56% (40-72%) 47% (34-60%) 0.244 Disclosures Off Label Use: Sirolimus for GVHD prophylaxis. Perkins:PDL Biopharma: Research Funding. Falantes:Celgene: Honoraria. Valcárcel:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Blood ◽

10.1182/blood-2019-128053 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4112-4112

Author(s):

Charline Moulin ◽

Romain Morizot ◽

Thomas Remen ◽

Hélène Augé ◽

Florian Bouclet ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Intermediate Risk ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Long Term Survivors ◽

First Line Treatment

Introduction: About 2 to 10% of patients (pts) diagnosed with Chronic Lymphocytic Leukemia (CLL) develop diffuse large B-cell lymphoma (DLBCL, so-called Richter transformation (RT)) over long-term follow-up. The outcomes of pts with RT are variable and poorly understood and there is no consensus on the best therapeutic approach. The aim of this study was to analyze the clinical characteristics, outcomes and factors predictive of survival in a large series of RT from the French Innovative Leukemia Organization (FILO). Methods: Biopsy-confirmed RT (limited to DLBCL and excluding Hodgkin lymphoma) diagnosed from 2001 to 2018 were identified from eight FILO centers. Clinical and biological characteristics of CLL and RT at diagnosis, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status, cell of origin (COO) analyzed by immunohistochemistry and RT score (Tsimberidou AM et al, J Clin Oncol, 2006) were analyzed as well as treatment and outcomes. Overall survivals (OS) were defined as time from CLL and RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analyses were performed with SAS version 9.4. Results: A total of 70 CLL pts who developed RT were identified. The median age at CLL diagnosis was 62 years old (range 35-82), and 50 (71.4 %) were male. The median time to transformation was 5.5 years (range 0 to 22 years), with 12 simultaneous diagnosis of CLL and RT. Prior to RT, 20 (29%) pts had not been treated for CLL, 50 received one (n=21) or more (n= 29) line of treatment ; 6 pts had received a novel agent (ibrutinib, idelalisib or venetoclax). The median age at RT diagnosis was 68 years old (range 42-88). All biopsies were centrally reviewed; 38/58 pts (66%) had elevated LDH (>1.5N) ; 35/65 pts (54 %) had bulky disease (≥ 5 cm); 10/54 (18.5%) pts had del(17p) or TP53 mutation ; 9/42 pts (21%) had a complex karyotype (at least 3 abnormalities). The CLL and RT were clonally related in 27/27 (100%) tested pts. COO by Hans algorithm was non germinal center B cell-like (GCB) in 26/28 pts (93%). EBV was positive or detected in 5/40 (12.5%) pts. The median of Ki67 positivity was 70% (range 30% to 100%). The RT score (based at RT diagnosis on ECOG performance status 2-4, LDH >1.5 x normal, platelets<100 x 109/L, tumor size >5 cm and >1 prior therapy for CLL) was : low risk in 17 pts (31%), low-intermediate risk in 10 pts (19%), high-intermediate risk in 14 pts (25%) and high risk in 14 pts (25%). The most common first-line treatment of RT was immunochemotherapy (n=57, 87%) including R-CHOP-like regimen (n=48, 73%). Autologous or allogeneic transplantation was performed for 7 pts (11%). Response to first-line treatment was complete or partial response in 26 pts (40%), and stable disease or progression in 39 pts (60%). After a median follow-up of 8 years, 51/64 pts (80%) have died. The main causes of death were progressive DLBCL (n=36, 71%), infection (n=8, 16%) or progressive CLL (n=2, 4%). The median OS of the cohort from CLL and RT diagnosis (Figure 1) were 7.8 years and 9.5 months, respectively. In univariate analysis, patients with TP53 disruption at CLL stage, low platelets count, elevated LDH, elevated beta2-microglobulin, high ECOG score, high RT score, EBV positivity and absence of response to first-line RT treatment had worse OS. The ECOG score, platelets count and TP53 disruption remain significant in multivariate Cox-regression. Last, we compared the clinical and biological parameters of two Richter groups defined as: (i) short-term survivors (<12 months, n = 34) and (ii) long-term survivors (>48 months, n = 18). Long survival was significantly associated with elevated platelets count, low LDH, low ECOG, low RT score and response to RT first-line treatment. Discussion: The clinical outcomes of RT patients is poor and novel treatment options are needed. However, a group of long-term survivors was identified, characterized by elevated platelets count, low LDH, low ECOG, low RT score and response to immunochemotherapy. Disclosures Leblond: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Roche: 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; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Cymbalista:Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Abbvie: Honoraria. Guièze:Abbvie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria. Broseus:Janssen: Honoraria; Gilead: Honoraria; Novartis: Research Funding. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

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Long-Term Experience with Large Granular Lymphocytic Leukemia Evolving after Solid Organ and Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-130167 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1226-1226

Author(s):

Hassan Awada ◽

Reda Z. Mahfouz ◽

Jibran Durrani ◽

Ashwin Kishtagari ◽

Deepa Jagadeesh ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Viral Infections ◽

De Novo ◽

Post Transplantation ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Post Transplant ◽

Stat3 Mutations

T-cell large granular lymphocyte leukemia (T-LGLL) is a clonal proliferation of cytotoxic T lymphocytes (CTL). T-LGLL mainly manifest in elderly and is associated with autoimmune diseases including rheumatoid arthritis (RA), B cell dyscrasias, non-hematologic cancers and immunodeficiency (e.g., hypogammaglobulinemia). LGL manifestations often resemble reactive immune processes leading to the dilemmas that LGLs act like CTL expansion during viral infections (for example EBV associated infectious mononucleosis). While studying a cohort of 246 adult patients with T-LGLL seen at Cleveland Clinic over the past 10 years, we encountered 15 cases of overt T-LGLL following transplantation of solid organs (SOT; n=8) and hematopoietic stem cell transplantation (HSCT; n=7). Although early studies reported on the occurrence of LGL post-transplant, these studies focused on the analysis of oligoclonality skewed reactive CTL responses rather than frank T-LGLL. We aimed to characterize post-transplantation T-LGLL in SOT and HSCT simultaneously and compare them to a control group of 231 de novo T-LGLL (cases with no history of SOT or HSCT). To characterize an unambiguous "WHO-defined T-LGLL" we applied stringent and uniform criteria. All cases were diagnosed if 3 out of 4 criteria were fulfilled, including: 1) LGL count >500/µL in blood for more than 6 months; 2) abnormal CTLs expressing CD3, CD8 and CD57 by flow cytometry; 3) preferential usage of a TCR Vβ family by flow cytometry; 4) TCR gene rearrangement by PCR. In addition, targeted deep sequencing for STAT3 mutations was performed and charts of bone marrow biopsies were reviewed to exclude other possible conditions. Diagnosis was made 0.2-27 yrs post-transplantation (median: 4 yrs). At the time of T-LGLL diagnosis, relative lymphocytosis (15-91%), T lymphocytosis (49-99%) and elevated absolute LGL counts (>500 /µL; 93%) were also seen. Post-transplantation T-LGLL were significantly younger than de novo T-LGLL, (median age: 48 vs. 61 yr; P<.0001). Sixty% of post-transplantation T-LGLL patients were males. Fifteen% of patients had more cytogenetic abnormalities compared to de novo T-LGLL, had a lower absolute LGL count (median: 4.5 vs. 8.5 k/µL) and had less frequent neutropenia, thrombocytopenia and anemia (27 vs. 43%, 33 vs. 35% and 20% vs. 55%; P=.01). TCR Vb analysis identified clonal expansion of ≥1 of the Vb proteins in 60% (n=9) of the patients; the remaining 40% (n=6) of the cases had either a clonal process involving a Vb protein not tested in the panel (20%; n=3) or no clear expansion (20%; n=3). Signs of rejection were observed in 20% (n=3/15) and GvHD in 13% (n=2/15) of the patients. Post-transplantation, 27% of cases presented with neutropenia (absolute neutrophil count <1.5 x109/L; n=4), 33% with thrombocytopenia (platelet count <150 x109/L; n=5) and 25% with anemia (hemoglobin <10 g/dL; n=3). T-LGLL evolved in 10 patients (67%; 10/15) despite IST including cyclosporine (n=5), tacrolimus (n=4), mycophenolate mofetil (n=5), cyclophosphamide (n=1), anti-thymocyte globulin (n=1), and corticosteroids (n=6). Lymphadenopathy and splenomegaly were seen in 13% (n=2) and 33% (n=5) of the patients. Other conditions observed were MGUS (20%; n=3) and RA (7%; n=1). Conventional cytogenetic showed normal karyotype in 89% (n=11, tested individuals 13/15). Somatic STAT3 mutations were identified in 2 patients. Sixty% of cases (n=9) were seropositive for EBV when tested at different time points after transplant. Similarly, 53% (n=8) were seropositive for CMV, of which, 5 were positive post-transplantation and 3 pre-/post-transplantation. The complexity of T-LGLL expansion post-transplantation might be due to several mechanisms including active viral infections, latent oncogenic viral reactivation and graft allo-antigenic stimulation. However, in our cohort graft rejection or GvHD was encountered in a few patients (2 allo-HSCT recipients). Autoimmune conditions were present in 50% of SOT recipients (n=4/ 8, including RA, ulcerative colitis, systemic lupus erythematosus). Some of our patients also had low immunoglobulin levels. Overt EBV (post-transplant lymphoproliferative disorder) and CMV reactivation was diagnosed in only 27% (4/15) of the patients. In sum we report the long term follow up of a cohort of T-LGLL and emphasize the expansion of T-LGLL post-transplant highlighting the difficulty in assigning one unique origin of LGLL. Disclosures Hill: Genentech: Consultancy, Research Funding; Takeda: Research Funding; Celegene: Consultancy, Honoraria, Research Funding; Kite: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Honoraria; Amgen: Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria. Majhail:Atara Bio: Consultancy; Mallinckrodt: Honoraria; Nkarta: Consultancy; Anthem, Inc.: Consultancy; Incyte: Consultancy. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.

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Targeted Treatment and Survival Following Relapse after Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia and MDS in the Contemporary Era

Blood ◽

10.1182/blood-2019-124533 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4567-4567

Author(s):

Sanghee Hong ◽

Lisa Rybicki ◽

Donna Corrigan ◽

Betty K. Hamilton ◽

Ronald Sobecks ◽

...

Keyword(s):

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Treatment Strategies ◽

Targeted Agents ◽

Advisory Committees ◽

Survival After Relapse ◽

Grade Ii

Introduction: Relapse is the most frequent cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). While transplant-related mortality has decreased substantially over the last few decades, little progress has been made in outcomes and no standard of care exists for patients (pts) with post-alloHCT relapse. In the recent era, several new therapies, including targeted agents, have been approved for ALL, AML, and MDS. We conducted a study to evaluate outcomes of pts with these diseases who relapse after alloHCT in the contemporary period with routine availability of these newer therapeutic agents. Methods: We performed a single-institution retrospective cohort study to review treatment strategies and outcomes of relapse post-alloHCT. We identified 420 adult pts who received their first alloHCT in 2010-2018 using any conditioning regimen or donor source. Overall, 115 (27%) pts experienced relapse (ALL=17/64 [27%], AML=67/242 [28%], MDS=31/114 [27%]) and were included in the analysis. Results: Myeloablative (54%) matched-unrelated donor grafts (50%) were the most common types of HCTs. Peripheral blood stem cell graft (49%) and bone marrow graft (48%) were used the most. Median time from alloHCT to relapse was 5 (range 1-65) months, and 83% of relapses occurred within the first year. Only 24% and 11% of pts experienced grade II-IV acute and any chronic GVHD prior to relapse, respectively. Seven of 17 pts had Philadelphia chromosome positive ALL. Mutation panel was tested in 56% of AML and MDS. Median follow-up period after relapse was 19 (range 6-80) months. The estimated survival after relapse for all diseases was 32% (95% CI 24-41%) at 6 months, 21% (14-28%) at 12 months, and 14% (8-21%) at 24 months (Fig 1). Excluding pts treated with supportive care only, the majority received a combination of different treatments; pts with ALL received median 3 (range 1-5), pts with AML received median 2 (1-4), and pts with MDS received median 1 (1-3) agent. Targeted therapies used for ALL pts included blinatumomab (n=5) and BCR-ABL targeting tyrosine kinase inhibitors with (n=2) or without (n=4) chemotherapy. Among AML pts, targeted agents were used in 15 pts (sorafenib [n=7], 2 each with enasidenib, gemtuzumab ozagamicin, and ivosidenib, and 1 each with venetoclax and SEL24 [a dual pan-PIM/FLT3 inhibitor]). One pt each was treated with enasidenib, gemtuzumab ozagamicin, and PTC299 (an inhibitor of VEGFA mRNA translation) followed by SEL24 for MDS. Second alloHCTs (n=5) were performed median 5 (range 1-16) months after first HCT and median 1 month (range 0-5 months) after relapse. Two pts received no bridging therapy, while 3 pts received chemotherapy (n=2) or donor lymphocyte infusions (DLI [n=1]) prior to the second transplant. DLI without second transplant was used in 25 pts at a median of 20 (range 3-18) months after ALL relapse, median 2 (range 0-13) months after AML relapse, and median 3 (range 1-5) months after MDS relapse. Following DLI, 53% pts developed GVHD. Targeted therapy was associated with a trend towards better survival compared to other therapies (Fig 2, HR 0.65, 95% CI 0.41-1.03, p=0.06). Based on multivariable analysis, matched unrelated (vs. matched sibling, HR 1.70, p=0.027) or haploidentical donor grafts (HR 2.69, p=0.003), presence of grade II-IV acute GVHD before relapse (HR 2.46, p<0.001), and less than 12 months from HCT to relapse (<6 vs. >12 months, HR 6.34, p<0.001; 6-12 vs. >12 months, HR 3.16, p=0.005) were adverse prognostic features with survival after relapse post-alloHCT (Table 1). Conclusion: Outcomes of pts with ALL, AML, and MDS who relapse following alloHCT remain poor in the contemporary era when several newer therapies, including targeted agents, are available for their treatment. Targeted agents were used only in a minority of post-alloHCT relapses likely due to the combination of pt status, absence of the target mutation, the agents' availability, and other factors. Pts who developed grade II-IV acute GVHD and had shorter "disease-free" duration from unrelated or haploidentical donor grafts had the significantly shorter survival following relapse. More innovative treatment strategies to prevent and treat relapse post-alloHCT are needed. Disclosures Hill: Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celegene: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding. Anwer:In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Majhail:Atara Bio: Consultancy; Anthem, Inc.: Consultancy; Nkarta: Consultancy; Mallinckrodt: Honoraria; Incyte: Consultancy.

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