Recipient HLA-B Leader Genotype, and Its Relationship to Total KIR Missing Ligand, Informs Relapse and Survival Following Haploidentical Transplantation Using Post-Transplant Cyclophosphamide

Abstract In addition to donor T cells, natural killer (NK) cells are proposed to play a significant role in the graft-versus-leukemia (GVL) effect following haploidentical donor transplantation (HIDT). Following HIDT, donor NK cells express activating (NKG2C) receptors (Ciurea, Leukemia 2021), whose ligand is the non-classical human leukocyte antigen, HLA-E. For surface expression, HLA-E requires binding of leader peptides derived from class I HLA molecules. The rs1050458C/T dimorphism at position -21 of exon 1 of HLA-B gives rise to leader peptides with either methionine (M) or threonine (T) at the second residue of the processed leader peptide. M-containing HLA-B leader peptides promote higher HLA-E expression than T-leaders, potentially favoring more robust natural NK cell recognition of HLA-E-expressing tumor cells. Alternatively, donor NK cells can be activated through inhibitory killer cell immunoglobulin-like receptors (iKIR: 2DL1, 2DL23, 3DL1, 3DL2), if they fail to engage a corresponding class I HLA ligand on recipient leukemia cells (missing ligand (ML) paradigm). We hypothesized that M-containing B-leaders (either MM or MT genotype), and potentially its association with KIR ML, may inform relapse and survival after HIDT using post-transplant cyclophosphamide (PTCy). A total of 322 patients with acute leukemia, MDS, lymphoma, CLL or CML, receiving a HIDT-PTCy from a single institution were evaluated with a median follow-up time of 45 months [range 6, 184]. Baseline characteristics included a median age of 50 years [19, 80], 47% non-white, HCT-CI ≥3 in 50%, PBSC graft in 80%, and myeloablative conditioning in 49%. M-containing B-leader genotype (either MM or MT) was seen in 42% and 44% of recipients and donors, respectively. The B-leader on the unshared donor-recipient haplotypes was matched (either T or M) in 61% of transplants. ML for iKIR 2DL1, 2DL23, 3DL1, and 3DL2 was noted in 29%, 20%, 24% and 72% respectively. Total ML was 0, 1, 2 and 3 in 10%, 43%, 40% and 7% respectively. In univariate analysis, an M-containing recipient B-leader genotype [R(M+)] improved OS and DFS compared to a recipient TT genotype [R(M-)] (75 vs. 53%, p<0.001; 66 vs. 47%, p<0.001), which was primarily due to a lower risk of relapse/progression (24% vs. 38%, p=0.012). In regard to total iKIR ML, the presence of 2-3 ML was associated with better overall (OS) and disease-free (DFS) survival compared with 0-1 (67% vs. 57%, p=0.08; 62% vs. 48%, p=0.019), which was due to lower relapse/progression (25% vs. 38%, p=0.015). There was no association of either recipient B-leader or total iKIR ML with the incidence of NRM, acute or chronic GVHD. When recipient B-leader and ML were combined, the detrimental effect of a R(M-) genotype was seen exclusively in patients with ML 0-1 (see figure). DFS for R(M-)/ML(0-1), R(M+)/ML(0-1), R(M-)/ML(2-3), R(M+)/ML(2-3) was 36%, 68%, 65% and 60%, respectively (p<0.001). Corresponding relapse/progression rates were 49%, 22%, 26% and 25%, respectively (P<0.001). In multivariate analysis, controlling for patient age/sex/race, disease risk index, donor age, HLA-DR mm, HLA-DP npmm and year of transplantation, both recipient B leader and total iKIR ML were independently associated with DFS (HR 0.57, p=0.002 and HR 0.67, p=0.026) and relapse/progression (HR 0.55, p=0.006 and HR 0.55, p=0.007). In summary, a recipient M-containing B-leader genotype (MM or MT) reduces relapse and improves survival following HIDT-PTCy, presumably through HLA-E-mediated effector cell engagement. Furthermore, the negative consequences of low total ML for iKIR, in terms of increased relapse risk and lower DFS, can be mitigated when a R(M+) B-leader is present. In addition to the clinical importance of this novel finding for optimizing HIDT-PTCy, it further supports the role of alloreactive donor NK cells for optimal GVL in this context. Figure 1 Figure 1. Disclosures Solh: Partner Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; BMS: Consultancy.

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Heterogeneous phenotypes of expression of the NKB1 natural killer cell class I receptor among individuals of different human histocompatibility leukocyte antigens types appear genetically regulated, but not linked to major histocompatibililty complex haplotype.

Journal of Experimental Medicine ◽

10.1084/jem.183.4.1817 ◽

1996 ◽

Vol 183 (4) ◽

pp. 1817-1827 ◽

Cited By ~ 116

Author(s):

J E Gumperz ◽

N M Valiante ◽

P Parham ◽

L L Lanier ◽

D Tyan

Keyword(s):

T Cells ◽

Cell Surface ◽

Nk Cells ◽

Natural Killer ◽

Killer Cell ◽

Peripheral Blood Lymphocytes ◽

Class I ◽

Cell Surface Expression ◽

Target Cells ◽

Hla Type

Natural killer (NK) cells that express the NKB1 receptor are inhibited from killing target cells that possess human histocompatibility leukocyte antigen (HLA) B molecules bearing the Bw4 serological epitope. To investigate whether NKB1 expression is affected by HLA type, peripheral blood lymphocytes of 203 HLA-typed donors were examined. Most donors had a single population of NKB1+ cells, but some had two populations expressing different cell surface levels of NKB1, and others had no detectable NKB1+ cells. Among the donors expressing NKB1, both the relative abundance of NKB1+ NK cells and their level of cell surface expression varied substantially. The percentage of NKB1+ NK cells ranged from 0 to >75% (mean 14.7%), and the mean fluorescence of the positive population varied over three orders of magnitude. For each donor, the small percentage of T cells expressing NKB1 (usually <2%), had a pattern of expression mirroring that of the NK cells. NKB1 expression by NK and T cells remained stable over the 2-yr period that five donors were tested. Patterns of NKB1 expression were not associated with Bw4 or Bw6 serotype of the donor or with the presence of any individual HLA-A or -B antigens. Cells expressing NKB1 are often found in donors who do not possess an appropriate class I ligand, and can be absent in those who express Bw4+ HLA-B antigens. Family studies further suggested that the phenotype of NKB1 expression is inherited but not HLA linked. Whereas identical twins show matching patterns of NKB1 expression, HLA-identical siblings can differ in NKB1 expression, and conversely, HLA-disparate siblings can be similar. Thus NKB1 expression phenotypes are tightly regulated and extremely heterogeneous, but not correlated with HLA type.

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The Bw4 public epitope of HLA-B molecules confers reactivity with natural killer cell clones that express NKB1, a putative HLA receptor.

Journal of Experimental Medicine ◽

10.1084/jem.181.3.1133 ◽

1995 ◽

Vol 181 (3) ◽

pp. 1133-1144 ◽

Cited By ~ 359

Author(s):

J E Gumperz ◽

V Litwin ◽

J H Phillips ◽

L L Lanier ◽

P Parham

Keyword(s):

Monoclonal Antibody ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Killer Cell ◽

Inhibitory Effect ◽

Glycosylation Site ◽

Class I ◽

Target Cells ◽

Cell Clones

Although inhibition of natural killer (NK) cell-mediated lysis by the class I HLA molecules of target cells is an established phenomenon, knowledge of the features of class I molecules which induce this effect remains rudimentary. Using class I alleles HLA-B*1502 and B*1513 which differ only at residues 77-83 which define the Bw4 and Bw6 serological epitopes, we tested the hypothesis that the presence of the Bw4 epitope on class I molecules determines recognition by NKB1+ NK cells. HLA-B*1513 possesses the Bw4 epitope, whereas B*1502 has the Bw6 epitope. Lysis by NKB1+ NK cell clones of transfected target cells expressing B*1513 as the only HLA-A, -B, or -C molecule was inhibited, whereas killing of transfectants expressing B*1502 was not. Addition of an an anti-NKB1 monoclonal antibody reconstituted lysis of the targets expressing B*1513, but did not affect killing of targets bearing B*1502. The inhibitory effect of B*1513 could be similarly prevented by the addition of an anti-class I monoclonal antibody. These results show that the presence of the Bw4 epitope influences recognition of HLA-B molecules by NK cells that express NKB1, and suggest that the NKB1 molecule may act as a receptor for Bw4+ HLA-B alleles. Sequences outside of the Bw4 region must also affect recognition by NKB1+ NK cells, because lysis of transfectants expressing HLA-A*2403 or A*2501, which possess the Bw4 epitope but are in other ways substantially different from HLA-B molecules, was not increased by addition of the anti-NKB1 antibody. Asparagine 86, the single site of N-linked glycosylation on class I molecules, is in close proximity to the Bw4/Bw6 region. The glycosylation site of the Bw4-positive molecule B*5801 was mutated, and the mutant molecules tested for inhibition of NKB1+ NK cells. Inhibition that could be reversed by addition of the anti-NKB1 monoclonal antibody was observed, showing the presence of the carbohydrate moiety is not essential for class I recognition by NKB1+ NK cell clones.

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Human natural killer cell receptors for HLA-class I molecules. Evidence that the Kp43 (CD94) molecule functions as receptor for HLA-B alleles.

Journal of Experimental Medicine ◽

10.1084/jem.180.2.545 ◽

1994 ◽

Vol 180 (2) ◽

pp. 545-555 ◽

Cited By ~ 146

Author(s):

A Moretta ◽

M Vitale ◽

S Sivori ◽

C Bottino ◽

L Morelli ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Killer Cell ◽

Hla Class I ◽

Cytolytic Activity ◽

Class I ◽

Target Cells ◽

Human Natural Killer Cell ◽

Ligand Interaction ◽

Hla Class I Molecules

GL183 or EB6 (p58) molecules have been shown to function as receptors for different HLA-C alleles and to deliver an inhibitory signal to natural killer (NK) cells, thus preventing lysis of target cells. In this study, we analyzed a subset of NK cells characterized by a p58-negative surface phenotype. We show that p58-negative clones, although specific for class I molecules do not recognize HLA-C alleles. In addition, by the use of appropriate target cells transfected with different HLA-class I alleles we identified HLA-B7 as the protective element recognized by a fraction of p58-negative clones. In an attempt to identify the receptor molecules expressed by HLA-B7-specific clones, monoclonal antibodies (mAbs) were selected after mice immunization with such clones. Two of these mAbs, termed XA-88 and XA-185, and their F(ab')2 fragments, were found to reconstitute lysis of B7+ target cells by B7-specific NK clones. Both mAbs were shown to be directed against the recently clustered Kp43 molecule (CD94). Thus, mAb-mediated masking of Kp43 molecules interferes with recognition of HLA-B7 and results in target cell lysis. Moreover, in a redirected killing assay, the cross-linking of Kp43 molecules mediated by the XA185 mAb strongly inhibited the cytolytic activity of HLA-B7-specific NK clones, thus mimicking the functional effect of B7 molecules. Taken together, these data strongly suggest that Kp43 molecules function as receptors for HLA-B7 and that this receptor/ligand interaction results in inhibition of the NK-mediated cytolytic activity. Indirect immunofluorescence and FACS analysis of a large number of random NK clones showed that Kp43 molecules (a) were brightly expressed on a subset of p58-negative clones, corresponding to those specific for HLA-B7; (b) displayed a medium/low fluorescence in the p58-negative clones that are not B7-specific as well as in most p58+ NK clones; and (c) were brightly expressed as in the p58+ clone ET34 (GL183-/EB6+, Cw4-specific). Functional analysis revealed that Kp43 functioned as an inhibitory receptor only in NK clones displaying bright fluorescence. These studies also indicate that some NK clones (e.g., the ET34) can coexpress two distinct receptors (p58 and Kp43) for different class I alleles (Cw4 and B7). Finally, we show that Kp43 molecules function as receptors only for some HLA-B alleles and that still undefined receptor(s) must exist for other HLA-B alleles including B27.

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Impact of HLA Class I Allele Mismatch on Viral Infection within 100 Days after Cord Blood Transplantation

Blood ◽

10.1182/blood-2019-123073 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3267-3267

Author(s):

Tomoki Iemura ◽

Yasuyuki Arai ◽

Junya Kanda ◽

Toshio Kitawaki ◽

Masakatsu Hishizawa ◽

...

Keyword(s):

Viral Infection ◽

Research Funding ◽

Viral Infections ◽

Cord Blood Transplantation ◽

Univariate Analysis ◽

Hla Class I ◽

Class I ◽

Virus Infections ◽

Blood Transplantation ◽

Cmv Antigenemia

Introduction: Viral infections occur more frequently in cord blood transplantation (CBT) than in transplantation of other stem cell sources, and they are often fatal. Thus, it is important to determine the predictors of viral infection to improve CBT outcomes. We hypothesized that incompatibility of human leukocyte antigen (HLA) class I can increase susceptibility to viral infections because donor HLA-restricted naïve cytotoxic T cells cannot recognize recipient infected cells properly in the early term after CBT. Herein, we focused on the impact of HLA class I incompatibility on viral infection within 100 days after CBT. Patients and Methods: We retrospectively analyzed 121 patients who underwent 126 CBT procedures at Kyoto University Hospital from February 2003 to January 2019. Viral infection was defined as infection of recipient somatic cells by viruses detected via pathology or molecular biology and confined to those specific for an immunocompromised condition. Cytomegalovirus (CMV) antigenemia was distinguished from viral infections, because in such cases, the infected cells are donor-derived cells. Characteristics were compared between two groups using Fisher's test. The incidences of viral infection, CMV antigenemia, and steroid use for pre-engraftment immune reaction, engraftment syndrome, and acute graft-versus-host disease (aGVHD) together (PIR/ES/aGVHD) were calculated considering death and relapse as competing events, and they were compared using Gray's test. Fine-Gray proportional hazards models were used for univariate and multivariate analyses to evaluate the effects of variables on outcome. Survival was estimated using the Kaplan-Meier method. Non-relapse mortality was estimated using Gray's method. Results: The median patient age was 47 (range, 19-68) years, and 69 patients were male. The underlying diseases were acute myeloid leukemia (n=53), acute lymphoblastic leukemia (n=17), myelodysplastic syndromes (n=17), anaplastic anemia (n=6), non-Hodgkin lymphoma (n=20), and others (n=9). Regarding the CBT protocol, 44 patients received myeloablative conditioning and 83 patients received a calcineurin inhibitor and mycophenolate mofetil for GVHD prophylaxis. We identified 50 virus infections in 42 transplants within 100 days after transplantation, including 7 human herpesvirus 6 infections, 14 CMV infections, 26 BK virus, JC virus, and adenovirus infections, 2 varicella-zoster virus infections, and 1 unknown virus infection. Univariate analysis showed that HLA-A and HLA-C allele mismatches in the GVH direction were associated with a significantly higher incidence of viral infection (mismatch vs. match; HLA-A: 42.7% vs. 25.8%, HR 1.86, P=0.049; HLA-C: 43.9% vs. 17.6%, HR 2.94, P=0.015; Figure 1A). Moreover, 3/6 or more HLA class I allele mismatch in the GVH direction was associated with a significantly higher viral infection incidence (50.0% vs. 26.9%, HR 2.29, P=0.010; Figure 1B), but not with CMV antigenemia (65.8% vs. 70.1%, HR 0.95, P=0.82). These patients with HLA class I mismatches showed no increase in steroid use for PIR/ES/aGVHD (70.4% vs. 64.2%, P=0.53) or prophylactic antiviral drug therapy (62.5% vs. 65.7%, P=0.84). Regarding HLA class II mismatches, HLA-DR mismatch in the GVH direction was not associated with viral infection (34.1% vs. 32.6%, HR 1.13, P=0.72). Univariate analysis showed that lymphoid neoplasm (P<0.01), no use of cytarabine for conditioning (P=0.035), fludarabine and melphalan use for conditioning (P=0.043 and 0.075, respectively), and second or subsequent transplant (P=0.067) were associated with a higher incidence of viral infection. Multivariate analysis showed that HLA class I mismatches and lymphoid neoplasm remained significant factors for viral infection (P=0.035 and <0.01, respectively). Regarding post-CBT outcomes, 5-year overall survival (OS) and non-relapse mortality (NRM) with landmark analysis at 100 days were inferior in patients with viral infection (OS: 66.5% vs. 73.6%, P=0.35; NRM: 14.6% vs. 4.6%, P=0.11). Conclusion: HLA class I allele mismatch, including HLA-C mismatch, was significantly associated with viral infection within 100 days of CBT. Our findings suggest the importance of HLA class I genotype compatibility, including HLA-C compatibility, for CBT. Graft matching can reduce the incidence of viral infection and thus improve outcomes. Figure 1 Disclosures Kanda: Chugai: Honoraria; Otsuka: Honoraria; JCR Pharmaceuticals: Honoraria; Bristol-Meyers Squib: Honoraria; Kyowa Hakko Kirin: Honoraria; NextGeM Incorporation: Patents & Royalties: 2019-011392; MSD: Honoraria; Daiichi Sankyo Company: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Astellas: Honoraria. Takaori-Kondo:Chugai: Research Funding; Janssen: Honoraria; Pfizer: Honoraria; Kyowa Kirin: Research Funding; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ono: Research Funding; Takeda: Research Funding.

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HLA Influence on NK Cell Expansion

Blood ◽

10.1182/blood.v112.11.4924.4924 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4924-4924

Author(s):

Jennifer Schellekens ◽

Anna Stserbakova ◽

Madis Tõns ◽

Hele Everaus ◽

Marcel GJ Tilanus ◽

...

Keyword(s):

Nk Cells ◽

Cell Lines ◽

Cell Expansion ◽

Nk Cell ◽

Killer Cell ◽

Hla Class I ◽

Class I ◽

Haematopoietic Stem Cell ◽

Specific Priming

Abstract Natural Killer (NK) cells are effector cells in the innate immune system. The anti-leukaemic capacities of NK cells in haematopoietic stem cell transplantation make these cells a potential treatment modality to improve clinical outcome. Immunotherapy with NK cells requires transfusion of large quantities, which obviates the need for an in vitro culture system for NK cells. The killer cell immunoglobulin-like receptors (KIR) on NK cells recognise defined groups of HLA class I alleles. To elucidate the influence of these interactions on proliferation, the peripheral blood mononuclear cells (PBMCs) of 29 patients and donors were cultured in CellGro SCGM with IL-2 and OKT3 antibody to expand the NK cell fraction. The killer cell immunoglobulin-like receptor (KIR) and HLA repertoire were determined by sequence specific priming and sequence based typing respectively. The percentage of NK cell expansion from the total PBMC fraction varied between 5.4% and 71.6%. A significantly better NK cell expansion was observed for individuals homozygous for HLA-C epitope group 2 (p<0.05). For evaluation of cytolytic competence of the cultured NK cells, specific killing of an HLA class I expression deficient LCL 721.221 cell line and three 721.221 cell lines transfected with different HLA-C alleles was determined. A significantly better NK cell-induced specific cytotoxicity was observed towards the untransfected 721.221 cells compared to the HLA-C transfected 721.221 cells. No significant differences were observed between killing of the three HLA-C transfected 721.221 cell lines. We have shown that cytolytic capacities of the cultured NK cells are maintained and in vitro expansion of NK cells is dependant on the presence of HLA-C alleles.

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Killer Cell Inhibitory Receptor Recognition of Human Leukocyte Antigen (HLA) Class I Blocks Formation of a pp36/PLC-γ Signaling Complex in Human Natural Killer (NK) Cells

Journal of Experimental Medicine ◽

10.1084/jem.184.6.2243 ◽

1996 ◽

Vol 184 (6) ◽

pp. 2243-2250 ◽

Cited By ~ 96

Author(s):

Nicholas M. Valiante ◽

Joseph H. Phillips ◽

Lewis L. Lanier ◽

Peter Parham

Keyword(s):

Human Leukocyte Antigen ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Killer Cell ◽

Human Leukocyte ◽

Class I ◽

Cell Cytotoxicity ◽

Leukocyte Antigen ◽

Nk Cell Cytotoxicity

The killer cell inhibitory receptors (KIR) of human natural killer (NK) cells recognize human leukocyte antigen class I molecules and inhibit NK cell cytotoxicity through their interaction with protein tyrosine phosphatases (PTP). Here, we report that KIR recognition of class I ligands inhibits distal signaling events and ultimately NK cell cytotoxicity by blocking the association of an adaptor protein (pp36) with phospholipase C-γ in NK cells. In addition, we demonstrate that pp36 can serve as a substrate in vitro for the KIR-associated PTP, PTP-1C (also called SHP-1), and that recognition of class I partially disrupts tyrosine phosphorylation of NK cell proteins, providing evidence for KIR-induced phosphatase activity.

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Hepatic Niche Leads to Aggressive Natural Killer Cell Leukemia Proliferation

Blood ◽

10.1182/blood-2021-151784 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3309-3309

Author(s):

Kazuaki Kameda ◽

Yuji Miyatake ◽

Yoshinobu Kanda ◽

Ai Kotani

Keyword(s):

Bone Marrow ◽

Natural Killer Cell ◽

Nk Cells ◽

Natural Killer ◽

Tumor Cells ◽

Rna Sequencing ◽

Research Funding ◽

Killer Cell ◽

Cell Leukemia

Abstract Aggressive natural killer cell leukemia (ANKL) is a rare form of natural killer (NK)-cell neoplasm with median survival of less than 2 months. Recently, the genomic mutation analysis using tumor cells reveled that the mutational profile of ANKL was similar to that of extranodal NK / T-cell lymphoma, which has relatively better prognosis than ANKL, explaining no causative mutations with a dismal prognosis. Here, using patient-derived xenograft model (PDX) mouse, we show that hepatic niche plays an important role in the ANKL biology. We established PDX mouse by intravenously injecting ANKL cells derived from patient peripheral blood or bone marrow samples to immunocompromised mice, which enables comprehensive analysis for tumor cells as well as tumor microenvironment. In total, we obtained four PDX strains derived from different patients. Time series pathological and flowcytometric analyses revealed that the ANKL cells initially engrafted and proliferated in sinusoidal or peri-portal area of the liver. This sinusoid or peri-portal distribution of ANKL in the liver was also confirmed with the patient liver specimen. To further determine the feature of ANKL in the liver, we selected liver or spleen tropic cells by serial adaptive transfer from each organ to the next mice. The liver-tropic ANKL cells proliferated more rapidly than splenic ANKL cells, which was evident by the significantly shorter survival of PDX mice injected liver-tropic cells (Figure). We performed RNA-sequencing using liver-tropic ANKL cells, spleen-tropic ANKL cells and NK-cells derived from healthy donors. These three types of cells showed distinct populations in principal component analysis. To further clarify the interaction between ANKL and liver niche, we performed additional RNA sequencing using total liver of mouse with or without bearing leukemic cells. In the cell-cell interaction analysis, we used two computational methods, mixed-species RNA-seq (Komura, et al. BMC Genomics 2016), which can distinguish transcripts derived from human (cancer) with mouse (non-cancer niche cells), and NicheNet (Browaeys, et al. Nat Methods 2020), which is a computational algorithm to model intercellular communication by linking ligands to target genes. These two methods allowed us to investigate the interaction between liver niche ligands and ANKL receptors. Among the listed ligand-receptor interactions, we focused on the macrophage migration inhibitory factor (MIF) and its receptor, CD74 axis. While CD74 was upregulated in ANKL cells compared with normal NK cells, MIF was highly expressed in the liver mainly liver sinusoid and Kupffer cells. Although we failed to culture primary ANKL cells in vitro, ANKL cells treated with MIF showed improved viability in vitro compared with untreated cells. Deletion of CD74 on the ANKL cells using CRISPR-Cas9 system attenuated the tumor formation in the liver as well as in bone marrow and spleen of PDX mouse compared with the wild type ANKL cells. These findings highlight that the liver, non-canonical hematopoietic organ in adults, is a principal niche where the liver specific components are required for survival and proliferation of ANKL cells. MIF-CD74 axis might play an important role in the communication between ANKL and hepatic niche. Figure 1 Figure 1. Disclosures Kanda: Otsuka Pharmaceutical: Honoraria, Research Funding; Sanofi: Research Funding; MSD: Honoraria.

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Functional Status Is Associated with Outcomes after Allogeneic Stem Cell Transplantation for Older Patients with Hematologic Malignancies

Blood ◽

10.1182/blood-2018-99-112025 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3599-3599 ◽

Cited By ~ 3

Author(s):

Li-Wen Huang ◽

Chiung-Yu Huang ◽

Charalambos Andreadis ◽

Aaron C. Logan ◽

Gabriel N. Mannis ◽

...

Keyword(s):

Physical Health ◽

Functional Status ◽

Cell Transplantation ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Univariate Analysis ◽

Health Score ◽

Post Transplant ◽

Transplant Outcomes ◽

Physical Health Score

Abstract Introduction: Allogeneic hematopoietic cell transplantation (alloHCT) has historically been reserved for younger, fit patients with hematologic malignancies. With the introduction of non-myeloablative conditioning regimens and improved supportive care, alloHCT has been increasingly offered to older adults. Objectives: To determine the association between functional status as measured by a cancer-specific comprehensive geriatric assessment (CGA) and post-transplant outcomes in an older alloHCT patient population. Methods: We conducted a prospective cohort study of patients aged 50 or older who underwent alloHCT at the University of California San Francisco between October 2011 and September 2017. A cancer-specific CGA (1) was administered prior to alloHCT, which included measures of functional status such as Lawton Instrumental Activities of Daily Living (IADL), Medical Outcomes Study (MOS) Physical Health scale, and patient-reported Karnofsky Performance Status (KPS). Post-transplant outcomes included length of hospital stay (LOS), non-relapse mortality (NRM), progression-free survival (PFS), and overall survival (OS). Results: A total of 148 patients were included in the analysis. The median age at transplant was 62 (range 50-76). Disease types included acute myeloid leukemia (43%), myelodysplastic syndrome (26%), myeloproliferative neoplasm (12%), acute lymphoblastic leukemia (10%), non-Hodgkin lymphoma (5%), multiple myeloma (1%), and other (3%); 68% received non-myeloablative conditioning. Median follow-up was 16.3 months (range 0.9-72.7 months). Median PFS and OS were 22.9 months and 47.6 months, respectively. At baseline, 39% had at least one IADL deficit, and 88% had at least one MOS Physical Health scale deficit. The mean patient-KPS was 82.4 and mean provider-KPS was 91.6; these were weakly correlated (Spearman's r=0.39, p<0.001). In univariate analysis, the presence of any IADL deficit was associated with inferior PFS (HR 1.78, p=0.01) and OS (HR 1.68, p=0.04) (Figure). MOS Physical Health score was associated with increased NRM (HR 1.06 per 1-point change in 20-point scale, p=0.04), inferior OS (HR 1.05, p=0.04), increased LOS (difference 0.63 days, p=0.007), but not with PFS (HR 1.04, p=0.06). Neither patient- nor provider-KPS was associated with NRM, PFS, or OS, but lower patient-KPS was associated with increased LOS (difference 1.94 days, p=0.01). In this study, the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), disease risk by American Society for Blood and Marrow Transplantation (ASBMT) classification, and conditioning intensity were not associated with NRM, PFS, or OS. Notably, chronologic age was not associated with NRM, PFS, or OS (Figure). In addition, age was not associated with baseline IADL score (r=-0.02, p=0.26) or MOS Physical Health score (r=-0.13, p=0.06). Conclusion: IADL impairment was associated with inferior PFS and OS, supporting previous studies (2, 3) identifying IADL as an important predictor for alloHCT. In univariate analysis, IADL was a stronger predictor of post-transplant outcomes than traditional prognostication tools such as age, HCT-CI, and provider-KPS. MOS Physical Health score was associated with multiple poor outcomes including NRM and LOS, suggesting a primary impact on alloHCT toxicity. Multivariate analyses, as well as examination of other CGA variables, are ongoing. References:J Clin Oncol. 2011 Apr 1;29(10):1290-6.Haematologica. 2014 Aug;99(8):1373-9.Bone Marrow Transplant. 2018 May;53(5):565-575. Figure. Figure. Disclosures Andreadis: Genentech: Consultancy, Employment; Gilead: Consultancy; Juno: Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; Kite: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Astellas: Consultancy. Logan:Napajen: Consultancy; Adaptive Biotech: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy; Astellas: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding. Mannis:Agios: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; NKarta: Membership on an entity's Board of Directors or advisory committees. Smith:Astellas Pharma: Research Funding. Martin:Roche: Consultancy; Amgen: Research Funding; Sanofi: Research Funding. Damon:Novartis: Other: spouse's relationship with company; Boston Scientific: Other: spouse's relationship with company; Actelion: Other: spouse's relationship with company; Gilead Sciences Inc: Other: spouse's relationship with company. Olin:Synapse: Honoraria; Astellas: Research Funding; Daiichi Sankyo: Research Funding; Genentech: Research Funding.

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From Ex-Vivo T-Cell Depletion to Post-Transplant Cyclophosphamide: Improved GvHD-Free & Relapse-Free Survival but Comparable Chronic GvHD Incidence in Haploidentical Transplantation. A 15 Years EBMT Registry Analysis on Behalf of the TCWP-EBMT

Blood ◽

10.1182/blood-2019-129105 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 876-876

Author(s):

Maria Teresa Lupo-Stanghellini ◽

Christophe Peczynski ◽

Hildegard T. Greinix ◽

Emmanuelle Polge ◽

Mohamad Mohty ◽

...

Keyword(s):

Research Funding ◽

Ex Vivo ◽

Chronic Gvhd ◽

Univariate Analysis ◽

Disease Status ◽

Free Survival ◽

Patient Gender ◽

Gvhd Prophylaxis ◽

Grade 3

Background: Haploidentical stem cell transplantation (Haplo HSCT) has emerged in the past three decades as an alternative curative option when an HLA match donor is not available. Over time, the use of Haplo has increased dramatically, reaching superimposable results when compared to unrelated and related HSCT strategies, confirming its validity. The widespread use of Haplo mainly relies upon technical advances, control of alloreactivity through graft-versus-host disease (GvHD) prophylaxis combined with a rapid and almost universal probability to find an Haplo donor for any candidate patient. The aim of our study was to provide a picture of acute (aGvHD) and chronic GvHD (cGvHD) incidence in Haplo HSCT across different platform in the past 15 years, where Haplo moved from ex-vivo T-cell depleted (TCD) platform to in-vivo TCD platform to the post-transplantation cyclophosphamide (PTCy). Methods: We compared the outcomes of adult patients receiving a 1st Haplo HSCT for any hematological malignancy according to GvHD prophylaxis - ex-vivo + in-vivo TCD (n=160), in-vivo only TCD (n=507) or PTCy (n=2593) - and reported to the EBMT registry in 2004-2016. Patients with missing data on disease status at last follow-up and GvHD information were excluded. Primary endpoint was GvHD-free & Relapse-free survival (GRFS) with events defined by death or relapse or grade ≥3 aGvHD or extensive (ext) cGvHD. Secondary endpoints were progression-free survival (PFS), overall survival (OS), aGvHD and cGvHD, incidence of relapse (IR) and non-relapse-mortality (NRM). Due to sample size in the first cohort of ex-vivo TCD, multivariate analysis compared only in-vivo TCD vs PTCy cohorts. Table 1 illustrates patients' characteristics. Results: Univariate analysis for 3-year outcomes are reported on table 2. PTCy provides better GRFS, OS, PFS, NRM versus ex-vivo or in-vivo. IR was not significantly different. Likewise, the 3-year CI of cGvHD and ext cGvHD were similar between PTCy, in vivo TCD and ex-vivo TCD (cGvHD 27% [25-29%], 25% [21-29%], 18% [12-25%], p 0.03; ext cGvHD 11% [10-12%], 10% [8-13%], 8% [4-13%], p 0.45). On the contrary the 100-day CI of grade ≥2 aGvHD were lower in the ex-vivo TCD vs PTCy and in-vivo TCD (19% [14-26%], 28% [26-30%], 32% [28-36%], p 0.002) while grade ≥3 aGvHD were lower in the PTCy group vs ex-vivo and in-vivo TCD (9% [8-10%], 11% [7-17%], 14% [11-18%], p <0.001). After adjustment for diagnosis, patient age, disease status, Karnofsky PS, donor/patient gender and CMV, cell source, conditioning intensity, previous auto and year of transplant, the multivariable model comparing in-vivo TCD and PTCy showed better outcome for PTCy. Compared to in-vivo TCD, the hazards for GRFS was 0.76 for PTCy (p 0.004), the HR for PFS was 0.71 (p 0.001) and the HR for OS was 0.7 (p 0.0008), the HR for NRM was 0.63 (p 0.001). Moreover, compared to in-vivo TCD, PTCy yielded similar hazards for grade≥2 aGvHD (HR: 1.02, p 0.89), grade≥3 aGvHD (HR 0.79, p 0.27), cGvHD (HR 1.17, p 0.37), ext cGvHD (HR 1.18, p 0.52) and relapse (HR 0.8, p 0.1). Variables associated with GRFS were active disease, Karnofsky PS ≥90%, diagnosis, donor/patient gender and CMV. An ancillary analysis evaluating the stem cell source effect in the PTCy cohort only, demonstrates comparable outcome endpoints (OS, PFS, NRM, IR) at 2-year between bone marrow (BM) and peripheral blood (PB) PTCy. In univariate analysis GRFS and the 2-year CI of cGvHD were not different between BM and PB (GRFS 47% [45-50%], 46% [44-49%], p 0.085; 2-year CI of cGvHD 25% [23-28%], 27% [25-30%], p 0.2) while ext cGvHD, 100-day CI of grade ≥2 aGvHD and grade ≥3 aGvHD were lower in BM PTCy vs PB PTCy (ext cGvHD 8% [7-10%], 12% [10-14%], p <0.001; grade ≥2 aGvHD 20% [18-22%], 36% [33-38%], p <0.001; grade ≥3 aGvHD 6% [5-7%], 12% [10-14%], p <0.001). Compared to BM PTCy, the HR for cGvHD was 1.55 for PB PTCy (p 0.001), the HR for ext cGvHD was 2.04 (p 0.0003), the HR for grade ≥2 aGvHD was 1,94 (p <0.0001), the HR for grade ≥3 aGvHD was 2.01 (p 0.0001). Conclusions: In the present EBMT registry study on more than 3000 patients transplanted from an Haplo donor, we report improved outcome (better GRFS - in spite of comparable chronic GvHD - OS and PFS, lower NRM) and widespread use in different diagnosis setting other than acute leukemia in PTCy platform. PTCy strategy provides a concrete progress into the field: even if cGvHD still represent a major issue, exploitation of BM PTCy seems to protect against most severe GvHD manifestation. Disclosures Mohty: Jazz Pharmaceuticals: Honoraria, Research Funding. Kröger:Sanofi-Aventis: Honoraria; Riemser: Research Funding; Novartis: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Medac: Honoraria; JAZZ: Honoraria; DKMS: Research Funding; Celgene: Honoraria, Research Funding. Basak:Celgene: Honoraria; Teva: Honoraria.

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Survival after T-Cell Replete Haploidentical Related Donor Transplant Using Post-Transplant Cyclophosphamide Compared with Matched Unrelated Donor (MUD) Transplant for Lymphoid Malignancies

Blood ◽

10.1182/blood.v126.23.194.194 ◽

2015 ◽

Vol 126 (23) ◽

pp. 194-194 ◽

Cited By ~ 1

Author(s):

Alberto Mussetti ◽

Abraham Sebastian Kanate ◽

Mohamed A Kharfan-Dabaja ◽

Kwang Woo Ahn ◽

Alyssa DiGilio ◽

...

Keyword(s):

Mortality Risk ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Study Cohort ◽

Platelet Recovery ◽

Post Transplant ◽

Gvhd Prophylaxis ◽

Significant Difference ◽

Conditioning Regimens

Abstract Background: The use of haploidentical hematopoietic cell transplantation (HCT) using post- transplant cyclophosphamide (PT-Cy), calcineurin inhibitors (CNI) and mycophenolate as graft-versus-host disease (GVHD) prophylaxis is rapidly increasing in patients (pts) lacking suitable HLA-matched donors. Herein we compare outcomes of haploidentical HCT using this GVHD prophylaxis with 8/8 allele-level MUD HCT. Methods: Included are 917 adult (>18) lymphoma pts who underwent allogeneic HCT between 2008 and 2013. All pts received non-myeloablative or reduced-intensity conditioning regimens. The study cohort was divided into 3 groups; haploidentical (n=185), MUD without (w/o) antithymocyte globulin (ATG; n=491) and MUD with (w/) ATG (n=291). The primary end-point was overall survival (OS). Secondary endpoints included cumulative incidence (Cum-Inc) of acute GVHD, chronic GVHD, non-relapse mortality (NRM), relapse/progression (rel/prog) and progression-free survival (PFS). The study had an 83% power to detect an 11% difference in OS. Results: The baseline characteristics are shown in Table 1. Pts in the haploidentical group received conditioning with Flu/CY/2Gy TBI and PT-Cy + CNI and mycophenolate as GVHD prophylaxis, while the two MUD cohorts received fludarabine-based (+ an alkylator or 2GyTBI) conditioning and CNI-based GVHD prophylaxis. Graft source was bone marrow in 93% of the haploidentical pts and peripheral blood in 94% and 91% of MUD w/o ATG and MUD w/ ATG pts, respectively. The 28-day neutrophil recovery and platelet recovery were 94%, 97%, 97% (p=0.32) and 63%, 89%, 84% (p<0.001) in the haploidentical, MUD w/o ATG and MUD w/ ATG groups respectively. Cum-Inc of grade II-IV acute GVHD at day100 and chronic GVHD at 1 year was 27%, 40% and 49% (p=0.07) and 13%, 51% and 33% (p<0.001) in the haploidentical, MUD w/o ATG and MUD w/ ATG groups, respectively. On multivariate analysis (MVA) higher risk of chronic GVHD was seen in MUD w/o ATG (RR=5.85, 95%CI 3.96-8.64; p<0.0001) and MUD w/ ATG (RR=3.64, 95%CI 2.37-5.59; p<0.0001) groups relative to the haploidentical cohort. The 3 year NRM was 17%, 22% and 26% in the haploidentical, MUD w/o ATG and MUD w/ ATG groups (p=0.08), respectively. On MVA a trend towards higher NRM was noted in MUD w/ ATG cohort, RR 1.54 (95%CI 0.98 - 2.41, p=0.06), relative to the haploidentical group. Among the haploidentical, MUD w/o ATG and MUD w/ ATG cohorts the 3 year Cum-Inc of rel/prog was 36% vs. 28% vs. 36%, PFS was 47% vs. 49% vs. 38% and OS was 60%, 62% and 50% (Figure), respectively. MVA demonstrated no significant difference between the three groups in terms of rel/prog (p=0.27) and PFS (p=0.07). Compared to the haploidentical group, the two MUD groups did not have a significantly different mortality risk (inverse of OS; p>0.05), but compared to MUD w/ ATG, the MUD w/o ATG pts had a reduced mortality risk (RR=0.67; p=0.001). We tested for a transplant center effect on survival and found none. Conclusion: With lower-intensity conditioning regimens the early (up to 3 years) survival outcomes are comparable between conventional MUD transplants (w/ or w/o ATG) and haploidentical HCT with PT-Cy approach. Chronic GVHD was significantly lower with haploidentical HCT. Prospective, randomized confirmation of these findings is necessary before wide spread adoption of haploidentical HCT over MUD transplants in lymphomas.Table 1.Haploidentical N=185 (%)MUD w/o ATG N=491 (%)MUD w/ ATG N=241 (%)p-valueAge @ HCT, median (range)55 (18-75)55 (19-74)55 (20-73)0.13Male sex118 (64)301 (61)163 (68)0.25White race149 (81)469 (96)227 (94)<0.001KPS ≥ 90145 (78)311 (63)153 (63)<0.001HCT-CI≥355 (30)175 (36)88 (37)<0.001Histology NHL Hodgkin139 (75) 46 (25)386 (79) 105 (21)193 (80) 48 (20)<0.001Months from diagnosis to HCT, median (range)31 (<1-255)34 (<1-342)32 (4-460)0.19High LDH @ HCT16 (31)31 (33)11 (27)<0.001BM +ve @ HCT6 (12)5 (5)2 (5)0.35Extranodal disease @ HCT18 (35)20 (21)6 (15)0.11Prior lines of therapy, median (range)3 (1-7)3 (1-12)3 (1-8)0.41Remission @ HCT CR PR Refractory Untreated / missing72 (39) 99 (54) 10 (5) 4 (2)215 (44) 215 (44) 55 (11) 6 (1)100 (41) 96 (40) 40 (17) 5 (2)0.02Disease Risk Index Low Intermediate High45 (24) 126 (68) 13 (7)199 (41) 263 (49) 48 (10)75 (31) 129 (54) 37 (15)<0.001Median follow-up, months (range)36 (5-73)35 (4-74)35 (<1-75) Figure 1. Figure 1. Disclosures Armand: Infinity: Consultancy, Research Funding; Merck: Consultancy, Research Funding; BMS: Research Funding; Sequenta, Inc.: Research Funding. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy. Sureda:Seattle Genetics Inc.: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau.

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