Donor KIR Selection to improve Allotransplant Outcomes

Daniel Weisdorf MDUniversity of Minnesota

Donor KIR Selection to improve Allotransplant Outcomes

Daniel Weisdorf MD

Conflicts: Unrelated to the topic of this presentation

Incyte     Research supportFATE Therapeutics    Consultation

Berlin, October, 2019

Polymorphic KIR interact with class I HLA molecules: mostly HLA-C

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Courtesy Peter Parham and Libby Guethlein, Stanford University

Natural Killer Cells in Transplantation NK cells are first lymphocytes to reconstitute after HCT Donor NK cell alloreactivity may improve outcomes in HCT by:◦ Preventing relapse◦ Fighting infection ◦ Promoting engraftment◦ Decreasing aGVHD

Can we choose donors with KIR which bind recipient KIR ligands (HLA) to limit relapse & improve survival in transplantation?

KIR receptor system

Steven Marsh, IPD Website Libby Guethlein, Paul Norman, Traherne et al 2010

•KIR genes and HLA genes segregate independently: •Inherited on different chromosomes as A or B haplotypes.

Controlled by a balance of Inhibitory & Activating interactions with KIR Ligands; mostly class I HLA

B haplotype

More activatinggenes

KIR Incompatibility Models KIR Ligand Mismatch◦ Mismatch between donor and recipient KIR ligand (HLA C1, C2, Bw4)◦ Requires HLA Mismatched HCT

KIR Ligand Absence◦ Recipient lacks C1, C2 or Bw4

Receptor Ligand Model◦ Mismatch between donor KIR and recipient KIR ligand (HLA)

KIR Mismatch (gene-gene model)◦ Mismatch between donor and recipient KIR

Donor KIR gene contentIPD KIR Ligand Calculator:

http://www.ebi.ac.uk/ipd/kir/ligand.html

448 adults with diagnosis of AML ◦ Received T cell replete unrelated donor HCT between 1988-2003◦ 47% 10/10 HLA M, 0% RIC 12% PBSC ◦ 46% Tacro +/- other GVHD prophy, 0% in vivo TCD

Donor DNA typed for presence/absence of 15 individual KIR genes◦ Validated single nucleotide polymorphism (SNP)-based MALDI-TOF

assay CHORI: Elizabeth Trachtenberg, PhD

Models tested:◦ Donor KIR haplotype (A/A vs. B/x)

Unrelated Donor KIR Haplotype in MACT-cell Replete HCT for AML

Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia. Cooley et al, Blood 2009

KIR B/x Genotype Unrelated Donors Limit Relapse in AMLB/x vs. A/A:

RR = 0.70 (0.55- 0.88)

p = .002

P = .002

• Myeloablative (MAC) N=448 T cell Replete

• Benefit in HLA Matched & Mismatched• No effect on TRM, aGVHD

• No benefit in ALL cohort

• Venstrom, Hsu et al (NEJM 2014)KIR B donors better (2DS1)

Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia. Cooley et al, Blood 2009

1086 adults with diagnosis of AML Received T cell replete unrelated donor HCT between 1988-2006

◦ 50% 10/10 HLA M, 0% RIC, 41% PBSC◦ 46% Tacro +/- other GVHD prophy, 0% in vivo TCD

Models tested:◦ Donor KIR haplotype (A/A vs. B/x)◦ Donor Cen vs. Tel KIR genes◦ Donor KIR B gene content (0, 1, 2)◦ Donor Neutral/Better/Best (Best includes Cen B/B)

Unrelated Donor KIR B genes in MAC T-cell Replete HCT for AML

Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia Cooley et al. Blood 2010

KIR Tel B Genes also Reduce AML Relapse

KIR Cen B/B Donors Reduce Relapse and Improve DFS after MAC T-cell Replete HCT for AML but not ALL

Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia Cooley et al. Blood 2010

AML

ALL

Pediatric T-cell deplete related haplo HCT (N=85)

KIR B/x genotype 51% DFS vs. 30% with KIR A/A donors

Donors with a higher KIR B content score led to the best outcomes

Related haplo donors with KIR B/x genotypes preferred for pediatric ALL HCT

Related Haploidentical KIR B Donors Reduce Relapse in Pediatric ALL

KIR B haplotype donors confer a reduced risk of relapse after haploidentical transplantation in children with acute lymphoblastic leukemia Oevermann et al. Blood 2014

KIR B

KIR B

KIR B 1-4

KIR B 3-4

EVENT FREE SURVIVAL

EVENT FREE SURVIVAL

RELAPSE

RELAPSE

Donors with more KIR B Genes Reduce Relapse and Improve DFS after HLA Matched or Mismatched MAC T-cell Replete HCT for AML

Cooley, Blood, 2010

HLA matched HLA Mismatched

0-1 Donor KIR B genes≥ 2 KIR B genes

--------

Relapse

DFS

Survival

Rel

apse

%

Years

B-content ≥2 not Cen-B/B (n = 213)B-content 0 or 1 (n = 727)

B-content ≥2 with Cen-B/B (n = 114)

Neutral

Better

Best (Cen B/B)

RR = 0.33 (0.20 – 0.55)

p = 0.003

Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia Cooley et al. Blood 2010

Benefit similar in HLA matched & HLA-MM HCT

KIR Better/Best Donors Reduce Relapse after HLA Matched or Mismatched MAC T-cell Replete URD HCT for AML

1532 adults with AML ◦ T cell replete URD HCT 1998-2009◦ 65% 8/8 HLA M, 0% RIC 47% PBSC

66% Tacro +/- other GVHD prophy 0% in vivo TCD

Models tested:◦ Donor KIR haplotype (A/A vs. B/x)◦ Donor KIR B gene content (0, 1, 2)◦ Donor Neutral/Better/Best (Best includes Cen B/B)

Unrelated Donor KIR B Gene Content and Recipient KIR Ligands

676 HLA Mismatch (44%)• 407 9/10 (60%)• 178 8/10 (26%)• 85 <8/10 (13%)• 357 Include MM at HLA C (53%)

Donor killer cell Ig-like receptor B haplotypes, recipient HLA-C1, and HLA-C mismatch enhance the clinical benefit of unrelated transplantation for acute myelogenous leukemia. Cooley et al, JI 2014

Cooley et al. JI 2014

KIR B Donors Improve Relapse and LFS in C1/x vs. C2/C2 Recipients

KIR B Donors limit Relapse and improve LFS in C1/x Recipients

KIR Better/BestLFS

Relapse

Cooley et al. J Immunology 2014

Cooley et al. JI 2014

Protective effect in Class I (mostly HLA-C) Mismatched HCT

KIR B Donor Benefit on Relapse and DFS is Enhanced in C1/x class I mismatched Recipients

KIR genotyping (CHORI/Stanford)◦ 535 AML searches (19% of US total) from 14 sites 2080 donors KIR typed ◦ 247 (49%) transplanted (Best 9.3%, Better 19%, Neutral 48%) unknown 24%◦ Did not delay transplant◦ Did not enrich for KIR B/B donors Average 1.8 donors/per search too few for enrichment of favorable donors

Conclude: with HapLogic, donor centers/registries need prospective KIR typing for use in donor selection (along with HLA, age, gender, parity, CMV, alloimmunization and other genetic factors)

Ideally pre-search high-throughput (NGS) donor KIR genotyping available◦ 3.16 million KIR-genotyped registered stem cell donors in DKMS◦ NMDP now prospectively KIR typing donors

Prospective KIR Donor Selection Trial: Feasibility 2012-2016

KIR Donor Selection: Feasibility in Identifying Better DonorsWeisdorf et al, BBMT 2018

Underpowered; not enriched for favorable KIR donorsAnalyzed with larger contemporaneous cohort

Analysis w/ NK cell functional data from correlative blood samplesDonor + Patient samples (pre, +1,2,3,6,12 and 24 months)

Prospective KIR Donor Selection Trial: Outcomes

KIR Donor Selection: Feasibility in Identifying Better DonorsWeisdorf et al, BBMT 2018

http://clinicaltrials.gov/ct2/show/NCT01288222

2149 adults with diagnosis of AML (plus prospective KIR DS) N = 2662◦ T replete URD HCT 2010-2016◦ 85% 8/8 HLA M, 41% RIC, 81-92% PBSC

7-17% Tacro +/- other GVHD prophy, 0% in vivo TCD

Models tested:◦ Donor KIR haplotype (A/A vs. B/x)◦ Donor KIR B gene content (0, 1, 2)◦ Donor Neutral/Better/Best (Best includes Cen B/B)◦ Donor KIR in context of Recipient C1/C2/Bw4

Expanded AML Cohort: RIC and MAC

Reduced relapse with KIR B donors: in RIC, but not MAC URD HCT for AMLRelapse

RIC MAC

Improved DFS with KIR B donors: in RIC, but not MAC URD HCT for AMLDFS

RIC MAC

*Adjusted for HLA match, disease status, cytogenetics, age

RIC URD HCT for AML: KIR B Donors Reduce relapse in C1/x recipients

RIC URD HCT for AML: KIR B Donors improve DFS in C1/x recipients

COHORT JI Cohort(N = 1532; 1988-2009)

Current Cohort (N = 2419; 2010-2016)

RIC (0%)

MAC (100%)

RIC (41%)

MAC (59%)

Months Follow Up (median range) ---

60 (3‐240) 38 (6‐99) 44 (2‐98)

DFS (Prob, CI)5 years

29 (26‐31) 35 (32‐39) 46 (43‐38)

Relapse (Prob, CI)3 Years ---

34 (32‐37) 34 (31‐36) 29 (27‐31)

TRM Rates (Prob, CI)1 Year ---

27 (25‐29) 16 (14‐18) 15 (13‐16)

Clinical Advances over Time

Changes over Time JI Cohort(N = 1532; 1988-2009)

KIR DS Trial(N = 243; 2012-2016)

New NMDP Cohort (N = 2419; 2010-2016)

RIC (0%) MAC (100%) RIC (40%) MAC (60%) RIC (41%) MAC (59%)

HLA MATCH8/8 or 10/10 (%) --- 57% 92% 92% 86% 84%

Recipient Age (median)% >60 y

------

383%

6566%

5120%

6471%

4917%

Poor Risk Cytogenetics --- 25% 22% 29% 18% 18%

KPS <90 --- 32% 43% 33% 46% 30%

% PBSC (vs. BM) --- 47% 89% 78% 92% 81%

AML status (% advanced) --- 32% 13% 38% 0% 0%

Recipient CMV+ (+) --- 54% 58% 57% 66% 68%

TAC +/- others (%)CSA +/- others (%)

------

51%46%

78%17%

93%6%

83%17%

93%7%

KIR B/x Donors (%) --- 67% 78% 71% 68% 68%

Donor KIR B/x genotype reduces relapse and improves progression-free survival after 10/10 matched URD HCT for NHL

26% (95%CI 21-32) vs. 37% (95%CI 27-46) 35% (95%CI 26-44) vs. 22% (95%CI 11-35)

Relapse PFS

KIR B Donors in URD HCT FOR NHLBachanova et al, BBMT, 2016

But no similar findingsin CLL

Bachanova, BBMT, 2018

Praveen Ramakrishnan Geethakumari et al. Blood 2016;128:2291

What About Haploidentical HCT? KIR B donors yield less relapse; better survival

• Haplo = 84 Matched Related = 44• More acute HR 1.97; p=0.047• & chronic GVHD HR 2.89; p=0.053

Selecting the Best Donor for Haploidentical Transplant: Impact of HLA, Killer Cell Immunoglobulin-Like Receptor Genotyping, and Other Clinical Variables Solomon et al, BBMT 2018

• 208 patients Haplo HCT for mixed diseases• KIR B/x donors better, especially if 2DS2+

RELAPSE

KIR B/x donors protective in URD HCT for AML but major changes in cohort and era◦ HLA-matched RIC HCT in current era◦ Specific KIR/KIR ligand (HLA) interactions may drive benefit in C1/x recipients

KIR B/x genotype donors associated with 11% reduction in relapse and improved PFS after 10/10 HLA-matched unrelated donor HCT for NHL

No donor KIR/recipient KIR ligand interactions alter outcome after URD HCT for CLL

No donor KIR benefit in URD HCT for adults; possible some for pediatric ALL

Haplo Related KIR B donors protective in small studies

Donor KIR in URD HCT

Disease and transplant variables are critical◦ Preparative regimen, graft source, T cell content, use of TBI, HLA

matching, transplant era…

Large cohorts are needed for adequate power

KIR typing should again be tested in a clinical trial

Why is B better? ◦ Presence of KIR2DS2 and/or KIR2DL2 ◦ Absence of KIR2DL3◦ KIR2DL2 binds both the C1 and C2 epitopes of HLA-C with greater

avidity than KIR2DL3 (better educator for functional NK cells)