Patient and Donor Factors

That Matter in HSCT

Mary Eapen MD MS
Medical College of Wisconsin
Patient Factors
• Regardless of donor type
– Age
– Performance score
– HCT-CI
– CMV serostatus
– Disease
– Disease status at HCT
– Cytogenetic / molecular markers for leukemia
– Chemotherapy sensitive NHL

2
Donor Type
• Everyone has a donor
– HLA matched sibling
– Mismatched first degree relative
– HLA-matched or mismatched adult unrelated
donor
– Unrelated umbilical cord blood
• Patient and disease characteristics also
influence transplant outcomes

3
HLA-matched sibling donor HCT
• Donor age is not considered as siblings are aged
within the same decade (±10 years)
• Not often do we have multiple siblings to choose
• Both BM and PB are acceptable grafts except
– CML in1st chronic phase, non-malignant diseases
and children with acute leukemia
– Higher chronic GVHD leads to lower survival
• Disease risk is an important determinant of
survival

4
 HLA-matched sibling donor HCT
• Who is the best donor for a patient with
leukemia/lymphoma aged ≥ 50 years:
– Younger MUD (age <50 years) or an older matched
sibling, aged ≥50 years?
• Higher acute and chronic GVHD with MUD HCT
• Better survival after matched sibling transplants for
patients with KPS 90 or 100
• No difference in survival for patients with KPS ≤ 80
• Conclusion: HLA-matched sibling when available

Alousi A, Blood 2013 5

Haplo-TCR HCT with ATG
Selection order Donor type
First choice Offspring, NIMA MM
Second choice Brother, NIMA mismatched
Third choice Sister, NIMA mismatched or father
Fourth choice Older sibling, NIPA mismatched
Last choice Mother

Wang, Blood 2014 6

Haplo-HCT PT-Cy: donor selection
Graft failure HR p-value

Patient (18-54 years) / parent 1.00 0.018

Patient (18-54 years) / sibling 0.32 0.002

Patient (18-54 years) / offspring 0.39 0.029

Patient (≥55 years) / sibling 0.73 0.39

Patient (≥55 years) / offspring 0.66 0.18

7
 Overall Survival
Haplo-TCR HCT with PT-Cy
Donor-Recipient relationship Donor-Recipient age
100 100

80 80
Probability, %

60 60

Parent – young (61%) Donor < 30 – young (61%)

40 Sibling – young (62%) 40 Donor > 30 – young (60%)
Offspring – young (58%) Donor < 30 – old (53%)
Sibling – old (45%) Donor > 30 – old (46%)
20 Offspring – old (48%) 20

0 0
0 1 2 0 1 2
Years Years

8
Haplo-TCR with PT-Cy: Graft type
BM vs. PB HR Probability P-value

Acute GVHD 0.45 42% vs. 25% <0.001

Chronic GVHD 0.35 41% vs. 20% 0.001

NRM 0.92 16% vs. 17% 0.78

Relapse/progression 1.49 28% vs. 45% <0.001

PFS 1.21 54% vs. 41% 0.002

Overall survival 0.99 57% vs. 54% 0.52

Bashey A et al. J Clin Oncol 2017

Haplo-TCR with PT-Cy: Summary
• Haplosibling or offspring are suitable
– Sex, parity, ABO match and CMV serostatus are
not relevant
• Patient age is more important than donor age or
D-R relationship
• Higher graft failure with parental donors
• Avoid donors to whom the recipient has donor
specific antibodies

10
Unrelated Adult Donor HCT
• 8/8 (matched at A, B, C, DRB1) as baseline
– Higher acute GVHD, TRM, treatment failure and
overall mortality with 7/8 and 6/8
• 6/8 vs. 7/8
– Higher TRM and overall mortality with 6/8
• Locus specific mismatch
– No adverse effect with isolated MM at DRB1
– Higher TRM and overall mortality with isolated
MM at A, B or C
– Higher acute GVHD with isolated MM at A and B

Pidala J Blood 2014 11

Unrelated Adult Donor HCT
• HLA DQB1
– No significant effects on transplant outcomes with
DQB1 MM in the setting of 8/8 or 7/8 matched
transplants
• HLA DPB1
– 8/8: isolated DPB1 MM associated with higher
risk for acute GVHD and lower risk for relapse
– No adverse effect on TRM or overall mortality
– 7/8: no significant effects of DPB1 MM

Pidala J. Blood 2014 12

Unrelated Adult Donor HCT
• T cell epitope matching based on DPB1
classification
– DPB1 permissive vs. non-permissive MM
– No differences in acute GVHD or relapse
– Higher TRM and overall mortality with non-
permissive MM transplants

Pidala J Blood 2014 13

 Adult Unrelated Donors: non-HLA
• Examined in 2 independent populations with
hematologic malignancy and allele-level HLA
matching of D-R pairs
• Cohort 1: 1988 – 2006; N = 6349
• Cohort 2: 2007 – 2011; N = 4690

Kollman C Blood 2016 14

 Multivariate Analysis: Cohort 1
- Donor Age -
1.60 1.60
Age 33-50 years Age >50 years
1.50 1.50
1.46
1.40 1.40
1.33
1.30 1.29 1.30

1.20 1.20 1.20

1.16 1.17 1.16
1.15 1.14
1.13
1.10 1.09 1.09 1.10
1.05 1.11
1.02 1.03
1.00 0.96 0.99 1.00
1.03
0.80 0.80 0.78 0.84 0.80
0.95
0.56
0.50 0.50
Baseline age: 18 – 32 years Baseline age: 18 – 32 years
0.00 0.00
Mortality Engraftment AGVHD CGVHD Mortality Engraftment AGVHD CGVHD

Kollman C Blood 2016 15

Multivariate Analysis: Cohort 1
- Donor Gender -
1.60 1.60

1.50 1.50

1.40 1.40

1.30 1.34 1.30

1.20 1.22 1.20

1.12 1.11
1.10 1.10
1.01
1.00 1.00
0.80 0.90 0.80
Baseline: Male
0.50 0.50

0.00 0.00
Female donor nulliparous Female donor, parous
Chronic GVHD Chronic GVHD

Kollman C Blood 2016 16

Multivariate Analysis: Cohort 2
• Best survival
– For every 10 year increment in donor age, there
was a 5.5% increase in the hazard ratio for overall
mortality
– The only other donor factor was HLA match:
matched transplants were associated with best
survival
– Blood group ABO match is no longer relevant
• The more recent cohort is predominantly PB grafts
– Donor CMV serostatus not associated with survival

Kollman C Blood 2016 17

 Overall Survival from Randomization
Intent-to-treat analysis
100 100

90 90

80 80
PBSC
Probability, %

70 70

60
51% 60

50 50

40 Marrow 46% 40

30 30

20 20

10 2-year point P value = 0.288 10

0 0
0 6 12 18 24 30 36
Months
Anasetti et al. N Engl J Med 2012
 PROs: Mean scores with SD
PROs 5 years post-HCT BM PB P
Number 80 72
MHI-psychological well being 78.9 ± 1.7 72.2 ± 1.7 0.01
FACT-BMT trial outcome index 76.7 ± 1.6 70.5 ± 1.9 0.01
MHI-psychological well being 16.0 ± 1.3 19.0 ± 1.5 0.13
CGVHD symptom score 13.1 ± 1.5 19.3 ± 1.6 0.004
Work (full or part-time) 1.5 1.0 0.002

Lee SJ et al, JAMA Oncol 2017

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Unrelated Adult donors: non-malignant
diseases
Baseline: 8/8 (N = 372) HR P-value

Graft failure 1.00; 11%

1 MM (N = 188) 2.81; 28% <0.0001

2 MM (allele or antigen) N = 89 2.22; 22% 0.006

Overall mortality 1.00

1 MM (N = 191) 1.29 0.08

2 MM (allele or antigen) N = 100 1.82 0.0004

Horan J et al. Blood 2012 20

 Overall Survival
Non-malignant Disorders
100
Unadjusted Probability, %

80
8/8 Matched (65%)

60 7/8 Mismatch (57%)

6/8 Mismatch (47%)

40

20 P-value = 0.0004

0
0 1 2 3 4 5
Years

Horan J; Blood 2012 21

Graft Type: URD HCT SAA-Overall Survival
100

Bone marrow, 76%

80
Probability, %

60
Peripheral blood, 61%

40

20
P-value = 0.04
0
0 6 12 18 24 30 36
Months
Eapen M et al. Blood 2011
22
Summary: URD selection
• Matching at HLA A, B, C and DRB1 is required for
optimal unrelated donor HCT survival
• Avoid non-permissive DPB1 mismatches in 8/8 or
10/10 matched pairs
• Non-malignant: higher graft failure with mismatched
HCT
• Young donors (within 2nd – 3rd decade)
• Avoid female donors with history of pregnancy if a
male donor is available
• PB: not desirable for SAA
• PB: increased burden of morbidity
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Cord Blood: Neutrophil Recovery
Allele-level Matched at A, B, C, DRB1
100

P=0.005 6/8 (66%)

80
Incidence, %

60
7/8 (62%)

40 8/8 (71%)
3/8 (53%)

20
4/8 (56%)
5/8 (58%)
0
0 5 10 15 20 25 30
Days
Eapen M et al, Blood 2014
 Cord Blood: Non-Relapse Mortality
Allele-level Matched at A, B, C, DRB1

100 100

80 80

4/8 HLA-matched (N=254; 37%)

Incidence, %

60 5/8 HLA-matched (N=464; 34%) 60

6/8 HLA-matched (N=410; 26%)
3/8 HLA-matched (N=85;41%)
40 40

20 7/8 HLA-matched (N=226; 26%) 20

8/8 HLA-matched (N=117; 9%)

0 0
0 1 2 3
Years
Eapen M et al, Blood 2014
Wagner JE et al, N Engl J Med 2014 26
Overall Survival: non-malignant diseases
Allele-level Matched at A, B, C, DRB1
100

80
Probability, %

60

40 8/8: 79%
7/8: 74% HR 1.18, p=0.40
6/8: 71% HR 1.55, p=0.02
20 5/8: 60% HR2.04, p= 0.001
3-4/8: 50% HR 3.5, p<0.0001
0
0 1 2 3 4 5
Years

Eapen M et al. Lancet Haematol 2017

Graft Failure: non-malignant diseases
Allele-level Matched at A, B, C, DRB1
100
Cumulative Incidence, %

80 8/8: 15%
7/8: 21% HR 1.51, p=0.08
6/8: 24% HR 1.74, p=0.02
60 5/8: 29% HR 1.98, p=0.004
3-4/8: 25% HR 1.77, p=0.4
40

20

0
0 1 2
Years

Eapen M et al. Lancet Haematol 2017

Cord blood Inventory: 2017
Likelihood of identifying a 6-8/8 matched unit

Children and Adults TNC > 2.5 x 107/kg

All patients 81.8%
European Caucasian 87.4%
Hispanic 69.9%
Asian or Pacific Islander 67.2%
African American 49.4%

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 Summary: Donor Selection
HLA matched sibling

Unrelated donor
• 8/8 HLA donor
• Adult – younger, males
• CB unit – TNC >2.5 x 107/kg

Haploidentical relative 7/8 adult unrelated donor

• DSA negative • Young, male
• Parents: graft failure • DSA negative

6/8 or 7/8 CB unit

• TNC >2.5 x 107/kg
• DSA negative