Supplementary materials for “Hematopoietic cell transplantation for severe combined immunodeficiency patients: A Japanese retrospective study” in the Journal of Clinical Immunology Satoshi Miyamoto

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Supplementary materials for “Hematopoietic cell transplantation for severe combined immunodeficiency patients:

A Japanese retrospective study” in the Journal of Clinical Immunology

Satoshi Miyamoto

^a,b

, Katsutsugu Umeda

^b,c

, Mio Kurata

^d

, Akira Nishimura

^a,b

, Masakatsu Yanagimachi

^b,e

, Masataka Ishimura

^f

, Maho Sato

^g

, Tomonari Shigemura

^h

, Motohiro Kato

ⁱ

, Yoji Sasahara

^b,j

, Akihiro Iguchi

^b,k

, Takashi Koike

^l

, Yoshiyuki Takahashi

^m

, Michiko Kajiwara

ⁿ

, Masami Inoue

^g

, Yoshiko Hashii

^o

, Hiromasa Yabe

^b,p

, Koji Kato

^b,q

, Yoshiko Atsuta

^d,r

, Kohsuke Imai

^b,s

, Tomohiro Morio

^a,b

*Corresponding Author:

Kohsuke Imai, MD, PhD

Department of Community Pediatrics, Perinatal, and Maternal Medicine, Tokyo Medical and Dental University (TMDU) 1–5–45, Yushima, Bunkyo-ku, Tokyo 113–8519, Japan

Phone: +81–3–5803–5249; Fax: +81–3–5803–0378; Email: kimai.ped@tmd.ac.jp

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Table S1 Distribution of HLA matching according to donor source

HLA, human leukocyte antigen; BM, bone marrow; MSD, matched sibling donor; MORD, matched other related donor; mMORD, mismatched other related donor; UBM, unrelated bone marrow; UCB, umbilical cord blood; MCB, matched cord blood; mMCB, mismatched cord blood; NA, not applicable; PB, peripheral blood

BM 91 (50%) UCB (unrelated) 81 (45%) PB 9 (5%)

MSD 22 (12%) MCB

Serological matching

8/8 6/6 Genotypical matching

8/8 6/6

21 (12%) 3 6

4 8

MORD (Genotypical 8/8) 1 (0.5%)

MORD

Serological 8/8 Genotypical 8/8

MORD without specific HLA data

5 (3%) 2 2 1

mMORD

1 mismatch 5/6

≥3 mismatches 5/8 4/8 3/8 Genotypically matching

1 mismatch 7/8

≥3 mismatches 4/8 mMORD without specific HLA data

7 (4%) 1 1 1 1

1 1 1 mMORD

1 mismatch 7/8 5/6 3/4 2 mismatches 6/8 4/6

≥3 mismatches 5/8 4/8 3/8 3/6 Genotypical matching

1 mismatch 7/8 2 mismatches 6/8 4/6

≥3 mismatches 5/8 mMORD without specific HLA data

53 (29%) 6 3 1 2 4 3 6 2 5

1 1 1 3 15

mMCB

1 mismatch 7/8 5/6 2 mismatches 6/8

≥3 mismatches 5/8 Genotypical matching

1 mismatch 7/8 5/6 2 mismatches 6/8 4/6

≥3 mismatches 5/8 4/8 3/6

59 (32%) 3 3 2 4

10 11 8 10

3 3 2

Related PB without specific HLA data 1 (0.5%)

Unrelated UCB without specific HLA data 1 (1%) Matched UBM

Genotypical 8/8

Matched UBM without specific HLA data

6 (3%) 5 1 Mismatched UBM

≥3 mismatches 5/8 Genotypically matching

1 mismatch 7/8 5/6

5 (3%) 1

3 1

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Table S2 Comparisons of the characteristics of patients by the period of HCT

aMann–Whitney U test; ^bFisher's exact test

HCT, Hematopoietic cell transplantation; Flu, fludarabine; Bu, busulfan; Mel, melphalan; GVHD, graft–versus–host–disease; BM, bone marrow; MSD, matched sibling donor; MORD, matched other related donor; mMORD, mismatched other related donor;

UBM, unrelated bone marrow; UCB, umbilical cord blood; MCB, matched cord blood; mMCB, mismatched cord blood; PB, peripheral blood

Characteristics (Number of patients evaluated) Overall ~2005 2006~ P value

Age at Diagnosis (n=173) 0.21^a

< 3 months 43 (25%) 25 (26%) 18 (24%)

≧ 3 months 130 (75%) 73 (74%) 57 (76%) Median (range) 5m (0m–16y) 5m (0m–8y) 6m (0m–16y)

Age at HCT (n=174) 0.9^a

< 4 months 24 (14%) 11 (11%) 13 (18%)

≧ 4 months 150 (86%) 89 (89%) 61 (82%) Median (range) 7m (1m–17y) 8m (1m–11y) 7m (1m–17y)

Time from diagnosis to HCT (n=175) 0.7^a

~3 months 116 (66%) 65 (65%) 51 (68%) 3~6 months 31 (18%) 17 (17%) 14 (19%) 6~ months 28 (16%) 18 (18%) 10 (13%) Median interval (range) 2m (0m–11y) 2m (0m–11y) 2m (0m–9y)

Conditioning (n=169) < 0.001^b

Flu/Bu 28 (17%) 6 (6%) 22 (29%)

Flu/Mel 34 (20%) 8 (9%) 26 (35%)

No conditioning/Immunosuppression 79 (47%) 58 (62%) 21 (28%)

Others 28 (17%) 22 (23%) 6 (8%)

GVHD prophylaxis (n=158) < 0.001^b

Cyclosporine 87 (55%) 65 (77%) 22 (30%) Tacrolimus 71 (45%) 19 (23%) 52 (70%)

Donor Type (n=181) < 0.001^b

BM 91 (50%) 70 (67%) 21 (28%)

MSD 22 (12%) 15 (14%) 7 (9%)

MORD 5 (3%) 3 (3%) 2 (3%)

mMORD 53 (29%) 46 (44%) 7 (9%)

UBM 11 (6%) 6 (6%) 5 (7%)

UCB 81 (45%) 28 (27%) 53 (70%)

MCB (unrelated) 21 (12%) 8 (8%) 13 (17%) mMCB (unrelated) 59 (33%) 20 (19%) 39 (51%)

PB 9 (5%) 7 (7%) 2 (3%)

MORD 1 (0.6%) 1 (1%) 0 (0%)

mMORD 7 (4%) 5 (5%) 2 (3%)

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Table S3 Association between donor type and age at diagnosis and HCT

aKruskal–Wallis test

HCT, Hematopoietic cell transplantation; MSD, matched sibling donor; MCB, matched cord blood; mMCB, mismatched cord blood;

ORD, other related donor; UBM, unrelated bone marrow

Characteristics (Number of patients evaluated) Overall MSD MCB mMCB ORD UBM P value

Age at Diagnosis (n=173) 0.02^a

<3 months 43 (25%) 8 (38%) 5 (25%) 18 (31%) 9 (15%) 2 (20%)

≧3 months 130 (75%) 13 (62%) 15 (75%) 40 (69%) 53 (85%) 8 (80%) Median age (range) 5m (0m–16y) 3m (0m–4y) 5m (0m–1y) 4m (0m–8y) 6m (0m–16y) 12m (2m–9y)

Age at HCT (n=174) <0.001^a

<4 months 24 (14%) 6 (29%) 4 (19%) 9 (16%) 5 (8%) 0 (0%)

≧4 months 150 (86%) 15 (71%) 17 (81%) 49 (84%) 58 (92%) 10 (100%) Median age (range) 7m (1m–17y) 5m (1m–6y) 7m (1m–1y) 6.5m (1m–10y) 8m (1m–17y) 3.5y (6m–16y)

Time from diagnosis to HCT (n=175) <0.001^a

<3 months 116 (66%) 15 (71%) 15 (75%) 42 (71%) 43 (67%) 0 (0%)

3~6 months 31 (18%) 5 (23%) 5 (25%) 12 (20%) 8 (13%) 1 (10%)

≧6 months 28 (16%) 1 (5%) 0 (0%) 5 (8%) 13 (20%) 9 (90%) Median interval (range) 2m (0m–11y) 1m (0m–2y) 2m (0m–4m) 2m (0m–2y) 2m (0m–11y) 1.6y (4m–9y)

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Table S4 Association between pre-transplant condition and bacterial or fungal infection status at HCT of the patients who received HCT between 2006 and 2016

aFisher's exact test;^bMann-Whitney U test

HCT, Hematopoietic cell transplantation; SCID, severe combined immunodeficiency, Hx, history; Flu, fludarabine; Bu, busulfan; Mel, melphalan; GVHD, graft-versus-host-disease; MSD, matched sibling donor; MCB, matched cord blood; mMCB, mismatched cord blood; ORD, other related donor; UBM, unrelated bone marrow

Characteristics (Number of patients evaluated) Overall Infection (−) Infection (+) P value Characteristics (Number of patients evaluated) Overall Infection (−) Infection (+) P value

Phenotype (n=72) 0.79^a Conditioning (n=74) 0.06^a

T−B+ SCID 52 (72%) 33 (73%) 19 (70%) Flu/Bu 22 (30%) 16 (34%) 6 (22%)

T−B− SCID 20 (28%) 12 (27%) 8 (30%) Flu/Mel 25 (34%) 18 (38%) 7 (26%)

Age at Diagnosis (n=74) 0.24^b No conditioning 16 (22%) 5 (11%) 11 (41%)

<3 months 18 (24%) 14 (30%) 4 (15%) Immunosuppression 5 (7%) 4 (9%) 1 (4%)

≧3 months 56 (76%) 33 (70%) 23 (85%) Others 6 (8%) 4 (9%) 2 (7%)

Median old (range) 6m (0m-16y) 5m (0m-16y) 6m (0m-5y) Donor Type (n=74) 0.19^a

Age at HCT (n=73) 0.91^b MSD 7 (9%) 2 (4%) 5 (19%)

<4m 13 (18%) 8 (17%) 5 (19%) MCB 13 (18%) 10 (21%) 3 (11%)

≧4m 60 (82%) 38 (83%) 22 (81%) mMCB 38 (51%) 25 (53%) 13 (48%)

Median old (range) 7m (1m-31y) 7m (1m-17y) 7m (1m-13y) ORD 11 (15%) 8 (17%) 3 (11%)

Time from diagnosis to HCT (n=74) 0.001^b UBM 5 (7%) 2 (4%) 3 (11%)

~3 months 50 (68%) 28 (60%) 22 (81%) Respiratory impairment at HCT(n=73) 0.02^a

3~6 months 14 (19%) 13 (28%) 1 (4%) Yes 27 (37%) 12 (26%) 15 (56%)

6~ months 10 (14%) 6 (13%) 4 (15%) No 46 (63%) 34 (74%) 12 (44%)

Median interval (range) 2m (0m–9y) 2m (0m-7y) 1m (0-9y) Liver dysfunction at HCT (n=69) 0.12^a

Hx of mechanical ventilation before HCT (n=73) 0.03^a Yes 14 (20%) 6 (13%) 8 (31%)

Yes 14 (19%) 5 (11%) 9 (33%) No 55 (80%) 37 (87%) 18 (69%)

No 59 (81%) 41 (89%) 18 (67%) Renal dysfunction at HCT (n=69) 0.14^a

Yes 2 (3%) 0 (0%) 2 (8%)

No 67 (97%) 43 (100%) 24 (92%)

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Table S5 Association between cause of death and conditioning regimen in the deceased patients

Cause of death Flu/Bu Flu/Mel NC IS Others P value

n=3 n=7 n=33 n=6 n=14 0.05^a

Infection 0 (0%) 2 (29%) 17 (52%) 2 (33%) 2 (14%)

Pulmonary (non-infection) 2 (66%) 1 (14%) 8 (24%) 2 (33%) 2 (14%) Others (non-infection) 1 (33%) 4 (57%) 8 (24%) 2 (33%) 10 (71%)

aFisher's exact test

Flu, fludarabine; Bu, busulfan; Mel. Melphalan; NC, no conditioning; IS, immunosuppression

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Table S6 Univariate analyses for 5-year OS by transplant-associated infectious events

Infectious events 5-year OS (95% CI) P value

CMV infection (n=116)

No 99 (85%) 71% (60–79%)

Yes^a

Infection since before HCT

17 (15%) 9 (8%)

27% (8–50%) 33% (8–62%)

< 0.001^b

< 0.001^b Other viral infection (n=111)

No 94 (85%) 68% (57–77%)

Yes^a

Infection since before HCT

17 (15%) 3 (3%)

54% (22–78%) 100% (NA)

0.8^b 0.29^b

Fungal infection (n=173) 0.98^b

No 168 (97%) 62% (54–69%)

Yes^c 5 (3%) 40% (1–83%)

Bacterial infection (n=106) 0.84^b

No 78 (74%) 70% (58–79%)

Yes^c 28 (26%) 67% (45–81%)

aIncluding those who diagnosed to have infection prior to HCT, after HCT, and the date of diagnosis is not available.

bP values are calculated by Logrank test with comparison to the patients without corresponding infection.

CIncluding only those who diagnosed to have infection after HCT.

OS, overall survival; CI, confidence interval; CMV, cytomegalovirus

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Table S7 Association of conditioning regimens and incidence of short stature

Conditioning regimen Short stature Normal stature P value

Flu/Bu 4 18 0.06

Flu/Mel 7 18

No conditioning / Immunosuppression 6 39

Others 7 8

Bu/CY 5 3

Flu/Bu/Mel 1 1

Flu+low dose TBI 1 1

Flu/CY+low dose TBI 0 1

Flu/CY/ETP/Mel 0 2

Flu, fludarabine; Bu, busulfan; Mel, melphalan; CY, cyclophosphamide; TBI, total body irradiation; ETP, etoposide

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Fig. S1 Outcomes of UCBT according to HLA disparity

Patients who received transplantation from 7/8 or 5/6 matched cord blood were classified as “1mis”, 6/8 or 4/6 as “2mis”, and 3 or more mismatches as “≥ 3mis”. Kaplan–Meyer survival curves for (a) OS and the cumulative incidences of (b) neutrophil recovery, (c) platelet recovery, (d) grades II–IV acute GVHD, (e) grades III–IV acute GVHD, (f) chronic GVHD, and (g) extensive chronic GVHD are shown. OS, overall survival; HCT, hematopoietic cell transplantation; MCB, matched cord blood; UCB, umbilical cord blood; GVHD, graft-versus-host disease; UCBT, umbilical cord blood transplantation; HLA, human leukocyte antigen

0 2 4 6 8 10 12

0.0 0.2 0.4 0.6 0.8 1.0

Months post HCT

Cumulative incidence

21 19 17 17 17 16 16

27 17 15 15 14 14 14

20 15 14 14 14 14 14

12 7 6 6 6 6 6

Number at risk

0 5 10 15 20

0.0 0.2 0.4 0.6 0.8 1.0

Months post HCT

18 17 15 15 15

17 15 13 13 13

16 12 11 10 10

8 5 5 4 3

Number at risk

0 2 4 6 8 10 12

0.0 0.2 0.4 0.6 0.8 1.0

Months post HCT

21 18 16 16 15 14 14

26 16 14 14 13 13 13

20 12 11 11 11 11 11

12 5 4 4 4 4 4

Number at risk

0 20 40 60 80 100 120

0.0 0.2 0.4 0.6 0.8 1.0

Days post HCT

18 18 4 2 2 1 1

18 14 6 2 1 1 1

14 10 5 5 3 2 2

9 9 4 1 1 1 1

Number at risk

0 20 40 60 80 100 120

0.0 0.2 0.4 0.6 0.8 1.0

Days post HCT

18 12 1 0 0 0 0

19 5 1 0 0 0 0

14 8 1 0 0 0 0

9 2 0 0 0 0 0

Number at risk

0 5 10 15 20 25 30

0.0 0.2 0.4 0.6 0.8 1.0

Years post HCT

Probability

21 13 5 0 0 0 0

27 10 4 0 0 0 0

20 11 3 0 0 0 0

12 2 1 0 0 0 0

Number at risk a

f d

Gray’s test P= 0.61

Gray’s test P= 0.45 LogrankP= 0.13

b

Gray’s test P= 0.42 c

MCB

1mis UCB 2mis UCB

≥ 3mis UCB

MCB 1mis UCB 2mis UCB

≥ 3mis UCB

MCB

1mis UCB 2mis UCB

≥ 3mis UCB

MCB

1mis UCB 2mis UCB

≥ 3mis UCB

MCB 1mis UCB

2mis UCB

≥ 3mis UCB

MCB

1mis UCB 2mis UCB ≥ 3mis UCB

≥ 3mis UCB

OS Neutrophil recovery

Platelet recovery Grades II–IV Acute GVHD

Chronic GVHD

≥ 3mis UCB

Gray’s test P= 0.69 Grades III–IV Acute GVHD

0 5 10 15 20

0.0 0.2 0.4 0.6 0.8 1.0

Months post HCT

18 17 15 15 15

17 16 14 14 14

15 12 12 11 11

9 6 6 5 3

Number at risk

≥ 3mis UCB

Extensive Chronic GVHD

MCB1mis UCB 2mis UCB

≥ 3mis UCB

1mis UCB≥ 3mis UCBMCB2mis UCB e

g

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Fig. S2 Cumulative incidence of retransplantation

The cumulative incidences of retransplantation according to (a) donor types, (b) disparity in HLA-match among UCBT, and (c) conditioning regimen are shown. HCT, hematopoietic cell transplantation; MSD, matched sibling donor; MCB, matched cord blood; mMCB, mismatched cord blood; ORD, other related donor; UBM, unrelated bone marrow; UCB, umbilical cord blood; Flu, fludarabine; Bu, busulfan; Mel, melphalan; NC, no conditioning; IS, immunosuppression; HLA, human leukocyte antigen; UCBT, umbilical cord blood transplantation

MSD MCB mMCB ORD UBM

Retransplantation a

MSD

MCB mMCB UBM

ORD

Flu/Bu NC/IS Flu/Mel

Others

Flu/Bu Flu/Mel NC/IS others

0 5 10 15 20 25 30

0.0 0.2 0.4 0.6 0.8 1.0

Years post HCT

21 13 5 0 0 0 0

27 10 4 0 0 0 0

20 11 2 0 0 0 0

12 2 1 0 0 0 0

Number at risk

Retransplantation

≥ 3mis UCB

1mis UCBMCB 2mis UCB

≥ 3mis UCB Retransplantation

c

b

0 5 10 15 20 25 30

0.0 0.2 0.4 0.6 0.8 1.0

Years post HCT

22 17 9 7 3 2 0

21 13 5 0 0 0 0

59 23 7 0 0 0 0

66 19 13 8 1 1 0

11 3 3 3 2 0 0

Number at risk

0 5 10 15 20 25 30

0.0 0.2 0.4 0.6 0.8 1.0

Years post HCT

28 9 5 0 0 0 0

34 18 4 0 0 0 0

79 33 21 14 4 3 0

28 13 6 3 1 0 0

Number at risk

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Fig. S3 Analysis of donor chimerism according to donor type

Donor chimerism is classified as 4 groups: “complete,” “donor dominant,” “mixed,” and “low,” which is also described in

“Methods.” Each column represents the number of patients with each chimerism grouped according to (a) donor type and (b) conditioning regimen. (a) The patients who received conditioning other than NC/IS are shown on the left, and those who received NC/IS are shown on the right. (b) The patients who received MAC, NC/IS, and RIC regimens are shown on the left, and among those who received RIC regimens, Flu/Bu and Flu/Mel and others are shown on the right. MSD, matched sibling donor; NC, no conditioning; IS, immunosuppression; MCB, matched cord blood; mMCB, mismatched cord blood; ORD, other related donor;

Supplementary materials for “Hematopoietic cell transplantation for severe combined immunodeficiency patients: A Japanese retrospective study” in the Journal of Clinical Immunology Satoshi Miyamoto