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Table 1.  

Entire cohort (N = 131) Treatment groups P
HCT with no preceding ERT (HCT) (N = 56) ERT followed by HCT (ERT-HCT) (N = 31) ERT followed by gene therapy (ERT-GT) (N = 35) ERT only (N = 9)
Sex .802*,†
   Female 74 (56.5%) 29 (51.8%) 19 (61.3%) 21 (60.0%) 5 (55.6%)
   Male 57 (43.5%) 27 (48.2%) 12 (38.7%) 14 (40.0%) 4 (44.4%)
Age at diagnosis (d) .040‡
   Median (min-max) 58 (0–4635) 89 (0–4635) 82 (0–634) 26 (0–1157) 58 (6–316)
Decade of ADA diagnosis <.001*
   1982–1989 16 (12.2%) 13 (23.2%) 3 (9.7%) 0 (0.0%) 0 (0.0%)
   1990–1999 30 (22.9%) 17 (30.4%) 7 (22.6%) 4 (11.4%) 2 (22.2%)
   2000–2009 29 (22.1%) 15 (26.8%) 8 (25.8%) 5 (14.3%) 1 (11.1%)
   2010–2017 56 (42.7%) 11 (19.6%) 13 (41.9%) 26 (74.3%) 6 (66.7%)
PIDTC protocol .053*,†
   6901 37 (28.2%) 10 (17.9%) 9 (29.0%) 13 (37.1%) 5 (55.6%)
   6902 94 (71.8%) 46 (82.1%) 22 (71.0%) 22 (62.9%) 4 (44.4%)
SCID subtype§ .710*,†
   Typical SCID 112 (85.5%) 48 (85.7%) 28 (90.3%) 28 (80.0%) 8 (88.9%)
   Leaky SCID 19 (14.5%) 8 (14.3%) 3 (9.7%) 7 (20.0%) 1 (11.1%)
   Omenn Syndrome 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
Trigger for diagnosis .021*,†
   Family history 24 (18.9%) 13 (25.0%) 5 (16.1%) 5 (14.3%) 1 (11.1%)
   Infection 73 (57.5%) 32 (61.5%) 21 (67.7%) 14 (40.0%) 6 (66.7%)
   Newborn screening 30 (23.6%) 7 (13.5%) 5 (16.1%) 16 (45.7%) 2 (22.2%)
   Missing 4 4 0 0 0
Infectious status at time of ADA diagnosis .002*,†
   Active infection 52 (41.9%) 24 (45.3%) 18 (64.3%) 5 (14.7%) 5 (55.6%)
   No previous infection 49 (39.5%) 17 (32.1%) 7 (25.0%) 21 (61.8%) 4 (44.4%)
   Resolved infection 23 (18.5%) 12 (22.6%) 3 (10.7%) 8 (23.5%) 0 (0.0%)
   Missing 7 3 3 1 0
Weight percentile for age|| .014*,†
   <5th 81 (68.1%) 44 (81.5%) 18 (66.7%) 14 (48.3%) 5 (55.6%)
   ≥5th 38 (31.9%) 10 (18.5%) 9 (33.3%) 15 (51.7%) 4 (44.4%)
   Missing 12 2 4 6 0
Height percentile for age|| .229*,
   <5th 52 (53.1%) 26 (63.4%) 11 (45.8%) 11 (40.7%) 4 (66.7%)
   ≥5th 46 (46.9%) 15 (36.6%) 13 (54.2%) 16 (59.3%) 2 (33.3%)
   Missing 33 15 7 8 3
Need for supplemental oxygen|| .005*,
   No 86 (72.9%) 43 (81.1%) 16 (59.3%) 24 (82.8%) 3 (33.3%)
   Yes 32 (27.1%) 10 (18.9%) 11 (40.7%) 5 (17.2%) 6 (66.7%)
   Missing 13 3 4 6 0
Need for CPAP|| .524*,
   No 110 (94.0%) 50 (96.2%) 24 (88.9%) 27 (93.1%) 9 (100.0%)
   Yes 7 (6.0%) 2 (3.8%) 3 (11.1%) 2 (6.9%) 0 (0.0%)
   Missing 14 4 4 6 0
Need for mechanical ventilation|| .019*,
   No 103 (86.6%) 49 (87.5%) 24 (88.9%) 26 (92.9%) 4 (50.0%)
   Yes 16 (13.6%) 7 (12.5%) 3 (11.1%) 2 (7.1%) 4 (50.0%)
   Missing 12 0 4 7 1
Autoimmunity|| .831*,
   Autoimmune cytopenia 1 (0.8%) 0 (0.0%) 1 (3.2%) 0 (0.0%) 0 (0.0%)
   None 124 (96.1%) 54 (96.4%) 29 (93.5%) 32 (97.0%) 9 (100.0%)
   Other 4 (3.1%) 2 (3.6%) 1 (3.2%) 1 (3.0%) 0 (0.0%)
   Missing 2 0 0 2 0
Absolute lymphocyte count at diagnosis .169‡
   N with data 120 50 31 31 8
   Median (cells/mm3) (min-max) 170 (0–2380) 159 (0–2380) 170 (0–1220) 222 (42–999) 99 (20–400)
CD3 + T-cell count at diagnosis .152‡
   N with data 115 55 26 27 7
   Median (cells/mm3) (min-max) 26 (0–734) 26 (0–713) 14.5 (0–404) 37 (0–734) 6 (2–75)
CD4 + T-cell count at diagnosis .010‡
   N with data 97 42 24 26 5
   Median (cells/mm3) (min-max) 13 (0–346) 18.9 (0–346) 8 (0–166) 26.5 (0–318) 2 (0–6)
CD8 + T-cell count at diagnosis .003‡
   N with data 97 42 24 26 5
   Median (cells/mm3) (min-max) 9 (0–501) 17.5 (0–501) 4 (0–253) 9.5 (0–429) 0 (0–3)
CD19 + (or CD20 + ) B-cell count at diagnosis .005‡
   N with data 97 38 25 27 7
   Median (cells/mm3) (min-max) 7 (0–663) 9 (0–97.3) 6 (0–122) 9 (2–663) 2 (1–5)
CD4 + CD45RO + T-cell count at diagnosis .112‡
   N with data 29 11 7 9 2
   Median (cells/mm3) (min-max) 11 (0–109) 35 (0–109) 5 (0–30) 25 (4–96) 2.5 (0–5)
CD4 + CD45RA + T-cell count at diagnosis .099‡
   N with data 36 11 9 12 4
   Median (cells/mm3) (min-max) 1 (0–63) 1 (0–63) 0 (0–4) 2 (0–35) 0 (0–0)
CD56 + NK-cell count at diagnosis .439‡
   N with data 82 34 18 23 7
   Median (cells/mm3) (min-max) 42.5 (0–470) 41.8 (3–311) 30.5 (0–194) 53 (4–470) 49 (2–174)
Baseline PHA response .616*,
   <10% of LLN 70 (84.3%) 41 (85.4%) 13 (86.7%) 13 (81.3%) 3 (75.0%)
   10–30% of LLN 4 (4.8%) 1 (2.1%) 1 (6.7%) 2 (12.5%) 0 (0.0%)
   >30% of LLN 9 (10.8%) 6 (12.5%) 1 (6.7%) 1 (6.3%) 1 (25.0%)
   Missing 48 8 16 19 5
Maternal engraftment of lymphocytes NA
   No 19 6 7 4 2
   Missing 112 50 24 31 7

Table 1. Baseline characteristics of patients with ADA-deficient SCID at the time of initial diagnosis

P value reflects comparison between patients receiving ERT only, GT, and HCT with or without pre-HCT ERT.
CPAP, continuous positive airway pressure; EF, ejection fraction; NA, not applicable; SF, shortening fraction.
2 test.
†Exact test.
‡Kruskal-Wallis test.
§Definition of SCID subtypes used in PIDTC 6901/6902 protocols based on published "Shearer criteria."57 Typical SCID: CD3+ T cells < 300 cells per cubic millimeter and proliferation to PHA < 10% of the lower limit of normal (except with documented maternal T-cell engraftment) with supporting genetic evidence when available. Leaky SCID: reduced number of CD3+ T cells (≤2 years old: <1000 cells per cubic millimeter; >2 years old and ≤4 years old: <800 cells per cubic millimeter; >4 years old: <600 cells per cubic millimeter) and proliferation to PHA < 30% the lower limit of normal and no maternal T-cell engraftment. Omenn syndrome: Generalized skin rash, no maternal lymphocytes, ≥80% of CD3+ or CD4+ T cells are CD45RO+, with at least 4 of 9 criteria being met including hepatomegaly, splenomegaly, lymphadenopathy, elevated IgE, elevated absolute eosinophil count, oligoclonal T cells, reduced PHA proliferation < 50%, hypomorphic mutation in known SCID gene, and low TRECs and/or CD4+CD31+CD45RA+ and/or CD4+CD45RA+CD62L+ T cells.
||Need for supplemental oxygen, CPAP, mechanical ventilation, weight and height percentiles, autoimmunity, and cardiac dysfunction refer to the presence or absence of these features between date of ADA diagnosis and either start of ERT or first definitive cellular therapy (not necessarily whether they were still present at the onset of these treatments).

Table 2.  

Characteristics of therapy Treatment groups P
HCT with no preceding ERT (HCT) (N = 56) ERT followed by HCT (ERT-HCT) (N = 31) ERT followed by gene therapy (ERT-GT) (N = 33)
Duration of ERT before first definitive cellular therapy occurred (d) .514
   N with data N/A 31 33
   Median (min-max) N/A 180 (20–5114) 202 (67–5268)
Duration of ERT before first definitive cellular therapy occurred (mo)
   0–3 N/A 10 (32.3) 5 (15.2%) .066*,
   3–12 N/A 10 (32.3) 20 (60.6%)
   >12 N/A 11 (35.5) 8 (24.2%)
Year of first cellular therapy <.001*,
   1982–1989 13 (23.2%) 3 (9.7%) 0 (0.0%)
   1990–1999 16 (28.6%) 5 (16.1%) 0 (0.0%)
   2000–2009 16 (28.6%) 8 (25.8%) 7 (21.2%)
   2010–2017 11 (19.6%) 15 (48.4%) 26 (78.8%)
Age at first cellular therapy (days) <.001
   N with data 56 31 33
   Median (min-max) 131.5 (8–4783) 361 (48–5318) 317 (98–5601)
Infection at time of first cellular therapy <.001*
   Active 22 (40.7%) 5 (21.7%) 0 (0.0%)
   None or resolved (not active) 32 (59.3%) 18 (78.3%) 33 (100%)
   Missing 2 8 0
Height percentile at time of first cellular therapy .025*
   <5th 26 (63.4%) 7 (35.0%) 10 (34.5%)
   ≥5th 15 (36.6%) 13 (65.0%) 19 (65.5%)
   Missing 15 11 4
Weight percentile at time of first cellular therapy <.001*
   <5th 44 (81.5%) 11 (40.7%) 10 (31.3%)
   ≥5th 10 (18.5%) 16 (59.3%) 22 (68.8%)
   Missing 2 4 1
Donor type (first HCT) <.001*
   HLA-identical sibling 9 (16.1%) 6 (19.4%) N/A
   HLA-matched family 6 (10.7%) 0 (0.0%) N/A
   HLA-mismatched other relative (haploidentical) 36 (64.3%) 6 (19.4%) N/A
   Unrelated donor 5 (8.9%) 19 (61.3%) N/A
Graft type (first HCT) .008*,
   Bone marrow 50 (89.3%) 19 (61.3%) N/A
   Cord blood 3 (5.4%) 7 (22.6%) N/A
   PBSC 3 (5.4%) 5 (16.1%) N/A
Product type (first GT) N/A
   Bone marrow CD34+ cells N/A N/A 33 (100%)
Vector type (first GT) N/A
   Lentiviral N/A N/A 21 (63.6%)
   Retroviral N/A N/A 12 (36.4%)
Conditioning intensity (first CT) <.001*,
   None 39 (69.6%) 6 (20.0%) 0 (0.0%)
   Immune suppression only 4 (7.1%) 2 (6.7%) 0 (0.0%)
   Reduced intensity 5 (8.9%) 8 (26.7%) 33 (100%)
   Myeloablative 8 (14.3%) 14 (46.7%) 0 (0.0%)
   Missing 0 1 0
Serotherapy in conditioning <.001*,
   ATG 6 (10.7%) 12 (38.7%) 0 (0.0%)
   Alemtuzumab 2 (3.6%) 4 (12.9%) 0 (0.0%)
   None 48 (85.7%) 15 (48.4%) 33 (100%)
GVHD prophylaxis (first HCT) <.001*,
   TCD w/soybean lectin 32 (57.1%) 7 (22.6%) N/A
   Other/unknown TCD 3 (5.4%) 0 (0.0%) N/A
   CD34 selection ± TCD 3 (5.4%) 1 (3.2%) N/A
   IS + ATG/alemtuzumab 3 (5.4%) 11 (35.5%) N/A
   IS only 10 (17.9%) 8 (25.8%) N/A
   None 5 (8.9%) 2 (6.5%) N/A
   Other 0 (0.0%) 2 (6.5%) N/A
Need for subsequent therapy following first definitive cellular therapy .054*,
   ERT 6 (10.7%) 0 (0.0) 4 (12.1%)
   GT 2 (3.6%) 0 (0.0) 0 (0.0%)
   HCT 8 (14.3%) 4 (12.9%) 0 (0.0%)
   None 40 (71.4%) 27 (87.1%) 29 (87.9%)
Total number of definitive cellular therapies performed over patient lifetime .043*,
   1 (initial one only) 46 (82.1%) 27 (87.1%) 33 (100%)
   2 (need for second CT) 10 (17.9%) 4 (12.9%) 0 (0.0%)

Table 2: Characteristics of first definitive cellular therapy

Two gene therapy patients, receiving autologous umbilical cord blood gene therapy in the 1990s, had only baseline characteristics evaluated and were then excluded from further survival analyses.
ATG, antithymocyte globulin; IS, immune suppression; N/A, not applicable; PBSC, peripheral blood stem cells; TCD, T-cell depletion.
2 test.
†Exact test.
‡Kruskal-Wallis test.

Table 3.  

Result (95% confidence interval) P Pairwise comparison P
Five-year EFS for entire cohort by FDCT
   ERT-GT 75.3% (34.4%-92.7%) .005 ERT-GT vs ERT-HCT: P = .26
   ERT-HCT 73% (53.1%-85.5%) ERT-GT vs HCT: P < .01
   HCT 49.5% (34.9%-62.5%) ERT-HCT vs HCT: P = .06
Five-year OS for entire cohort by FDCT
   ERT-GT 100% (NA) .01 ERT-GT vs ERT-HCT: P = .01
   ERT-HCT 79.6% (60%-90.3%) ERT-GT vs HCT: P < .01
   HCT 72.5% (57.7%-82.8%) ERT-HCT vs HCT: P = .56
Five-year EFS for all transplant patients by donor type*
   MSD/MFD 90.5% (67%-97.5%) .001 MSD/MFD vs. URD/UCB: P = .1
   URD/UCB 69.4% (46%-84.2%) MSD/MFD vs. MMRD: P < .01
   MMRD 34.6% (19.7%-50.1%) URD/UCB vs MMRD: P = .02
Five-year OS for all transplant patients by donor type*
   MSD/MFD 100% (NA) .004 MSD/MFD vs. URD/UCB: P = .03
   URD/UCB 78.5% (55.7%-90.5%) MSD/MFD vs. MMRD: P < .01
   MMRD 60.2% (42.6%-73.9%) URD/UCB vs MMRD: P = .19
Five-year EFS for all transplant patients by age at transplant*
   <3.5 mo 71.6% (49.4%-85.3%) .18 NA
   ≥3.5 mo 51.9% (37.5%-64.4%)
Five-year OS for all transplant patients by age at transplant*
   <3.5 mo 91.6% (70.5%-97.9%) .02 NA
   ≥3.5 mo 67.9% (53.7%-78.6%)
Five-year EFS for all transplant patients by absence or presence of active infection at transplant*
   Without infection 68.2% (52.6%-79.6%) .003 NA
   With infection 33.1% (14.3%-53.4%)
Five-year OS for all transplant patients by absence or presence of active infection at transplant*
   Without infection 82.3% (67.3%-90.9%) .02 NA
   With infection 64.7% (43.1%-79.9%)

Table 3: EFS and OS for ADA-SCID

P value is from a log-rank test.
MMFD, mismatched family donor (haploidentical); NA, not applicable.
*Includes all allogeneic hematopoietic cell transplant patients, including those who did not (HCT) and those who did (ERT-HCT) receive pretransplant ERT.

Table 4.  

HCT (n = 33) GT (n = 33) P
Sex .80†
   Female 22 (66.7%) 21 (63.6%)
   Male 11 (33.3%) 12 (36.4%)
Age at diagnosis (d) .47‡
   Median (min-max) 42 (0–4635) 27 (0–1157)
Decade of ADA diagnosis .42*,
   1990–1999 1 (3%) 2 (6.1%)
   2000–2009 10 (30.3%) 5 (15.2%)
   2010–2017 22 (66.7%) 26 (78.8%)
PIDTC protocol .14*
   6901 19 (57.6%) 13 (39.4%)
   6902 14 (42.4%) 20 (60.6%)
SCID subtype .52*
   Typical SCID 28 (84.8%) 26 (78.8%)
   Leaky SCID 5 (15.2%) 7 (21.2%)
Trigger for diagnosis .08*
   Family history 8 (25%) 3 (9.1%)
   Infection 16 (50%) 14 (42.4%)
   Newborn screening 8 (25%) 16 (48.5%)
   Missing 1 0
Baseline PHA response .58*
   <10% lower limit of normal 18 (81.8%) 12 (80%)
   10–30% lower limit of normal 1 (4.5%) 2 (13.3%)
   >30% lower limit of normal 3 (13.6%) 1 (6.7%)
   Missing 11 18
Infectious status at time of ADA diagnosis .40*
   Active infection 9 (29%) 5 (15.2%)
   No previous infection 16 (51.6%) 20 (60.6%)
   Resolved infection 6 (19.2%) 8 (24.2%)
   Missing 2 0
Need for supplemental oxygen§ .61*
   No 22 (75.9%) 22 (81.5%)
   Yes 7 (24.1%) 5 (18.5%)
   Missing 4 6
Need for CPAP§ .61*,
   No 27 (96.4%) 25 (92.6%)
   Yes 1 (3.6%) 2 (7.4%)
   Missing 5 6
Need for mechanical ventilation§ .68*,
   No 28 (87.5%) 24 (92.3%)
   Yes 4 (12.5%) 2 (7.7%)
   Missing 1 7
Failure to thrive (reported by center)§ .007*
   No 12 (42.9%) 24 (77.4%)
   Yes 16 (57.1%) 7 (22.6%)
   Missing 5 2
Decade of FDCT .27*
   2000–2009 11 (33.3%) 7 (21.2%)
   2010–2017 22 (66.7%) 26 (78.8%)
Duration of ERT before FDCT (days) .015‡
   Median (range) 90 (20–2723) n = 15 patients 202 (67–5268)
Age at FDCT (days) .002‡
   Median (range) 135 (8–4783) 317 (98–5601)
HCT donor N/A
   HLA-matched sibling donor 9 (27.3%) N/A
   HLA-matched family donor 3 (9.1%) N/A
   Unrelated donor 13 (39.4%) N/A
   HLA-mismatched related donor (haploidentical) 8 (24.2%) N/A
Graft type N/A
   Bone marrow 21 (63.6%) N/A
   Cord blood 8 (24.2%) N/A
   Peripheral blood stem cells 4 (12.1%) N/A
Conditioning regimen intensity <.001*,
   None 15 (45.5%) 0 (0%)
   Immune suppression only 1 (3%) 0 (0%)
   Reduced intensity 6 (18.2%) 33 (100%)
   Myeloablative 11 (33.3%) 0 (0%)
Serotherapy in conditioning N/A
   ATG 8 (24.2%) N/A
   Alemtuzumab 3 (9.1%) N/A
   None 22 (66.7%) 33 (100%)

Table 4. Baseline ADA-SCID and transplant/GT characteristics of contemporary cohort receiving either HCT or GT as FDCT after 2000 and without an active infection at the time of cellular therapy

N/A, not applicable.
2 test.
†Exact test.
‡Wilcoxon rank-sum test.
§Need for supplemental oxygen, CPAP, mechanical ventilation, and failure to thrive refer to the presence or absence of these features between date of ADA diagnosis and the start of first definitive cellular therapy. In this analysis, however, all patients had no active infection at the time of starting first definitive cellular therapy.

CME / ABIM MOC

Outcomes Following Treatment for ADA-Deficient Severe Combined Immunodeficiency: A Report From the PIDTC

  • Authors: Geoffrey D. E. Cuvelier, MD; Brent R. Logan, PhD; Susan E. Prockop, MD; Rebecca H. Buckley, MD; Caroline Y. Kuo, MD; Linda M. Griffith, MD, MHS, PhD; Xuerong Liu, MS; Alison Yip, BS; Michael S. Hershfield, MD; Paul G. Ayoub, BA; Theodore B. Moore, MD; Morna J. Dorsey, MD; Richard J. O’Reilly, MD; Neena Kapoor, MD; Sung-Yun Pai, MD; Malika Kapadia, MD; Christen L. Ebens, MD, MPH; Lisa R. Forbes Satter, MD; Lauri M. Burroughs, MD; Aleksandra Petrovic, MD; Deepak Chellapandian, MD; Jennifer Heimall, MD; David C. Shyr, MD; Ahmad Rayes, MD; Jeffrey J. Bednarski, MD, PhD; Sharat Chandra, MD; Shanmuganathan Chandrakasan, MD; Alfred P. Gillio, MD; Lisa M. Madden, MD; Troy C. Quigg, DO, MS; Emi H. Caywood, MD; Blachy J. Dávila Saldaña, MD; Kenneth DeSantes, MD; Hesham Eissa, MD, MSC; Frederick D. Goldman, MD; Jacob Rozmus, MD, PhD; Ami J. Shah, MD; Mark T. Vander Lugt, MD; Monica S. Thakar, MD; Roberta E. Parrott, BS; Caridad A. Martinez, MD; Jennifer W. Leiding, MD; Troy R. Torgerson, MD, PhD; Michael A. Pulsipher, MD; Luigi D. Notarangelo, MD; Morton J. Cowan, MD; Christopher C. Dvorak, MD; Elie Haddad, MD, PhD; Jennifer M. Puck, MD; Donald B. Kohn, MD
  • CME / ABIM MOC Released: 8/18/2022
  • THIS ACTIVITY HAS EXPIRED FOR CREDIT
  • Valid for credit through: 8/18/2023, 11:59 PM EST
Start Activity


Target Audience and Goal Statement

This activity is intended for hematologists, immunologists, pediatricians, and other clinicians caring for patients with adenosine deaminase (ADA) deficiency causing severe combined immune deficiency (SCID).

The goal of this activity is for learners to be better able to describe baseline clinical, immunologic, and genetic characteristics and treatment outcomes from first definitive cellular therapy (FDCT) in 131 patients with ADA-SCID diagnosed between 1982 and 2017 who were enrolled in the Primary Immune Deficiency Treatment Consortium (PIDTC) SCID studies, including 56 receiving hematopoietic stem cell transplant (HCT) without preceding enzyme replacement therapy (ERT); 31 HSCT preceded by ERT; and 33 gene therapy (GT) preceded by ERT.

Upon completion of this activity, participants will:

  • Describe baseline clinical, immunologic, and genetic characteristics in 131 patients with adenosine deaminase (ADA) deficiency causing severe combined immune deficiency (SCID) diagnosed between 1982 and 2017 who were enrolled in the Primary Immune Deficiency Treatment Consortium (PIDTC) SCID studies
  • Determine treatment outcomes from first definitive cellular therapy (FDCT) in 131 patients with ADA-SCID diagnosed between 1982 and 2017 who were enrolled in the PIDTC SCID studies
  • Identify clinical implications of baseline clinical, immunologic, and genetic characteristics and treatment outcomes from FDCT in 131 patients with ADA-SCID diagnosed between 1982 and 2017 who were enrolled in the PIDTC SCID studies


Disclosures

Medscape, LLC requires every individual in a position to control educational content to disclose all financial relationships with ineligible companies that have occurred within the past 24 months. Ineligible companies are organizations whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

All relevant financial relationships for anyone with the ability to control the content of this educational activity are listed below and have been mitigated. Others involved in the planning of this activity have no relevant financial relationships.


Faculty

  • Geoffrey D. E. Cuvelier, MD

    Manitoba Blood and Marrow Transplant Program
    CancerCare Manitoba
    University of Manitoba
    Winnipeg, Manitoba, Canada

  • Brent R. Logan, PhD

    Division of Biostatistics
    Medical College of Wisconsin
    Milwaukee, Wisconsin

  • Susan E. Prockop, MD

    Stem Cell Transplant Service
    Dana Farber Cancer Institute/Boston Children’s Hospital
    Boston, Massachusetts

  • Rebecca H. Buckley, MD

    Duke University Medical Center
    Durham, North Carolina

  • Caroline Y. Kuo, MD

    Division of Allergy, Immunology, Rheumatology
    Department of Pediatrics
    David Geffen School of Medicine
    University of California Los Angeles (UCLA)
    Los Angeles, California

  • Linda M. Griffith, MD, MHS, PhD

    DAIT
    NIAID
    National Institutes of Health
    Bethesda, Maryland

  • Xuerong Liu, MS

    Division of Biostatistics
    Medical College of Wisconsin
    Milwaukee, Wisconsin

  • Alison Yip, BS

    University of California San Francisco (UCSF) Benioff Children’s Hospital
    San Francisco, California

  • Michael S. Hershfield, MD

    Duke University Medical Center
    Durham, North Carolina

  • Paul G. Ayoub, BA

    Microbiology, Immunology & Molecular Genetics
    University of California Los Angeles (UCLA)
    Los Angeles, California

  • Theodore B. Moore, MD

    Department of Pediatric Hematology-Oncology
    Mattel Children’s Hospital
    University of California, Los Angeles (UCLA)
    Los Angeles, California

  • Morna J. Dorsey, MD

    University of California San Francisco (UCSF) Benioff Children’s Hospital
    San Francisco, California

  • Richard J. O’Reilly, MD

    Stem Cell Transplantation and Cellular Therapy
    MSK Kids, Memorial Sloan Kettering Cancer Center
    New York, New York

  • Neena Kapoor, MD

    Division of Hematology, Oncology and Blood and Marrow Transplant
    Children’s Hospital Los Angeles
    Los Angeles, California

  • Sung-Yun Pai, MD

    Immune Deficiency Cellular Therapy Program
    Center for Cancer Research
    National Cancer Institute
    Bethesda, Maryland

  • Malika Kapadia, MD

    Boston Children’s Hospital
    Dana-Farber Cancer Institute
    Boston, Massachusetts

  • Christen L. Ebens, MD, MPH

    Division of Pediatric Blood and Marrow Transplant and Cellular Therapy
    MHealth Fairview Masonic Children’s Hospital
    Minneapolis, Minnesota

  • Lisa R. Forbes Satter, MD

    Immunology, Allergy and Retrovirology
    Baylor College of Medicine
    Texas Children’s Hospital
    Houston, Texas

  • Lauri M. Burroughs, MD

    Fred Hutchinson Cancer Research Center
    University of Washington
    Department of Pediatrics and Seattle Children’s Hospital
    Seattle, Washington

  • Aleksandra Petrovic, MD

    Fred Hutchinson Cancer Research Center
    University of Washington
    Department of Pediatrics and Seattle Children’s Hospital
    Seattle, Washington

  • Deepak Chellapandian, MD

    Center for Cell and Gene Therapy for Non-Malignant Conditions
    Johns Hopkins All Children’s Hospital
    St. Petersburg, Florida

  • Jennifer Heimall, MD

    Division of Allergy and Immunology
    Children’s Hospital of Philadelphia
    Department of Pediatrics
    Perelman School of Medicine at University of Pennsylvania
    Philadelphia, Pennsylvania

  • David C. Shyr, MD

    Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine
    Lucile Packard Children’s Hospital
    Stanford School of Medicine
    Palo Alto, California

  • Ahmad Rayes, MD

    Primary Children’s Hospital
    University of Utah
    Salt Lake City, Utah

  • Jeffrey J. Bednarski, MD, PhD

    Washington University
    St Louis Children’s Hospital
    St Louis, Missouri

  • Sharat Chandra, MD

    Division of Bone Marrow Transplantation and Immune Deficiency
    Cincinnati Children’s Hospital Medical Center
    Department of Pediatrics
    University of Cincinnati College of Medicine
    Cincinnati, Ohio

  • Shanmuganathan Chandrakasan, MD

    Bone Marrow Transplantation and Immune Deficiency
    Children’s Hospital of Atlanta
    Atlanta, Georgia

  • Alfred P. Gillio, MD

    Children’s Cancer Institute
    Hackensack University Medical Center
    Hackensack, New Jersey

  • Lisa M. Madden, MD

    Methodist Children’s Hospital of South Texas
    San Antonio, Texas

  • Troy C. Quigg, DO, MS

    Pediatric Blood and Marrow Transplant and Cellular Therapy Program
    Helen DeVos Children’s Hospital
    Michigan State University College of Human Medicine
    Grand Rapids, Michigan

  • Emi H. Caywood, MD

    Nemours Children’s Health
    Thomas Jefferson University
    Wilmington, Delaware

  • Blachy J. Dávila Saldaña, MD

    Division of Blood and Marrow Transplantation
    Children’s National Hospital
    Washington, DC

  • Kenneth DeSantes, MD

    Division of Pediatric Hematology-Oncology & Bone Marrow Transplant
    University of Wisconsin
    American Family Children’s Hospital
    Madison, Wisconsin

  • Hesham Eissa, MD, MSC

    Division of Pediatric Hematology-Oncology-BMT
    Children’s Hospital Colorado
    Aurora, Colorado

  • Frederick D. Goldman, MD

    Division of Pediatric Hematology and Oncology and Bone Marrow Transplant
    University of Alabama at Birmingham
    Birmingham, Alabama

  • Jacob Rozmus, MD, PhD

    British Columbia Children’s Hospital
    Vancouver, British Columbia, Canada

  • Ami J. Shah, MD

    Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine
    Lucile Packard Children’s Hospital
    Stanford School of Medicine
    Palo Alto, California

  • Mark T. Vander Lugt, MD

    Blood and Marrow Transplant Program
    University of Michigan
    Ann Arbor, Michigan

  • Monica S. Thakar, MD

    Fred Hutchinson Cancer Research Center
    University of Washington
    Department of Pediatrics
    Seattle Children’s Hospital
    Seattle, Washington

  • Roberta E. Parrott, BS

    Duke University Medical Center
    Durham, North Carolina

  • Caridad A. Martinez, MD

    Hematology/Oncology/BMT
    Texas Children’s Hospital
    Baylor College of Medicine
    Houston, Texas

  • Jennifer W. Leiding, MD

    Division of Allergy and Immunology
    Johns Hopkins University
    St. Petersburg, Florida

  • Troy R. Torgerson, MD, PhD

    Allen Institute for Immunology
    Seattle, Washington

  • Michael A. Pulsipher, MD

    Division of Pediatric Hematology and Oncology
    Intermountain Primary Children’s Hospital
    Huntsman Cancer Institute at the University of Utah Spencer Fox Eccles School of Medicine
    Salt Lake City, Utah

  • Luigi D. Notarangelo, MD

    Laboratory of Clinical Immunology and Microbiology
    NIAID
    National Institutes of Health
    Bethesda, Maryland

  • Morton J. Cowan, MD

    University of California San Francisco (UCSF) Benioff Children’s Hospital
    San Francisco, California

  • Christopher C. Dvorak, MD

    University of California San Francisco (UCSF) Benioff Children’s Hospital
    San Francisco, California

  • Elie Haddad, MD, PhD

    Department of Pediatrics
    CHU Sainte-Justine
    University of Montreal
    Montreal, Quebec, Canada

  • Jennifer M. Puck, MD

    University of California San Francisco (UCSF) Benioff Children’s Hospital
    San Francisco, California

  • Donald B. Kohn, MD

    Microbiology, Immunology & Molecular Genetics
    University of California Los Angeles (UCLA)

CME Author

  • Laurie Barclay, MD

    Freelance writer and reviewer
    Medscape, LLC

    Disclosures

    Laurie Barclay, MD, has the following relevant financial relationships:
    Formerly owned stocks in: AbbVie

Editor

  • Robert Zeiser, MD

    Associate Editor, Blood

Compliance Reviewer

  • Leigh Schmidt, MSN, RN, CMSRN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC

    Disclosures

    Leigh Schmidt, MSN, RN, CMSRN, CNE, CHCP, has no relevant financial relationships.


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From Blood
CME / ABIM MOC

Outcomes Following Treatment for ADA-Deficient Severe Combined Immunodeficiency: A Report From the PIDTC

Authors: Geoffrey D. E. Cuvelier, MD; Brent R. Logan, PhD; Susan E. Prockop, MD; Rebecca H. Buckley, MD; Caroline Y. Kuo, MD; Linda M. Griffith, MD, MHS, PhD; Xuerong Liu, MS; Alison Yip, BS; Michael S. Hershfield, MD; Paul G. Ayoub, BA; Theodore B. Moore, MD; Morna J. Dorsey, MD; Richard J. O’Reilly, MD; Neena Kapoor, MD; Sung-Yun Pai, MD; Malika Kapadia, MD; Christen L. Ebens, MD, MPH; Lisa R. Forbes Satter, MD; Lauri M. Burroughs, MD; Aleksandra Petrovic, MD; Deepak Chellapandian, MD; Jennifer Heimall, MD; David C. Shyr, MD; Ahmad Rayes, MD; Jeffrey J. Bednarski, MD, PhD; Sharat Chandra, MD; Shanmuganathan Chandrakasan, MD; Alfred P. Gillio, MD; Lisa M. Madden, MD; Troy C. Quigg, DO, MS; Emi H. Caywood, MD; Blachy J. Dávila Saldaña, MD; Kenneth DeSantes, MD; Hesham Eissa, MD, MSC; Frederick D. Goldman, MD; Jacob Rozmus, MD, PhD; Ami J. Shah, MD; Mark T. Vander Lugt, MD; Monica S. Thakar, MD; Roberta E. Parrott, BS; Caridad A. Martinez, MD; Jennifer W. Leiding, MD; Troy R. Torgerson, MD, PhD; Michael A. Pulsipher, MD; Luigi D. Notarangelo, MD; Morton J. Cowan, MD; Christopher C. Dvorak, MD; Elie Haddad, MD, PhD; Jennifer M. Puck, MD; Donald B. Kohn, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED FOR CREDIT

CME / ABIM MOC Released: 8/18/2022

Valid for credit through: 8/18/2023, 11:59 PM EST

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Abstract and Introduction

Abstract

Adenosine deaminase (ADA) deficiency causes ~13% of cases of severe combined immune deficiency (SCID). Treatments include enzyme replacement therapy (ERT), hematopoietic cell transplant (HCT), and gene therapy (GT). We evaluated 131 patients with ADA-SCID diagnosed between 1982 and 2017 who were enrolled in the Primary Immune Deficiency Treatment Consortium SCID studies. Baseline clinical, immunologic, genetic characteristics, and treatment outcomes were analyzed. First definitive cellular therapy (FDCT) included 56 receiving HCT without preceding ERT (HCT); 31 HCT preceded by ERT (ERT-HCT); and 33 GT preceded by ERT (ERT-GT). Five-year event-free survival (EFS, alive, no need for further ERT or cellular therapy) was 49.5% (HCT), 73% (ERT-HCT), and 75.3% (ERT-GT; P < .01). Overall survival (OS) at 5 years after FDCT was 72.5% (HCT), 79.6% (ERT-HCT), and 100% (ERT-GT; P = .01). Five-year OS was superior for patients undergoing HCT at <3.5 months of age (91.6% vs 68% if ≥3.5 months, P = .02). Active infection at the time of HCT (regardless of ERT) decreased 5-year EFS (33.1% vs 68.2%, P < .01) and OS (64.7% vs 82.3%, P = .02). Five-year EFS (90.5%) and OS (100%) were best for matched sibling and matched family donors (MSD/MFD). For patients treated after the year 2000 and without active infection at the time of FDCT, no difference in 5-year EFS or OS was found between HCT using a variety of transplant approaches and ERT-GT. This suggests alternative donor HCT may be considered when MSD/MFD HCT and GT are not available, particularly when newborn screening identifies patients with ADA-SCID soon after birth and before the onset of infections. This trial was registered at www.clinicaltrials.gov as #NCT01186913 and #NCT01346150.

Introduction

Deficiency of the purine catabolic enzyme adenosine deaminase (ADA) is the cause for ~13% of cases of severe combined immune deficiency (SCID).[1,2] Absence of ADA activity results in adenosine and 2'-deoxyadenosine, along with their deoxyadenosine phosphorylated derivatives (dAXP), accumulating in multiple tissues.[3–5] Excessive dAXP inhibits ribonucleotide reductase, blocks DNA synthesis and repair, and induces DNA breaks.[6] ADA-deficient lymphocytes are particularly sensitive to these effects, leading to profound T-cell, B-cell, and natural killer (NK)-cell lymphopenia. Left untreated, the cellular and humoral immune deficiency results in life-threatening community acquired and opportunistic infections, as well as extra-immune complications, including pulmonary alveolar proteinosis,[7–9] neurologic and neurocognitive deficits,[10–12] sensorineural hearing loss,[13,14] neutropenia and myeloid dysplasia,[15–17] skeletal dysplasia,[18,19] hepatic dysfunction,[20,21] and malignant tumors.[22–25]

Treatment options for ADA-SCID include PEGylated ADA enzyme replacement therapy (ERT), allogeneic hematopoietic cell transplant (HCT), and ex vivo autologous gene therapy (GT). ERT enables systemic detoxification of adenine metabolites, promotes lymphopoiesis, and decreases opportunistic infections.[26–31] Disadvantages of ERT include its high cost, dependence on once to twice weekly intramuscular injections, and frequent failure to achieve complete lymphocyte reconstitution.[32] Complications in patients on long-term PEG-ADA include waning efficacy over time, breakthrough infections, autoimmunity, and malignancy.[33–36] Although initial HCT approaches in the 1980s to 1990s were often not preceded by a period of ERT before HCT, recent consensus guidelines recommend ERT be initiated as soon as ADA-SCID is confirmed, bridging infants to definitive cellular therapy (HCT or GT).[37] Concern has been raised, however, that ERT before HCT might negatively impact engraftment due to improvement in recipient immunity.

By comparison, HCT using a human leukocyte antigen (HLA) matched sibling or matched family donor (MSD/MFD), when available, is considered the optimal first definitive cellular therapy (FDCT) in ADA-SCID.[37–39] In the largest, retrospective, multi-institution study of HCT for ADA-SCID between 1981 and 2009, 42 of 106 (41%) received MSD and 12 of 106 (13%) received MFD HCT, with overall survival (OS) of 86% and 83%, respectively.[40] Most patients with MSD/MFD received unconditioned HCT, with 26 of 30 of these engrafting. This same study showed donor source and HLA-matching dramatically impacted outcomes, with recipients of matched unrelated donors (MUD), haploidentical donors (mismatched related donors [MMRD]), and mismatched unrelated donors (MMUD) having significantly worse OS of 67%, 43%, and 29%, respectively.[40] These findings, along with promising results from recent GT trials,[41] led many physicians to avoid alternative donor HCT and instead treat patients with ERT while awaiting GT. The impact of population-based SCID newborn screening (NBS), however, is important to consider in the current era of treatment.[42] SCID NBS is now universally available in the United States and much of Canada and can modify the 2 most important predictors of successful HCT: absence of infection and HCT before 3.5 months of age.[43–46] HCT outcomes, therefore, need re-examination in the contemporary era (after the year 2000) given NBS and general improvements in HCT over time, including refinements in HLA typing and supportive care.

Gammaretroviral vector transduced autologous CD34+ bone marrow cells were first reported to restore immunity in ADASCID by researchers from Milan, Italy.[47–49] However, a case of T-cell leukemia in a patient with ADA-SCID 4 years following GT with the European Medicines Agency–approved gammaretrovirus product was reported in 2020,[50] a reminder of the potential for genotoxic events with gammaretrovirus vectors.[51–53] In recent years, GT has advanced to use lentiviral vectors, with clinical trials demonstrating excellent long-term gene correction of engrafted hematopoietic stem cells, immune reconstitution, event-free survival (EFS), and OS.[41] GT requires low-intensity conditioning with single-agent busulfan.[54] Importantly, recent GT trials have exclusively enrolled patients pretreated with ERT and without infection when starting the conditioning regimen, meaning the patient's clinical status at FDCT was optimized. Despite the success of GT for ADA-SCID, worldwide availability is a concern. Clinical trials are currently limited and no commercial ADA-SCID GT exists in North America. Commercialized lentiviral gene-modified cell products, when available, may also be expensive.

Questions therefore remain regarding the optimal treatment approaches for ADA-SCID. (1) Does ERT before HCT impact survival? (2) How does immune reconstitution, EFS, and OS compare between HCT and GT? (3) How do HCT (including from alternative donors) and GT compare in the contemporary era, when infants are more likely to be diagnosed soon after birth and infection-free because of NBS?

The Primary Immune Deficiency Treatment Consortium (PIDTC) was established in 2009 to conduct multi-institutional observational studies of treatments for primary immunodeficiency diseases, including SCID.[55] Despite the rarity of ADA-SCID (estimated to occur in 1 in 500 000 births),[56] the prospective PIDTC 6901 and retrospective and cross-sectional PIDTC 6902 studies presented here encompass the largest cohort of patients with ADA-SCID reported to date, offering a comprehensive picture of the baseline clinical, molecular, and immunologic characteristics and outcomes following therapy for ADA deficiency.