Sunday, September 24, 2023
| 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.
*χ2 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).
| 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.
*χ2 test.
†Exact test.
‡Kruskal-Wallis test.
| 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.
| 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.
*χ2 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.
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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.
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.
