european journal eur. j. pediatr. 131, 155--177 (1979) … journal of eur. j. pediatr. 131, 155--177...

European Journal of

Pediatrics Eur. J. Pediatr. 131, 155--177 (1979)

�9 by Springer-Verlag 1979

Bone Marrow Transplantation for Severe Combined Immunodeficiency Disease

Reported from 1968 to 1977

A. B. Kenny and W. H. Hitzig*

University Children's Hospital, CH-8032 Z[irich, Switzerland

Abstract. Patients who received bone marrow transplantation (= BMT) for the treatment of severe combined immunodeficiency (= SCID), and who were reported in the medical literature from 1968 to 1977, were collected and analysed. Eighteen of these 80 children are still alive, 10 months to 9 years after transplantation. It is thus the first successful form of therapy for this otherwise invariably fatal disease.

Fifteen of the 18 survivors received bone marrow cells from H L A and M L C compatible donors; the remaining 3 survivors received grafts from MLC-compatible but HLA-incompat ible donors. Bone marrow transplantation is the treatment of choice for SCID when recipient and donor are HLA- and MLC-identical. All patients who received MLC-incompatible grafts died, and bone marrow transplantation for SCID from MLC-incompatible donors should be abandoned.

Mild-to-severe graft-versus-host disease (= GVHD) occurred in spite of HLA- and /o r MLC-compatibil i ty, with some correlation to the number of cells transplanted. This should preferably be kept below 50 million cells per kilo body weight. Infection was the chief cause of death in all groups. Strict reverse isolation, bowel decontamination and routine pre- and post-transplant Pneumocystis carinii prophylactic treatment are recommended.

The clinical picture and laboratory findings of these 80 children before BMT did not differ from non-transplanted SCID patients. Three of the 18 survivors are adenosinedeaminase deficient.

Key words: Immunodeficiency, severe combined - Transplantation - Bone marrow - Adenosine deaminase deficiency - Histocompatibility.

Introduction

Severe combined immunodeficiency (= SCID) is a disease of infancy character- ized by absence - -o r marked i m p a i r m e n t - - o f both humoral and cell-mediated immune functions so that the affected infants are highly susceptible to infection

* Address for offprint requests: Prof. W. H. Hitzig, Kinderspital, CH-8032 Ziirich, Schweiz

0340-6199/79/0131/0155/$ 04.60

156 A.B. Kenny and W. H. Hitzig

by bacteria, viruses, fungi and other organisms which are non-pathogenic in immunocompetent individuals. More than 434 cases have been reported [60] since the first description in 1950 [45]. The disease is not rare, and individual cases are no longer published, except to illustrate some special feature. The mortality was 100% until 1968, when immunologic reconstitution was achieved by bone marrow transplantation (= BMT) for the first time in a 5-month-old boy with SCID [3@ Since then, a total of 80 SCID patients treated with BMT have been reported in the medical literature up to 1977. Eighteen of these 80 children are alive 10 months to 9 years after transplantation (=aT).

A review of this extensive work seems timely in order to draw the necessary conclusions for further attempts at treatment. Since several cases have been published repeatedly or included into more than one report, the field became confusing. In this review we attempt to list every single case. By doing so, we wish to complement the work of the Bone Marrow Transplant Registry of the A C S / N I H [17] by considering published cases not reported to the Registry, and identifying those included in multiple publications.

Material and Method

Reports on bone marrow transplantation in 80 SCID patients have been collected from the medical literature from 1968 to December 31, 1977 (Table 1). No cases were intentionally omitted. The cases are listed according to the histocompatibility of donor and recipient as follows:

group I (n=31) HLA and MLC compatible group II (n= 11) only MLC compatible group III (n= 3) only HLA compatible group IV (n= 31) HLA and MLC incompatible group V (n= 4) histocompatibility not stated

Cases from the same transplant team are listed consecutively. Age is in months at the time of the first transplant. Survival time is in months from the date of the first transplant to the time of the last report. Evaluation of the occurrence and severity of graft versus host disease (GVHD), and immunological reconstitution are given as evaluated by the doctors in charge of the patient.

Results

1. Pretransplant clinical and laboratory data are summarized in Table 2. From this, the following facts are worth emphasizing:

The male to female ratio was 2:1. The four most frequent clinical manifestations were pneumopathy, failure to

thrive, diarrhea and thrush. The age at onset of the first signs of illness was below 7 months in all cases,

less than 3 months in 79%, and less than 1 month in 36%. Three infants were symptomatic at birth or in the newborn period.

One half or more of the patients for whom laboratory data are available had absolute lymphocyte counts: of less than 1000/lal, serum IgG less than 200 rag%, serum IgA less than 10 mg%, and serum IgM less than 20 rag%. Isoantibodies

Bone Marrow Transplantation 157

were absent in 19, and 1:1 and 1:2 in two cases. Skin tests with 2 or more antigens were negative in all the patients tested. PHA stimulation and one-way MLC tests were negative in 88% and 86% respectively, and "low" in the rest. Erythrocyte adenosine deaminase activity was negative in 8 of the 23 patients tested.

2. Transplantation data are summarized in Table 3. A total of at least 123 BMTs were performed in 80 patients. Recipients and donors: BMT was performed at the age of 6 months or younger in 58% of group I patients, and in 33% of groups III and IV combined. 82% of the donors in group I were siblings (sister 47%, brother 27%, "sib" 8%), in contrast to only 10% in groups III and IV combined. In the latter group 78% of the donors were parents. In group I and groups III and IV combined, 72% of the patients received only one BMT, while in group I! 66% of the patients received multiple (2 to 7) BMTs.

Cells transplanted: the majority (83%) of group I patients received more than 10 • 10 6 bone marrow equivalent cells/kg body weight. In contrast, 62% of groups III and IV combined received less than this amount, usually 5 x 10 6

cells/kg. The route of administration was intravenous in 76% and intraperitoneal in 24% of the patients. The bone marrow cells for transplantation were given unfractionated in 58% of the patients, separated by albumin gradient in 28%, and in the remaining 14% of the patients other methods designed to remove GVHD- producing cells (velocity sedimentation, treatment of the cells with ALG or Mitomycine-C) were used.

3. Post-transplant data are summarized in Table 4 and Figures 1-3. Twenty three percent (18/80) are alive and 77% (62/80) are dead. GVHD occurred in 70% of the latter (44/62). There was direct evidence of engraftment in 57% (35/62), B- and T-cell immunological reconstitution in 56% (35/62), and reconstitution o fT- cell function alone in 16% (10/62). There was no evidence of immunological reconstitution in 21% (13/62). Because the results in group ! and group IV often cancel each other out, the outcome in each group will be discussed separately.

Group I (HLA and MLC matched)

Forty eight percent (15/31) are alive 10 months to 9 years after transplantation (aT), usually after just one BMT (78% or 23/30), with reconstitution of B- and T- cell functions in 72% (18/25), and of T-cell function alone in 16% (4/25). Two patients without humoral immunological reconstitution are under gamma globulin replacement therapy. Direct evidence of engraftment was demonstrable in 50% (13/26) by one or more of the following markers: change in the recipient's karyotype, serum protein, neutrophil or lymphocyte properties. Two patients (cases 7 and 23) had ADA-positive lymphocytes from the donor but exhibited their own ADA-negative erythrocytes. Case 22 had donor T-cells (XY) but her own B-cells (XX). GVHD occurred in 68% (17/25). This was mild in 48% (12/25), moderate in 8% (2/25), and severe in 12% (3/25). GVHD was the cause of death in 2 patients (questionably so in one of them). The remaining patient who had severe GVHD is still alive more than 5 years aT.

Sixteen of the 31 patients in group I died (52%), 8 from infection, 2 from severe GVHD, 2 from aspiration pneumonia, and one each from respiratory


Table 1. Bone marrow transplantation data performed in 80 severe combined immunodeficient children

Case /name/sex / Reference D o n o r / Survival Cause Cells Route age (mon ths ) /ADA No. BMT (months) of death 106/kg

I. HLA + MLC compatible

1 / J M / M / 5 / + Koning 69 sis/1 88 5 IV

2 / G C / M / 5 / N R Vossen 72 uncl/1 59 5 IV

3 / E F / F / 6 / N R Ammann 70 sis/2 90 900t IP

4 / C R / M / 1 3 / + Mwissen 71 sis/1 0.9 PcarPn 1000t IP

5 / J P / M / 4 / N R Biggar 72 sis/1 3 AspPn 9 IP

6 / K S / F / 7 / N R Biggar 72 sis/2 47 20 IP 7 / T T / F / 1 0 / 0 Biggar 73 sis/7 57 230 IV

8 / A V / F / 6 / N R Levey 71 sis/1 0.6 Sepsis 5 IV

9 / R R / M / 6 / N R kevey 71 sis/2 12 AspPn 50 IV

1 0 / I B / F / 2 / 0 Prkman 75 bro/1 60 50 IV

1 1 / A W / M / 5 / 0 Prkman 75 sis/1 60 50 IV

1 2 / W W / F / 2 / 0 Prkman 75 bro/3 17 RespAr 100 IV 1 3 / T H / F / 1 1 / N R Glfand 75 sis/1 0.4 CerGli 50 IV

1 4 / J M / M / 7 / N R Glfand 75 bro/1 0.4 Sepsis 50 IV

1 5 / T D / F / 7 / N R Ymamra 72 bro/1 61 50 IV

1 6 / M S / M / 5 / N R Hobbs 72 ~2sis/1 0.2 UlcHge 52 IV

1 7 / M P / M / 5 / N R Andrsn 75 fath/1 44 32 IV

18/PM/M/9 /+ Robnsn 75 bro/1 10 i0 IV

1 9 / M E / M / 1 1 / N R Stiehm 72 sis/1 63 2000t IP

20 /?? /M/24 /NR Stiehm 74 bro/1 52 1000t NR

2 1 / ? S / M / 9 / N R Grsclli 72 sis/l 3 Meng 900t IV

2 2 / S A / F / 2 / + Selgman 74 bro/1 52 1700t IV

2 3 / J C / M / 2 / 0 Incefy 75 bro /4 36 NR NR 2 4 / D B / M / 6 / + Mwissen 75 N R / N R 0.2 Polymy NR NR

2 5 / J A / F / 1 0 / + Geha 76 fath/1 15 25 IV

2 6 / ? A / F / 3 / + Geha 77 sis/3 4 VirusI 40 IV

27 /?? /M/7 /? Bortin 77 sib/1 0.1 PcarP 350 IV 28 /?? /M/5 /? Bortin 77 sib/1 0.7 GVHD 120 IV

29 /?? /M/5 /? Bortin 77 moth/1 0.1 PcarP 100 IV

30 /?? /M/8 /? Bortin 77 fath/1 0.3 PcarP 920 IV

31 /?? /M/4 /? Bortin 77 grdm/1 1.5 ?GVHD 65 IV

II. Only MLC compatible

3 2 / D C / M / 5 / N R Gatt i 68 sis/2 96 120 IP 3 3 / C M / M / 1 2 / N R Biggar 73 bro/3 2.3 Sepsis 30 IP

34 / ?? /M/4 /NR Levey 71 bro/3 5 Sepsis 5 IV 3 5 / K J / M / 6 / + Copnhgn 73 uncl/3 52 56t IV

3 6 / J B / M / 5 / N R Lawton 73 bro/1 0.7 PcarPn 660t IP 3 7 / M P / F / 1 2 / + Mwissen 75 s ib /NR NR NR NR NR 3 8 / T H / F / 9 / 0 Mwissen 73 moth /3 3.5 CMV 19 NR 3 9 / ? ? / M / 7 / + Horwitz 75 unrel/1 1 CMV 1.3 IP

4 0 / M R / M / 5 / + OReilly 74 unrel /7 30 670 IV

Bone Marrow Transplantation

from 1968 to 1977

Preparation GVHD Chimera

A G mild XX

A G 0 0 UF mild 0

UF mild 0

UF mild drumst.

UF mild 0 UF mild Lym=ADA+

A G 0 NR

UF mild XX, Gin, ImV UF mild XY, Gm

UF mild XX

UF mild 0

UF mild NR

UF 0 0

UF 0 XY

UF NR NR

UF modr NR UF 0 NR

UF sevr XX, G m

NR 0 0

NR modr XX

UF 0 T-XY; B-XX NR NR Lym=ADA+

NR NR NR

UF mild XY

UF 0 XY

NR NE NE

NR sevr 0 NR NE NE NR NE NE

NR sevr 0

Reconstitution

159

B-cell T-cell

+ +

+ +

+ +

0 + + +

+ + + +

+ +

+ +

+ +

+ +

+ +

NR NR

+ (PM) 0 + +

+ (PM) 0 + +

+ +

+ +

0 +

+ +

+ +

+ +

NR NR

0 +

0 + NE NE

NE +

NE NE NE NE

0 0

References

UF modr XX, dRBC + +

UF sevr 0 0 0 UF 0 Gin, lnV + 0 UF mild HLA, InV + +

UF mild NR + +

NR NR NR NR NR NR 0 NR + 0

UF mild HLA + + UF modr XX, RBC + +

69, 2I, 29, 32, 79, 99, 100, 111, 120

122, 29, 100, 120

3, 13, 21, 68, 75, 79, 80, 81, 92, 109, 120

79, 13, 75, 80, 81, 83, 92, 109, 120

9, 5, 13, 68, 75, 92, 109

10, 5, 12, 13, 75, 83, 84, 92, 109

11, 5, 12, 13, 75, 76, 83, 84, 92, 99, 118 74, 21, 29, 42, 79, 120

74, 21, 42, 79, 120

42, 1, 83, 84, 95

42, 12, 83, 95

42, 83, 95

42 42

125, 4, 49, 65

49, 4, 65

49, 4, 65

101 112, 113, 115, 21

113

48, 49, 96

85, 106, 49, 50, 96

66, 118, 15, 67

84

38, 39

40

17

17

17 17

17

36, 5, 13, 21, 46, 47, 51, 68, 75, 78, 126 11, 12, 13, 75, 76, 92, 109 74, 21, 94, 120 33, 23, 25, 31, 83, 92, 53a

72, 14, 21 84

82, 83, 84, 43 62 88, 66, 117, 67, 90

Table 1 (continued)

Case/name/sex/ Reference Donor / Survival Cause Cells Route age (months)/ADA No. BMT (months) of death 106/kg

4 1 / M W / M / 9 / + Niethmr 76 moth/3 11 Sepsis 650 NR 42/??/M/10/? Bortin 77 moth/1 0.9 AspPn 31 IV

III. Only HLA-A, B compatible

4 3 / G W / M / 9 / N R Speck 71 moth/1 0.4 PcarPn 5 IV 4 4 / N N / M / 1 0 / N R Rbstein 72 bro/1 1.4 MilkAs 8 IV 4 5 / C M / M / 7 / N R Park 73 unrel/3 3.5 PcarPn 20 IP

IV. HLA +MLC incompatible

46/SS/M/12 /+ Mwissen 71 fa th/ l 1.4 GVHD 1 IV 47 /NF /? /12 /NR Mwissen 71 m+unrl/? 0.7 GVHD NR NR 4 8 / L H / F / 9 / + Park 73 moth/1 0.2 InflPn 50 IP 4 9 / B H / M / 9 / + Park 73 moth/1 0.8 GVHD 70 IP 5 0 / K R / F / 7 / + Park 73 fath/2 3.5 Sepsis 5t IP

5 1 / J M / M / 1 0 / N R Gelfand 74 moth/2 3.4 GVHD 35 IV 52/??/?/?/NR Parkman 75 parent/1 0.6 NR 2 IV 53/?? /M/? /NR Parkman 75 moth/1 0.8 VirusI 5 IV 5 4 / ? / M / 6 / N R CS"LAPAZ" 77 moth/1 0.2 Sepsis 57ml IP 5 5 / A / M / 1 3 / N R Buckley 71 fath/1 0.6 GVHD 5 IV

56 /B /M/15 /NR Buckley 71 fath/1 0.7 GVHD 5 IV

57 /?? /F /5 /NR Buckley 71 moth/2 14 PcarPn 5 IV 58/?S/M/15/NR Buckley 71 moth/1 0.8 GVHD 6 IV 59 /Sn /M/15 /NR Buckley 71 moth/1 0.5 Sepsis 5 IV 60 /?? /M/7 /NR Buckley 71 moth/1 0.9 GVHD 15 IV

61/?? /M/5/NR Buckley 71 sis/1 0.3 PcarPn 1500t IV 62/??/?/? /NR Buckley 71 NR/NR 0.1 Sepsis NR NR 63/M J / F / 5 / 0 Copnhgn 73 fath/2 3.3 Sepsis 20t IV 6 4 / C P / F / 9 / + Huang 73 fath/1 1 GVHD 5 IP 65 /?? /M/2 /NR Amato 71 moth/1 1.7 Sepsis 1400t IV

6 6 / W R / M / 1 0 / N R Flad 71 moth/1 76 Brain d 5 IV 6 7 / R P / F / 5 / N R Rubstein 72 bro/3 0.9 Sepsis 3 IV 6 8 / D K / M / 1 6 / N R Wu 72 moth/1 1.4 GVHD 200t IV 69 /?? /F /2 /NR vBekkum 72 fath/NR 14 Sepsis 250t IV 7 0 / M M / M / 1 / N R Buckley 71 NR/1 0,2 Sepsis 5 IV

71/??/? /? /NR Dicke 73 N R / N R 0.4 NR 5 IV 72/??/?/? /NR Dicke 73 NR/3 4.7 Sepsis 10 IV 73/??/? /? /NR Sieber 74 lath/+ 1 4+ NR NR IP 74 /?? /M/4 /NR Tubrgn 75 moth/2 3+ NR 10 NR 75/?? /F/8 /? Bortin 77 aunt/1 0.5 Pneu, 68 IV

76/?? /F/7 /? Bortin 77 aunt/1 1.2 Myocar 1300 IV

V. Histocompatibility not given

7 7 / K W / F / 9 / 0 Hirschn 75 lath/1 NR NR NR NR 78 /?? /F /? /NR LPointe 72 NR NR NR NR NR 79 /?? /F /5 /NR Watson 77 NR/NR NR Sepsis NR NR 80 /?? /F /6 /NR Watson 77 N R / N R 1.2 GVHD NR NR

Preparation GVHD Chimera Reconstitution References

B-cell T-cell

NR sevr HLA

NR modr +

+ + 86, 54

0 0 17

AG 0 0

UF modr 0

VS mild 0

0 0 + +

0 +

l l l , 21, 29

102, 103

91, 92, 93, 5, 75, 109

AG sevr RBC 0 +

NR sevr NR NR NR

UF, ALG 0 0 0 0

UF sevr 0 0 0

UF modr XY, HLA + +

VS, FG sevr XX 0 0 3HThy 0 0 0 0

3HThy mild 0 0 0

NR NR 0 0 0

AG sevr dHLA + +

AG sevr dHLA + +

AG 0 0 + +

AG sevr NR NR NR

AG 0 + NR NR

MitC sevr 0 0 +

UF 0 Barr b. 0 0

NR NR NR NR NR

AG modr HLA, Y-chr 0 +

ALG sevr 0 0 +

VS 0 0 0 0

AG 0 0 + +

UF + HLA, RBC + +

UF sevr XX + +

NR modr XY + +

AG 0 NR NR NR

AG NR NR NR NR

AG + + NR NR 3HThy modr + + +

ATG mild dLyms 0 +

NR NE NE NE NE

NR mild + + +

80, 81, 21, 29, 30, 75, 100, 92, 108, 109, 120

80

91, 92, 93, 75, 83, 109

91, 92, 93, 75, 83, 109, 76

91, 92, 93, 75, 83, 109, 76

41, 94, 104

94

94

24

20, 21, 120

20, 21, 120

19, 2l, 120

21

21

21

21

21

26, 21, 29, 30, 31, 83, 100

64, 21

2, 21, 120

35, 21, 29, 120, 114

102, 103

124, 21

120, 21

21, 29, 120

21, 29

29, 30

107

119

17

17

NR NR 0

NR NR NR

NR NR NR

NR + NR

0

NR

NR

NR

0

NR

NR

NR

55

7 1

123

123


Abbreviations: AG albumin gradient ALG anti-lymphocyte globulin ATG anti-thymocyte globulin AspPn aspiration pneumonia Brain d. brain damage bro brother fath father CerGli cerebral gliosis CMV cytomegalovirus d donor 3HThy 3H thymidine InflPn influenza pneumonia IP intraperitoneal IV intravenous Meng meningitis MilkAs milk aspiration MitC mitomycine C modr moderate moth mother m+unrl mother + unrelated NE not evaluable NR not recorded Polymy polymyositis PM post mortem PcarPn pneumocystis carinii pneumonia RespAr respiratory arrest

sis sister s e v r s e v e r e

t total unrel unrelated UlcHge ulcer hemorrhage uncl uncle UF unfractionated VirusI virus infection VS velocity sedimentation

ADA deficient: cases 7, 10, 11, 12, 23, 38, 63, 77 (2 boys + 6 girls).

Sibs: cases 1I and 12, 25 and 26, 40 and 50, cousins: 32 and 46, twins: 55 and 56.

Plus fetal thymus transplantation: cases 1, 22, 34, 38, 43, 57, 58.

Pins fetal liver transplantation: cases 38 and 67. Plus transfer factors: cases 19 and 38. Plus enhancement: cases 47, 49, 51, 55, 56, 57, 58,

59, 67, 68, 76. Adoptive transfer: Donor of case 26 was her sister,

case 25. Case 66: BMT resulted in partial and temporary

reconstitution now considered as a case of common variable ID.

arrest (17 months aT), cerebral gliosis, polymyositis and hemorrhage from a duodenal stress ulcer. The autopsy findings, reported in 50% (8/16), confirmed the clinically-suspected main cause of death and the primary diagnosis of SCID, and revealed absent or only minimal signs of G V H D . The following signs provided pos tmor tem evidence of engraftment: periarteriolar cuffs of lymphocytes in the spleen with IgM staining 12 days aT; normal numbers of lymphocytes and /o r the presence of plasma cells in the bone marrow, thymus, spleen, appendix and lamina propria, but absent peripheral lymph nodes and Peyer's patches 3 months aT; and lymphocytic colonization and germinal center proliferation in the peripheral lymph nodes 12 months aT.

Of the 5 ADA-deficient patients in group I (cases 7, 10, 11, 12, 23) 4 are alive 3 to 5 years aT and 1 died 17 months aT from respiratory arrest due to neuro- logical damage suffered during the pretransplant period [22]. The sibling donors of these 5 patients were normal homozygotes in 4, and one normal heterozygote (case 10). After BMT, the A D A activity remained absent in the erythrocytes of all 5 recipients and became positive in the lymphocytes of 2 (cases 7 and 23).

Group H (only MLC matched)

Three of the 11 patients in this group are alive 9, 4.5, and 2.5 years aT. They received 2, 3, and 7 BMTs respectively, with full immunological reconstitution in 2, and full cellular but partial humoral immunological reconstitution in 1 (case 35). These 3 survivors are:

Case 32 [36] who is the first successfully transplanted SCID patient, the first to receive H L A incompatible but MLC compatible marrow, and the first success-


Table 2. Pretransplant clinical and laboratory data of 80 SCID patients treated with bone marrow transplantation from 1968 to 1977

Sex: Male 47 Female 26 NR 7

Age at onset: 0--1 month 16 (36%)

2--3 months 19 (43%)

4--7 months 9 (21%)

NR 36

Serum IgA mg/lOOml (n = 40)

0 1--10

11--20

20

"low"

"normal"

NR

19 (48%)

11 (28%) 4 (10%)

3 (8%)

2 (5%)

1 (2%) 40

Symptoms (n = 50): Serum IgM mg/lOOml (n = 42) Pneumopathy 31 (62%) 0 13 (31%)

Failure to thrive 27 (54%) 1-- i0 I0 (24%)

Diarrhea 25 (50%) 11--20 7 (17%)

Thrush 25 (50%) 21--75 7 (17%)

Rash 14 (28%) "low" 3 (7%) Other infections 17 (34%) 100 1 (2%)

P. carinii pneumonia 9 (18%) "normal" I (2%) NR 30

Lymphocyte count/ram ~ (n = 43)

< 1000 22 (51%)

< 2000 6 (14%)

< 3O00 4 (9%)

< 4000 3 (7%)

"decreased" 8 (19%) NR 37

Isoantibodies (n = 21)

Absent 19 1:1 1

1:2 1

Skin tests (n = 33)

Negative 33

PHA Lymphocyte stimulation test (n = 50) negative 44 (88%)

"low" 6 (12%) Serum IgG mg/lO0 ml (n -- 48)

0--200 32 (66%) One-way MLC test (n = 21)

201--300 5 (10%) negative 18 (86%)

301--600 4 (8%) "low" 3 (14%)

"low" 4 (8%) RBC Adenosine deaminase activity (n -- 23) > 600 3 (8%) negative 8 (6 females, 2 males)

NR 32 positive 15 (7 females, 8 males)

fully t rea ted for aplas t ic anemia due to B M T by a second BMT f rom the same d o n o r [78].

Case 35 [33] is the first S C I D pat ien t successfully t rea ted with BMT f rom a non- s ibl ing relat ive (uncle) who was compa t ib l e only at the M L C locus.

Case 40 [90] is the first S C I D pa t i en t successfully t rea ted with B M T f rom an unre la ted d o n o r compa t ib l e only at the M L C locus. H e ma to log i c a l and i m m u n o - logical recons t i tu t ion was f inal ly achieved af ter the 7th BMT using p re t r ansp lan t cond i t ion ing with c y c l o p h o s p h a m i d e and t r ansp l an t a t i on o f 100 t imes more than the usual n u m b e r o f cells.

Table 3. Transplantation data of 80 SCID patients treated with BMT from 1968 to 1977

I II III+ IV V Total

Age at first BMT

1--6 months 18 (58%) 5 (45%) 9 (33%) 2 (66%) 32 (46%)

7--12 months 11 (35%) 6 (55%) 13 (48%) 1 (33%) 30 (44%)

13--24 months 2 (7%) 0 5 (19%) 0 7 (10%)

Not reported 0 0 7 1 8

Total 31 11 34 4 80

Donors

Sister 14 (47%) 1 (9%) 1 (3%) 0 16 (22.%)

Brother 8 (27%) 3 (27%) 2 (7%) 0 13 (18%)

"Sibling" 2 (8%) 1 (9%) 0 0 3 (4%)

Mother 1 (4%) 3 (27%) 14 (48%) 0 18 (25%)

Father 3 (10%) 0 8 (27%) 1 12 (17%)

"Parent" 0 0 1 (3%) 0 1 (1%)

Grandmother 1 (3%) 0 0 0 1 (1%)

Aunt 0 0 2 (7%) 0 2 (3%)

Uncle 1 (3%) 1 (9%) 0 0 2 (3%)

Unrelated 0 2 (18%) 2 (7%) 0 4 (7%)


Total 31 11 34 4 80

Number of BMT

1 23 (78%) 3 (30%) 21 (72%) 1

2 4 (13%) 1 (10%) 5 (17%) 0

3 1 (3%) 5 (50%) 3 (11%) 0

4 1 (3%) 0 0 0

7 1 (3%) 1 (10%) 0 0

Not reported 1 1 5 3

48 (68%)

10 (14%)

9 (13%)

1 (1%) 2 (3%)

10

Total 31 11 34 4 80

Total number of BMT performed > 123

Cells transplanted per kg body weight

1--10 x 106 5 (17%) 2 (20%) 19 (62%) 0

11--50 x 106 11 (38%) 4 (40%) 5 (17%) 0

51--100 X106 4 (14%) 0 3 (10%) 0

101--300X 106 7 (24%) 2 (20%) 2 (7%) 0

300X 106 2 (7%) 2 (20%) 1 (4%) 0


26 (38%)

20 (29%)

7 (10%)

11 (16%)

5 (7%)

11

Total 31 11 34 4 80

Route of administration

Intravenous 23 (82%) 4 (50%) 24 (77%) 0 Intraperitoneal 5 (18%) 4 (50%) 7 (23%) 0


51 (76%) 16 (24%)

13

Total 31 11 34 4 80

Bone Marrow Transplantation

Table 3 (continued)

165

I II III+ IV V Total

Preparation of graft Unfractionated 19 (86%) 6 (86%) 8 (29%) 0 33 (58%)

Albumin gradient 3 (14%) 1 (14%) 12 (43%) 0 16 (28%)

3H thymidine 0 0 3 (11%) 0 3 (5%)

Velocity sediment 0 0 2 (7%) 0 2 (4%)

Mitomycine C 0 0 1 (4%) 0 t (2%)

ALG 0 0 2 (7%) 0 2 (4%)


Total 31 11 34 4 80

Table 4. Post-transplant data of 80 SCID patients treated with BMT from 1968 to 1977

I II III IV V Total

Recipient donor compatibility HLA-A+ B + - + - NR

HLA-D (MLC) + + - - NR

Number of cases 31 11 3 31 4 80

Alive 15 (48%) 3 (27%) 0 0 0 18 (23%)

Dead 16 (52%) 8 (73%) 3 (100%) 31 (100%) 4 (100%) 62 (77%)

GVHD 0 8 (32%) 2 (20%) 1 (33%) 8 (32%) 0 19 (30%)

Mild 12 (48%) 3 (30%) 1 (33%) 3 (12%) 0 19 (30%)

Moderate 2 (8%) 3 (30%) 1 (33%) 4 (16%) 0 10 (16%)

Severe 3 (12%) 2 (20%) 0 10 (40%) 0 15 (24%)

Not reported 6 1 0 6 4 i8

Total 31 11 3 31 4 80

Chimerism 13/26 7/8 0/3 15/24 NR 35/67

50% 88% 63% 57%

Reconstitution B+T-cell 18 (72%) 6 (60%) 1 (33%) 10 (42%) 0 35 (56%)

B-cell only 2 (8%) 2 (20%) 0 0 0 4 (7%)

T-cell only 4 (16%) 0 1 (33%) 5 (21%) 0 10 (16%)

None l (4%) 2 (20%) 1 (33%) 9 (37%) 0 13 (21%)

Not reported 6 1 0 7 4 18

Total 31 11 3 31 4 80


I , HLA+ MLC 351 compatible

Group I

30

Only MLC compatible Group II

Not compatible at MLC locus

0 �84

Surviving % 48 27 0

r-.---1 = alive i = d e a d

Fig. 1. The relation between donor-recipient histocompatibi l i ty and survival, n = 76

Surviving % 26 47 32 -(

r 'm:alive I : d e 0 d

Fig. 2. The relation between seventy of G V H D and survival, n = 63


I0_

I0_

I0_

~o2

o

No Mi ld Moderate Severe GVHD GVHD GVHD GVHD

( n=19 , (n =19) ( n = 9 , ~ n ~ 1 4 )

1300

o �9

:) �9 �9

o �9

i

~ u

�9 =alive e=dead

Fig. 3. The relation between severity of GVHD and number of bone marrow cells given, n = 61

Direct evidence of engraftment was found in 88% of the patients in group II. T- and B-cell function was restored in 60%, B-cell function alone in 20%, and in 20% no reconstitution was achieved. Although G V H D developed in 80%, it was never a cause of death in this group. The cause of death was reported in 7 of 8 who died. All were due to infections (sepsis 3, cytomegalovirus 2, P. carinii pneumonia 1, and aspiration pneumonia 1).

The autopsy findings were reported in 5 of 8 deaths. As in group 1, the findings were compatible with SCID and with the clinically suspected main cause of death. In contrast to group I, evidence of still active G V H D was found in case 36 (aplastic marrow and chronic periportal inflammation with bile duct proliferation 11 months aT), and questionable evidence in case 34 (aplastic marrow unaccompanied by other stigma of G V H D one month aT). Also, unlike group I there was no evidence of engraftment other than the presence of single lymphocytes and plasma cells positive for Ig in lymphoid tissues and periarteriolar cuffing of splenic vessels by lymphocytes. Lymph nodes were difficult to find macroscopically; microscopically, the lymphoid tissue showed no cortico-medul- lary organization and no germinal centers [4, 54].

Group III (only H L A compatible)

The 3 patients in group I I I died 0.4, 1.4, and 3.5 months aT, respectively. Chimerism was not noted in any case, but early B- and T-cell functions were noted in one, and an increase in small lymphocytes and slight increase in PHA reactivity in another. Two died of P. carinii pneumonia and one of milk aspiration. The autopsy findings were typical for SCID. In one case, who died 1.4 months aT, signs of G V H D and cells in the spleen stained with immunofluores- cent sera were seen.


Table 5. Causes of death in 62 cases of SCID treated with BMT from 1968 to 1977

I II III IV V Total

Infection 10 (63%) 7 (100%) 3 (100%) 17 (63%) 1 (50%) 38 (61%) GVHD 2 (12%) 0 0 9 (33%) 1 (50%) 12 (12%) Duodenal Ulcer HGE 1 (6%) 0 0 0 0 1 (1,5%) Polymyositis 1 (6%) 0 0 0 0 1 (1.5%) Respiratory arrest 1 (6%) 0 0 0 0 1 (1,5%) Cerebral gliosis I (6%) 0 0 0 0 1 (1.5%) Epileptic seizure 0 0 0 1 (4%) 0 1 (1.5%) Not reported 0 1 0 4 2 7 (11.5%)

Total died 16/31 8/11 3/3 31/31 4/4 62/80 52% 73% 100% 100% 100% 77%

Procedures used to mitigate the anticipated G V H D were: strict reverse isolation and bowel decontamination, microaspiration of bone marrow to minimize contamination with peripheral blood, albumin and velocity sedimentation to obtain stem cells, and treatment with Methotrexate aT.

Group IV (HLA and MLC incompatible)

All 31 patients in this group died. In one patient who survived 76 months aT, the diagnosis of SCID is questionable [17]. Chimerism was noted in 63% (15/24), signs of B- and T-cell reconstitution in 42% (10/24), and T-cell reconstitution alone in 21% (5/24). G V H D developed in 68% (17/25). It was mild in 12% (3/25), moderate in 16% (4/25), and severe in 40% (10/25). The cause of death was infection in 63% (17/27), and G V H D in 33% (9/27). The autopsy findings in 17 cases were compatible with the primary disease, with the clinically-suspected main cause of death and with G V H D . Periarteriolar cuffing in the spleen and lymphocytic regeneration in lymphnodes were seen in 3 cases. Hypoplastic marrow was noted in 2 cases at autopsy and aplastic anemia in 3 cases during life. All 5 had mild to severe G V H D and infection.

Procedures used to mitigate the anticipated G V H D were the same as in group III .

Discussion

The review o f 80 cases of SCID treated by bone marrow transplantation yielded a number of valuable insights.

The features of SCID have been extensively described in a number of previous publications [7, 27, 44, 56, 57, 59, 116]. The pretransplantar data of the present cases do not differ f rom non-transplanted patients. A remarkable laboratory finding was the presence of multiple extraneous H L A antigens in a number of patients [34, 87, 115].


Bone marrow transplantation (BMT) resulted in immunological reconstitution with 1 to 9 years survival in 18 patients with SCID. It is thus the first successful form of therapy for this otherwise invariably fatal disease. Fifteen of the 18 survivors received bone marrow from donors compatible for the properties coded at the HLA region, i.e. HLA-A, HLA-B and HLA-D (= mixed leukocyte culture = MLC). This is without doubt the treatment of choice. However, (see p. 10) the majority of SCID patients do not have such an ideal donor. The chances of finding such a donor among the siblings is 1:4, among the parents in a first- cousin-marriage 3 : 64 [40], and among the sibs of the parents in a first cousin marriage 1:30 [122].

If a HLA- and MLC-compatible donor is not available, the second best choice seems to be MLC-compatibility inspite of HLA-incompatibility (group II). Eleven patients in this report received such a BMT, with 3 longterm survivors. However, the incidence of complications was higher and permanent engraftment was only achieved after multiple BMTs.

Donors compatible at the MLC locus alone are also difficult to find. In a family, siblings of identical MLC type are usually also compatible for the other HLA properties. However, in rare instances of recombination in the major histocompatibility region, siblings become MLC-identical but HLA non-identical (or vice-versa). Hansen [53] has reported increased frequency of MLC compatibility between SCID patients and their parents (14% vs 2.1% in control families). Horowitz [62], the first to report BMT from an unrelated but MLC compatible donor, found this person among 8000 individuals tested at random. With the increased frequency of HLA testing of voluntary blood donors, this therapeutic possibility becomes increasingly important. Testing at the A and B sublocus with serological methods is relatively simple, whereas recognition of the D sublocus by serological methods is still in an experimental stage, and the usually performed mixed leukocyte culture (MLC) is too complicated as a routine procedure.

BMT incompatible at both HLA and MLC locus was performed in 31 patients. All but one died of infection and /o r GVHD. The single long-term survivor (case 66) had only transient engraftment and soon redeveloped signs of SCID. He later died of an epileptic seizure with brain damage. Strict criteria for SCID were not fulfilled. We therefore conclude that HLA and MLC incompatible BMT should not be attempted in the future.

An additional criterion of compatibility was revealed by the review of the International Bone Marrow Transplant Registry [17] which clearly showed that a donor/recipient sex difference (female donor, male recipient) increases the frequency of significant GVHD and lowers the six-month survival rate.

The main complications of the post-transplant period are infection and graft versus host disease (GVHD). Prevention and treatment of infection are sterile care (preferably under reverse isolation), decontamination of skin and gut, and appropriate antibiotics and antimycotics. Since Pneumocystis carinii infection was one of the leading causes of death, prevention with appropriate treatment (Pentamidin or Bactrim/Septrin) before and after transplantation is now gener- ally recommended.

The prevention or treatment of GVHD has been less successful. The most important factor is undoubtedly histocompatibility, but even with identity of


donor and recipient at the HLA region, mild to severe GVHD occurred in 65% of the patients in group I.

Tremendous efforts to circumvent the anticipated G V H D did not prevent the disease, and it is doubtful whether it influenced its severity. Procedures were designed to eliminate or greatly reduce the 'number of immunocompetent cells (which are responsible for the GVHD) from the bone marrow graft. With discontinuous albumin gradients [28], velocity sedimentation [96] and the continuous Ficoll gradient [41] the separation of the lighter stem-cell population (1.068 g/cm 3) from the heavier immunocompetent, GVHD-producing cells was performed. Inactivation of these cells by pre-incubation of the donor marrow with anti-lymphocyte globulin (ALG) or 3H-thymidine [105] was tried. Enhance- ment by the administration of donor plasma or anti-HLA serum in the immediate pre- and post-transplant period was widely used in an attempt to coat the recipient's tissue antigens with antibody, and thus prevent the grafted immunocompetent donor cells from reacting against the recipient. In animal experiments, enhancement sustained incompatible tumor-cell and incompatible normal tissue grafts and reduced mortality but sometimes accelerated and aggravated GVHD instead of preventing it [19,121].

There may be a correlation between the number of bone marrow cells transplanted and the severity of GVHD. In the relatively homogeneous group of 18 survivors (all MLC compatible and alive more than one year after BMT), 10 of 14 who had absent or only mild GVHD received 50 million bone marrow cells per kilo bodyweight or less. In contrast, 3 of 4 survivors who presented moderate or severe G V H D had been transplanted with more than twice as many cells.

The route of administration and the use of unfractionated or fractionated bone marrow grafts did not influence the outcome.

The response of ADA deficient SCID patients to BMT does not differ from those with normal ADA activity.

The 48 SCID patients reported to the International Bone Marrow Transplant Registry [17] are also included in this report. We agree with their recommendations:

1) The donor and recipient should be HLA and MLC identical. If this is not possible, MLC compatible donors should be used in preference to donors whose cells are stimulated in MLC by recipient cells.

2) Male donors are preferable to female donors for male patients. 3) Transplantation should be performed before the patient reaches 6 months

of age. We would like to add the following recommendations: 4) MLC incompatible BMT for SCID should be abandoned. 5) The number of bone marrow cells transplanted should be kept as low as

possible, preferably below 50 x 106 per kg body weight. 6) Strict reverse isolation and bowel decontamination should be provided, in

particular for patients in poor clinical condition, for patients in whom GVHD is anticipated, and for patients receiving immunosuppressive therapy.

7) Prophylactic treatment for pneumocystis carinii pneumonia should be instituted before and continued for several weeks after BMT.


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98. Preud'Homme, J. L., Griscelli, C., Seligman, M.: Immunoglobulins on the surface of lymphocytes in fifty pati~ents with primary immunodeficiency diseases. Clin. Immunol. Immunopath. 1, 24t--256 (1973)

99. RadI, J., Doore, L. J., Eijsvooget, V. P., Van Went, J. J., Hijsmans, W.: An immunological study during posttransplantation follow-up of a case of severe combined immunodeficiency. Clin. exp. Immunol. 10, 367--382 (1971)


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103. Rubinstein, A., Jeannet, M., Pelet, B.: Bone marrow transplantation in combined immune deficiencies. In: Immunodeficiency in man and animals, D. Bergsma, R. A. Good, J. Finstad, N. W. Paul, eds., p. 397. The National Foundation 1975

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106. Seligman, M., Griscelli, C., Preud'Homme, J. L., Sasportes, M., Herzog, C., Brouet, J. C.: A variant of severe combined immune deficiency with normal in vitro response to allogeneic ceils and an increase in circulating B lymphocytes persisting several months after successful bone marrow graft. Clin. exp. Immunol. 17, 245--252 (1974)

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114. Teller, W. M.: Rearing of non-identical twins with lymphopenic hypogammaglobulinemia under g notobiotic conditions. Acta Scand. Suppl. 240, Uppsala 1973

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117. Touraine, J. L., Touraine, F., Incefy, G. S., Good, R. A.: Effect of thymus factors on the differentiation of human marrow cells into T-lymphocytes in vitro in normals and patients with immunodeficiency. Ann. N.Y. Acad. Sci. USA 235--342 (1975)

118. Trotta, P. P., Smithwick, E. M., Bales, M. E.: A normal level of adenosine deaminase activity in the red cell lysates of carriers and patients with severe combined immunodeficiency. Proc. Natl. Acad. Sci. USA 73, 104--108 (1976)

119. Tubergen, D. J., Petty, R. E.: Lymphoid chimerism with mild graft versus host reaction following non-matched marrow transplantation in combined immune deficiency. Pediat. Res. 9, 336 (1975)


120. Van Bekkum, D. W.: Use and abuse of hemopoietic cell grafts in immune deficiency disease. Transplant. Rev. 9, 3--53 (1972)

121. Van Bekkum, D. W.: Combined immune deficiency: Its nature and treatment. Clin. Immunol. Immunopath. 6, 115--122 (1976)

122. Vossen, J. M., De Koning, J., Van Bekkum, D. W., Dicke, W. A., Eijsvoogel, V. P., Hijmans, W., Erna, V. L., Radl, J., Van Rood, J., Van der Waay, D., Dooren, J. L.: Success- ful treatment of an infant with severe combined immune deficiency by bone marrow transplantation from an uncle. Clin. exp. Immunol. 13, 9--20 (1973)

123. Watson, J. G., Rogers, T. R., Selwyn, S., Smith, R. G.: Evaluation of Vickers-Trexler isolator in children undergoing bone marrow transplantation. Arch. Dis. Childh. 52, 563--568 (1977)

124. Wu, L. Y. E, Rothberg, R. M., Pachman, L. M., Coppelson, L. W., Lamer, B. J., Peter- son, R. D. A.: Hemiatlogeneic bone marrow transplantation in a child with severe combined immune deficiency. J. Pediat. 80, 441--449 (1972)

125. Yamamura, M., Newton, R. C. F., James, D. C. O., Humble, J. G., Butler, L. J., Hobbs, J. R.: Uncomplicated HLA matched sibling bone marrow graft for combined immune deficiency. Brit. Med. J. 1972 II, 265--269

125a. Yount, W. J., Utzinger, P. D., Gatti, R. A., Good, R. A.: Immunoglobulin classes, IgG subclasses, Gm genetic markers, and Clq following bone marrow transplantation in X- linked combined immunodeficiency. J. Pediat. 84, 193--199 (1974)

126. Further references for case 32: 69, 70, 81, 106, 125a

Received November 20, 1978

european journal eur. j. pediatr. 131, 155--177 (1979) … journal of eur. j. pediatr. 131, 155--177...

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