Rate of marrow engraftment does not appear to be adversely affected by early marrow infusion after total body irradiation.

Bone marrow transplantation (BMT) provides a means of increasing chemo-radiotherapy doses beyond the limits imposed by marrow toxicity. The time interval between myeloablative therapy and marrow infusion needs to be optimized to ensure prompt engraftment. It has been suggested that early marrow infusion after completion of total body irradiation (TBI) may be detrimental to rapid marrow reconstitution. Hence a retrospective analysis of 75 BMT patients was performed to document the rate of marrow engraftment following marrow infusion given immediately after TBI. Engraftment rates (time to absolute neutrophil count to greater than 0.5 x 10(9)/L) of patients receiving different conditioning regimens were compared. Results show similar engraftment rates in patients receiving bone marrow infusion 27.7 and 32.1 hours after completion of chemotherapy in autologous (20.5 days) and allogeneic (18.5 days) transplants respectively, or 2.9 and 2.0 hours after completion of TBI in autologous (20.1 days) and allogeneic (19.4 days) transplants respectively. These results are similar to those reported for delayed marrow infusion after TBI and would support that early marrow infusion after TBI does not adversely influence rate of engraftment. Thus it appears appropriate to give marrow immediately after completion of TBI.

Factors affecting hair regrowth after bone marrow transplantation.

Permanent alopecia after BMT has been reported as a side-effect associated with GVHD or after busulphan conditioning therapy, primarily in adults. We have reviewed children undergoing BMT to document the frequency of incomplete hair regrowth and to evaluate factors associated with this problem. Hair regrowth was studied in 74 children who survived > 6 months following BMT undertaken for malignant and non-malignant diseases. Alopecia was categorised as severe (< 50% of pre-transplant status), moderate (50-75%) or mild (> 75% but less than normal). Overall, 18 (24.3%) of 74 patients had mild (n = 5), moderate (n = 4) or severe (n = 9) alopecia. Risk factors for alopecia were presence of chronic GVHD (67%; p < 0.001), older age (p < 0.001) and prior cranial irradiation (42%; p = 0.03). Alopecia occurred in children receiving either busulphan (31%) or total body irradiation (16%; p = 0.15) as conditioning therapy. The highest frequency was seen in patients conditioned with busulphan with or without melphalan and who received prior cranial irradiation and/or developed chronic GVHD (75%). These data indicate that alopecia after BMT in children is a significant problem and confirm, in children, the previously noted association between alopecia and chronic GVHD and busulphan. Further risk factors of older age and prior cranial irradiation are identified. Consideration needs to be given to the use of an alternative to busulphan in children who are of older age, have received prior cranial irradiation and/or are at increased risk of GVHD.

Bone marrow transplantation in children using closely matched related and unrelated donors.

Seventeen bone marrow transplants were undertaken on 15 patients with leukemia or aplastic anemia using marrow from closely matched (phenotypic or five out of six HLA-A, B and DR antigen matched related and unrelated) donors. Donors were siblings (four), parents (seven), aunt (one), great aunt (one) or matched unrelated (two). When compared with transplants using matched sibling donors, survival was not different (51.4 +/- 13.4% vs. 48.1 +/- 9.6%; p = 0.87) but transplant-related complications and morbidity were higher as follows: graft-versus-host disease (GVHD) (87% vs. 15%; p less than 0.001), interstitial pneumonitis (59% vs. 14%; p less than 0.003), days in hospital (51 vs. 26; p less than 0.001), and chronic transplant related morbidity 50% vs. 11%; p + 0.033). The age of donors who were closely matched was significantly greater than that of their recipients (29.7 +/- 13.9 years vs. 8.1 +/- 3.1 years; p less than 0.001) and was associated with poorer transplant outcome. Median transplant-related complication-free survival for patients receiving transplants from age non-disparate donors was 53 months (range 18-86 months) compared with 12 months (range 2-42 months) for age disparate donors (p = 0.028). Transplants from closely matched donors were undertaken in the ratio of one to every three matched donors, indicating the importance of this source of marrow in a transplant program.

Bone marrow transplantation: a review of a programme and its first 100 patients.

We review the first 100 patients receiving a bone marrow transplant as definitive therapy for their underlying disease. These patients were treated between May 1975 and June 1988. Median age was 8 years (range, 1 month to 43 years). Initially, patients were given transplants late in their disease but, as the programme progressed, patients were given transplants earlier and while in remission from their disease. The types of disease considered for treatment by bone marrow transplantation (BMT) expanded from leukaemia, and aplastic anaemia to include neuroblastoma, thalassaemia and immune deficiency. Initially matched donors were used but the source of marrow broadened to include mismatched family members, matched unrelated donors and autologous marrow. Problems after BMT were rejection (11%), acute graft-versus-host disease (GVHD) (45%), interstitial pneumonitis (22%) and relapse (36%). Recurrence of disease was the cause of half the deaths. GVHD was less frequent with the use of methotrexate and cyclosporin, T-cell depleted marrow or matched donors. Interstitial pneumonitis was more commonly associated with the use of mismatched donors and the development of GHVD. Relapse was less likely when BMT was undertaken in the first remission. At least one long-term side effect was seen in all patients treated with total body irradiation whereas no patient treated without irradiation had long-term side effects. The rate of disease free survival of patients at 24 months was 56% for matched, 48% for closely matched, 46% for autologous and 29% for mismatched transplants. For matched transplants mortality within the first 6 months after transplantation decreased from 28% before 1984 to 5% since 1984. Fifty-one patients have survived to June 1989, 49 of them disease free, for periods ranging from 12 to 123 months (median 29 months).

Use of granulocyte-macrophage colony-stimulating factor in two children treated with cord blood transplantation.

Cord blood contains stem cells in amounts similar to or slightly less than those present in a bone marrow collection to be used for bone marrow transplantation (BMT). Too few cord blood transplants (CBT) have yet been performed to define the ability to achieve engraftment and the rate of engraftment. Two cord blood transplants have been performed using granulocyte-macrophage colony stimulating factor (GM-CSF) to hasten engraftment. Two children, aged 5 and 6 years received a CBT using HLA-identical stem cells collected at the birth of a sibling. One child had X-linked lymphoproliferative disease (XLP), and the other, acute lymphoblastic leukemia in second complete remission. One had an ABO and one an Rh blood group mismatch. Conditioning therapy consisted of cyclophosphamide, melphalan, and antithymocyte globulin or busulphan and cyclophosphamide. Graft-versus-host disease prophylaxis was methotrexate and cyclosporine or cyclosporine. Both children were given GM-CSF at 5 micrograms/kg/day from day 1 until the absolute neutrophil count (ANC) reached 1.0 x 10(9)/L for 3 consecutive days. If this level was not reached by day 14, the dose of GM-CSF was doubled. Both children engrafted rapidly, with ANCs reaching 0.5 x 10(9)/L in 12 and 16 days. Engraftment was confirmed by blood group in both and sex chromosome typing in one. Both children developed mild GVHD localized to skin, which resolved with steroid therapy. The child with XLP was cured and has survived for 34 months; the second child has survived 27 months with normal marrow function but has had a relapse of leukemia.(ABSTRACT TRUNCATED AT 250 WORDS)

HLA non-identical T-cell-depleted bone marrow transplantation for primary immunodeficiency diseases.

BACKGROUND: Bone marrow transplantation (BMT) is usually the only procedure offering cure for children with life-threatening immune deficiency disorders, but compatible sibling donors are frequently unavailable. AIMS AND METHODS: To examine the outcome of HLA non-identical T-cell-depleted BMT carried out between April 1985 and May 1992 in 11 patients with primary immunodeficiency diseases and to seek prognostic factors. RESULTS: Eight patients achieved sustained engraftment, one after a second BMT. One further patient engrafted transiently, but rejected the graft five months later. Acute graft-versus-host disease (GVHD) grade II was seen in one and chronic GVHD was seen in three children. Seven patients survived beyond six months, six with donor T cell and five with donor B cell engraftment. At present, five patients (46%) are alive with immune reconstitution at a median follow-up of 14 months (range 6 to 78 months). The major factor associated with outcome was the presence of any infection within one week of BMT (p = 0.01). The presence of lung infection also tended to be a poor prognostic factor (p = 0.06) but did not reach significance, presumably because of the small sample size. HLA non-identical (parental) T-cell depleted BMT plays an important role in the cure of children with immunodeficiencies who do not have an identical sibling donor. Survival can be further improved if the diagnosis of immunodeficiency disease is made early and BMT undertaken before significant infections occur. CONCLUSIONS: The availability of T-cell depleted haploidentical parental bone marrow transplant can be anticipated to improve outcome significantly for children with severe immunodeficiency, especially when diagnosed early.

Allogeneic and autologous bone marrow transplantation for acute non-lymphoblastic leukaemia.

Bone marrow transplantation (BMT) has had an increasing role in the treatment of acute nonlymphoblastic leukaemia (ANLL). A review of patients transplanted between May 1975 and August 1991 was undertaken in order to evaluate problems and outcome, and examine the role of both autologous and allogeneic BMT at various stages in the treatment of ANLL. Forty-seven patients received either an allogeneic (n = 24) if a suitable donor was identified or autologous (n = 23) BMT if there was no allogeneic donor. Conditioning therapy consisted of total body irradiation (TBI) and cyclophosphamide (n = 14) or busulfan and cyclophosphamide (n = 33) with or without melphalan. Graft-versus-host disease prevention was with methotrexate (n = 9), methotrexate and cyclosporin (n = 10) or T cell depletion (n = 5). Minimum follow-up for surviving patients was 24 months (median 65 months). For patients transplanted in first remission there was a 0% and 9 +/- 6% transplant-related mortality, a 37 +/- 11% and 33 +/- 12% relapse risk and a 63 +/- 11% and 63 +/- 12% event-free survival for autologous and allogeneic BMT, respectively. In second remission, there was a 14% mortality, 50 +/- 20% relapse risk and 43 +/- 19% event-free survival for allogeneic BMT. No patient transplanted in relapse survived. In patients who survived greater than 24 months, late side effects were noted in all 8 (100%) patients given TBI and in 2 of 19 (10.5%) given busulfan.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone marrow transplantation for malignant histiocytosis in childhood.

This report describes a girl who was diagnosed with malignant histiocytosis at the age of 5 years. The disease was controlled initially with chemotherapy for 3 years and had then recurred with meningeal involvement on three occasions. Four years and 8 months from diagnosis, bone marrow transplantation (BMT) was undertaken from an HLA-identical and mixed lymphocyte culture (MLC) nonreactive brother after conditioning with VP-16-213 5 mg/kg/day X 2, cyclophosphamide 60 mg/kg/day X 2, and total body irradiation 200 rad twice daily to a total dose of 1000 rad delivered at 7 rad/minute. At the time of transplant, the disease was in remission. Currently, more than 48 months after the transplant, the child remains free of disease, with a normally functioning donor marrow and with no evidence of graft versus host disease. This is the first recorded case of BMT in the treatment of malignant histiocytosis. The outcome in this patient in late-stage disease suggests that BMT could be considered early in management as definitive therapy.

Searches for matched and closely matched related and unrelated bone marrow donors undertaken in a single paediatric unit.

Information regarding the likelihood of finding suitable marrow donors is limited. In order to determine this potential, all patients who received their primary care at a single paediatric institution over a 9 year period and in whom tissue typing studies were initiated are reviewed. Forty-five (31.3%) of 144 patients had a sibling who was human leucocyte antigen (HLA) identical. A further 16 (11.2%) patients had immediate or more distant relatives who were either HLA identical (2.7%) or matched for five of six HLA antigens (8.3%). The possibility that a parent was closely matched with the patient was suggestive from the typing of siblings alone in only half the cases. Unrelated HLA matched donors were identified in four (27%) of 17 bone marrow bank searches. Overall, a potential related donor was identified within the family for 42% of patients and this figure rose to 45% when successful marrow bank searches were included. It can be concluded that initial typing should include both the parents and siblings. If a suitable donor is not found then an extended family and/or bone marrow bank search will identify additional suitable donors in a significant number of families.

Bone marrow transplantation for childhood acute lymphoblastic leukaemia after marrow relapse.

Children with acute lymphoblastic leukaemia in whom relapse in bone marrow occurs have a poor outlook when treated with chemotherapy alone. Twenty-seven patients with childhood acute lymphoblastic leukaemia were treated for marrow relapse with high-dose chemotherapy with or without total body irradiation followed by bone marrow transplantation (BMT). Twenty patients received allogeneic marrow from partially or completely matched histocompatible donors. In this group, nine patients (45%) were free of disease with a median follow-up of 57 months (range, 22 to 126 months) after transplantation, four (20%) died from interstitial pneumonitis and seven (35%) died after a further relapse. Seven patients received autologous marrow collected while they were in remission. In this group, one patient died from infection and six died after a further relapse. We conclude that allogeneic BMT is more effective than autologous transplantation and results in long-term disease-free survival in a significant number of patients. New methods are needed to eradicate residual disease in the patient and to purge marrow ex vivo.