Bone Marrow Transplantation for Hematologicai Diseases in Hokkaido--June 1985 to December 1991

Bone marrow transplantation (BMT) was started in Hokkaido in1985. In the present report we have reviewed the clinical outcomeof patients treated with BMT for hematologicai diseases in Hokkaido.Fifty-eight allogeneic and 19 autologous transplants were registeredby December 1991. The underlying diseases consisted of 47 leukemias,14 lymphomas, 10 aplastic anemias and six myelodysplastic syndromes.Among the allogeneic BMT cases, 55 were human leuhocyte antigen(HLA) identical and three were mismatched. Among the autologousBMT patiets, two recieved their marrow purged with 4-hydroperoxycyclophosphamideand five, with monoclonal antibodies and complements. The conditioningregimens used for malignancies were chiefly cyclophosphamide(CY) plus total body irradiation, or busulfan plus CY. In manycases, cytokines were used for rapid recovery of decreased leukocytes.Engraftment was observed in 50 out of 52 evaluated allogeneicand 18 out of 19 autologous transplants. Ten allogeneic patientssuffered from severe acute graft-versus-host diseases (GVHD),and extensive chronic GVHD appeared in 16 patients. Relapseswere observed in four cases of allogeneic BMT and six of autologous.BMT. The major complications were interstitial pneumonitis (IP)and severe infections. Long-term, survival rates were almost60% in both allogeneic and autologous transplants. Mild acuteGVHD and limited chronic GVHD increased the survival rates.The results indicated that substantial problems such as GVHD,IP and relapses must be controlled in the near future for animproved outcome to be made possible.     

Bone marrow transplantation today

Today, bone marrow transplantation (BMT) is an established therapy. This statement is best verified by the number of BMTs performed. Between January 1990 and December 1992, 172 European teams in 26 countries carried out a total of 14334 transplants. There were 6642 allogeneic transplants: 5513 BMT from an HLA-identical sibling donor, 370 from a non-identical family member, 88 from an identical twin donor and 671 from an unrelated volunteer donor. There were 7692 autologous transplants: 6577 autologous bone marrow, 777 peripheralblood stem-cell and 338 combined bone-marrow and peripheral-blood stem-cell transplants. Indications were: leukaemias in 52% (7479), lymphoproliferative disorders in 29% (4125), solid tumours in 11% (1540), aplastic anaemia and thalassaemia in 3% (487) and inborn errors an miscellaneous disorders in the remaining 5% (703). The results of these transplants are not yet known. From previous analyses it can be expected that more than 50% of patients will be alive and well 10 years after BMT. The main factors influencing outcome are known; they depend on type, subtype, stage of disease at time of transplant, the time from diagnosis to transplant and the conditioning regimen for all transplants. For allogeneic BMT, donor source, donor and recipient age, sex, donor/ recipient sex combination, donor and recipient viral status, graft-versus-host disease prevention method and region are additional factors. Knowledge of these factors enables us today to estimate the potential risk and adjust the therapy for an individual patient.Presented as an invited lecture at the 4th International Symposium: Supportive Care in Cancer, St. Gallen, Switzerland, 24–27 February 1993     

Plasma levels of D-dimer and circulating endothelial adhesion molecules in veno-occlusive disease of the liver following allogeneic bone marrow transplantation

Abstract: Veno-occlusive disease (VOD) of the liver is a frequent and life-threatening complication of BMT. Recently, successful treatment by t-PA has been reported but has been compromised by fatal bleeding events. Therefore, t-PA application should be restricted to patients with severe VOD. However, moderate and severe forms of VOD are difficult to distinguish in early stages. We analyzed plasma levels of cross-linked fibrin degradation products (D-dimer) and soluble endothelial adhesion molecules such as sE-selectin, sVCAM-1 and sICAM-1 in 10 consecutive patients undergoing allogeneic BMT to evaluate their use in identifying severe forms of VOD. During the observation period, 4 episodes of VOD occurred, 2 of which were fatal due to early onset of multiorgan failure. Concentrations of D-dimer generally increased after transplantation. However, there was an additional significant increase in D-dimer levels during severe VOD. Thus, D-dimer levels above 1000 μg/1 were only found in 2 cases with severe VOD and fatal outcome. When compared with bilirubin concentrations substantial increases of D-dimers appeared earlier during the course of severe VOD. In contrast, VOD episodes were not accompanied by significant increases in sE-selectin, sVCAM-1 and sICAM-1 levels. It is concluded that measurement of D-dimer concentrations may aid accuracy to the early diagnosis of severe VOD.     

Potential costs and benefits of newborn screening for severe combined immunodeficiency

OBJECTIVE: Severe combined immunodeficiency (SCID) is a rare, treatable disorder of the immune system. The incidence is unknown but may be more common than published estimates because infants frequently die of infection before diagnosis. SCID is a candidate for universal newborn screening, so there is a need to determine under which circumstances screening would be cost-effective. STUDY DESIGN: We assumed a screening program for SCID would use T-cell lymphopenia as the screening criterion and performed a cost-utility analysis comparing universal screening with screening only those with a family history of SCID. RESULTS: Assuming society is willing to pay $50,000 for every quality-adjusted life-year saved, a SCID screening test that cost less than $5 with a false-negative rate of 0.9% and a false-positive rate of 0.4% would be considered cost-effective. A nationwide screening program would cost an additional $23.9 million per year for screening costs but would result in 760 years of life saved per year of screening. The cost to detect 1 case of SCID would be $485,000. CONCLUSION: SCID screening could result in a large benefit to detected individuals, making screening relatively cost-effective in spite of the low incidence of the disease. However, an adequate test is critical to cost-effectiveness.     

Mutation analysis should be performed to rule out gammac deficiency in children with functional severe combined immune deficiency despite apparently normal immunologic tests

To study the correlation between genotype and phenotype in x-linked SCID, we have characterized the presentation of 2 unrelated patients. Both had infections suggestive of immunodeficiency, but their immune function and lymphoid tissues were normal. They were found to have an identical R222C mutation in the gammac gene.     

Pulmonary function impairment in children following hematopoietic stem cell transplantation

BACKGROUND: Deterioration of pulmonary function after hematopoietic stem cell transplantation (SCT) is a well-known late effect of this treatment, but the course of pulmonary function over time is less clear. The aim of our study was to establish both the prevalence and course of pulmonary function abnormalities in children following SCT. METHODS: Thirty-nine of 106 patients, who visited a post-SCT late effects clinic and who underwent a pulmonary function test (PFT) both before and at least twice after SCT were included in this study. Forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), total lung capacity (TLC), and total lung diffusion capacity (TLCO) were determined and recorded as percentage predicted for age, sex, and length matched controls. Values of less than 80% of predicted were considered abnormal. Change in PFT parameters over time was determined by comparing the mean PFT parameter in our group at three different time points: pre-SCT, < or =1 year post-SCT (SCTpost1) and >1 year post-SCT (SCTpost2). RESULTS: After SCT restrictive and/or diffusion abnormalities are most prevalent (45% and 76% at SCTpost1, respectively). A significant decrease of TLC (-9.7%) and TLCO (-20.3%) was observed during the first year after SCT, with improvement over time, but no normalization. Obstructive lung disease was less common (6% at SCTpost1). Clinical signs of lung function impairment were rare. CONCLUSIONS: Restrictive and diffusion lung function disorders are common after SCT. They improve over time but do not normalize. As only a few patients with pulmonary function abnormalities had clinical signs of lung function impairment, the clinical relevance of performing long-term follow-up of PFT is questionable.     

VEGF disrupts the neonatal blood-brain barrier and increases life span after non-ablative BMT in a murine model of congenital neurodegeneration caused by a lysosomal enzyme deficiency

The course of certain congenital neurodegenerative diseases like lysosomal storage diseases (LSDs) begins shortly after birth and can progress quickly. Ideally, therapeutic interventions for LSDs, which include bone marrow transplantation (BMT), recombinant enzyme replacement, or systemic viral-mediated gene therapy, should be initiated at birth. However, the blood-brain barrier (BBB) remains an obstacle to effective therapy even when these strategies are initiated at birth. We studied whether VEGF, an endothelial cell mitogen and permeability factor, can open the BBB in newborn mice for therapeutic purposes. Intravenous (IV) administration of VEGF at birth increased BBB permeability within 2 h. The increased permeability persisted for at least 24 h, became undetectable 48 h after injection, and was restricted to newborns. Systemic VEGF treatment before BMT or administration of recombinant lentivirus resulted in increased numbers of both donor cells and virus-transduced cells, respectively, in the recipient brain. Administration of VEGF before BMT in newborn mice with a neurodegenerative LSD, globoid-cell leukodystrophy, resulted in a significant increase in life span compared to affected animals that were injected with saline before BMT.     

Analysis of T-cell repertoire and mixed chimaerism in a patient with aplastic anaemia after allogeneic bone marrow transplantation

We analysed 26 T-cell receptor (TCR) beta chain subfamilies (VB) of a patient with aplastic anaemia (AA) who underwent allogeneic bone marrow transplantation (allo-BMT). The patient developed pancytopenia at d 80. The patient's T cells were skewed in 10 of 26 TCR-VB on d 83. These TCR-VB, especially VB15, which were almost entirely CD8-positive cells, were skewed throughout her clinical course. Chimaerism analysis of the CD8-positive cells indicated that they were of recipient origin. Therefore, some immune responses induced by the recipient CD8-positive T cells had an important role in pancytopenia in AA patients after allo-BMT.     

Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide/Bendamustine in Pediatric and Young Adult Patients with Hematologic Malignancies

More than half of patients undergoing hematopoietic cell transplantation at our institution are ethnic or racial minorities, making the search for matched unrelated donors more challenging. Since the introduction of haploidentical bone marrow transplant (haplo-BMT) into our pediatric BMT program in 2015, 69.2% of recipients have been minorities. Herein, we describe our experience with the first 13 pediatric and young adult patients with hematologic malignancies who have undergone T cell–replete haplo-BMT after myeloablative conditioning (MAC) at our institution. We have previously documented that in experimental haplo-BMT, post-transplant bendamustine (PT-BEN) is at least as effective as post-transplant cyclophosphamide (PT-CY) against graft-versus-host disease (GVHD) and elicits superior graft-versus-leukemia (GVL) effects. We report on, for the first time in humans, 4 patients treated with PT-CY and PT-BEN after haplo-BMT as part of our ongoing institutional phase I/II study (NCT02996773). The remaining 9 patients reviewed in this report received PT-CY. Our findings indicate that MAC haplo-BMT is well tolerated by children and young adults with advanced hematologic malignancies with no observed nonrelapse mortality or grades III to IV GVHD. All patients who underwent haplo-BMT remain alive and disease-free with a median follow-up of 15.6 months (range, 1.5 to 31.2). Preliminary findings from our ongoing clinical trial demonstrate that partial substitution of PT-BEN for PT-CY is feasible and safe after haplo-BMT as an immune modulatory strategy to alleviate GVHD and potentially more effectively preserve GVL.