Sibling Allogeneic Bone Marrow Transplantation Research Articles

Management of sickle cell disease: outpatient and community aspects

<h2>Abstract</h2> Sickle cell disease (SCD) is the commonest inherited disorder in England, affecting 1 in 2000 births, the majority born in London and of Black African family origins. Newborn bloodspot screening for SCD has now been implemented across the whole of England and this review considers the neonatal screening pathway and aspects of outpatient and community care which should be delivered within the comprehensive care networks. Morbidity and mortality during childhood has declined due to implementation of effective care programmes, which include infection and stroke prophylaxis. Children still suffer from complications of SCD affecting long-term health, quality of life, self esteem, school performance and attainment. Treatment options for long-term control of the disease include hydroxycarbamide, regular transfusion and sibling allogeneic bone marrow transplantation. The indications, evidence of efficacy and adverse effects of these treatments are discussed.

A Successful Second Stem Cell Transplantation in Fanconi Anemia: A Case Report

ObjectiveThe aim was to describe a case of successful second stem cell transplantation in Fanconi anemia (FA). MethodsA 7.5-year-old boy with FA was admitted for stem cell transplantation. The first matched sibling allogeneic bone marrow transplantation was done in January 2005. Until August 2008, the patient's blood count had been decreasing and the patient depended on transfusions, and anti-A Ab was detected (donor blood GP is A RH+). Therefore, the second matched sibling allogeneic peripheral blood stem cell transplantation was performed on November 27, 2008 with anti-thymocyte globulin alone as a second transplant conditioning. ResultThe child has been disease-free for 5 years. ConclusionAnti–thymocyte globulin alone as a second transplant conditioning may give first transplant failure FA patients the opportunity for a long-term disease-free survival.

Management of sickle cell disease: out-patient and community aspects

Sickle Cell Disease (SCD) is the commonest inherited disorder in England, affecting 1 in 2000 births, the majority born in London and of Black African family origins. Newborn bloodspot screening for SCD has now been implemented across the whole of England. This review considers the neonatal screening pathway and aspects of out-patient and community care which should be delivered within comprehensive care networks. Morbidity and mortality during childhood has declined due to implementation of effective care programmes, which include infection and stroke prophylaxis. Children still suffer from complications of SCD affecting long-term health, quality of life, self esteem, school performance and attainment. Treatment options for long-term control of the disease include hydroxycarbamide, regular transfusion and sibling allogeneic bone marrow transplantation. The indications, evidence of efficacy and adverse effects of these treatments are discussed.

Comparative analysis of unrelated cord blood transplantation and HLA-matched sibling hematopoietic stem cell transplantation in children with high-risk or advanced acute leukemia

The aim of this report was to present a clinical comparison of unrelated cord blood transplantation (CBT) and human leukocyte antigen (HLA)-matched sibling allogeneic peripheral blood stem cell or bone marrow transplantation (allo-PBSCT/BMT) in children with high-risk or advanced acute leukemia. A total of 115 consecutive pediatric patients received unrelated CBT (n = 90) or sibling allo-PBSCT/BMT (n = 25) between 2000 and 2012. Neutrophil and platelet recovery were significantly delayed after CBT compared to allo-PBSCT/BMT. There was no difference in the incidence of acute graft-versus-host disease (GVHD) or chronic GVHD between the two groups. The cumulative incidence of transplant-related mortality (TRM) was higher in the CBT group than in the allo-PBSCT/BMT group (32.5 vs 12.8 %) (p = 0.03). The cumulative incidence of relapse was 13.1 % after CBT, which was significantly lower than that of after allo-PBSCT/BMT (45.3 %) (p = 0.015). The overall survival (OS) and leukemia-free survival (LFS) in the CBT group were similar to those of the allo-PBSCT/BMT group; however, for acute myeloid leukemia (AML) patients, the 5-year LFS in the CBT group was slightly better than the allo-PBSCT/BMT group (55.7 % for CBT and 32.7 % for allo-PBSCT/BMT) (p = 0.08). Our comparisons suggest that for high-risk or advanced childhood acute leukemia, unrelated CBT has a higher TRM and similar long-term survival, but better antileukemia effect than HLA-matched sibling PBSCT/BMT. New strategies and better supportive care are required to decrease the TRM of CBT.

Toxic Tacrolimus Levels After Application of Topical Tacrolimus and Use of Occlusive Dressings in Two Bone Marrow Transplant Recipients with Cutaneous Graft‐versus‐Host Disease

Tacrolimus, a macrolide immunosuppressant, is used topically for the treatment of cutaneous manifestations of graft-versus-host disease (GVHD) for rapid, symptomatic relief of pruritus and erythema. Despite the manufacturer's product information reporting minimal systemic effects of topical tacrolimus, this has not been evaluated in patients with cutaneous GVHD and with occlusive dressings. We describe two patients with cutaneous GVHD who developed toxic tacrolimus levels after receiving several applications of tacrolimus ointment along with occlusive dressings to enhance skin effectiveness. The first patient was a 62-year-old woman with a history of acute myelogenous leukemia (AML) who underwent allogeneic bone marrow transplantation and developed chronic GVHD involving 70% of her body surface area. Her GVHD treatment plan consisted of oral corticosteroids, oral tacrolimus, topical corticosteroids, topical tacrolimus 0.1% ointment twice/day, emollient creams, intravenous rituximab, and photopheresis. The patient's tacrolimus trough levels rose rapidly over the course of 6 days from less than 2 ng/ml to 23 ng/ml, despite oral tacrolimus dosage adjustments. The second patient was a 25-year-old man who developed severe, chronic skin GVHD after undergoing allogeneic sibling bone marrow transplantation for AML. In addition to intravenous corticosteroids, corticosteroid creams, and oral tacrolimus, the patient also received topical tacrolimus twice/day with occlusive dressings. Over the course of 2 days, his tacrolimus trough levels increased from 7.10 ng/ml to 22.10 ng/ml. Although improvement was noted in both patients' skin GVHD with application of the occlusive dressings, the practice was discontinued due to increased and erratic systemic tacrolimus absorption. These case reports suggest that substantial use of topical tacrolimus with occlusive dressings in patients with cutaneous GVHD may contribute to increased systemic absorption resulting in toxic tacrolimus levels. Based on the findings from our two patients as well as published case reports, systemic absorption appears to increase with greater skin permeability, skin barrier dysfunction, amount of body surface area applied, and use of occlusive dressings. When one or more of these factors are present, it may be prudent to monitor tacrolimus levels.

Comparison of Unrelated Cord Blood Transplantation and HLA-Matched Sibling Hematopoietic Stem Cell Transplantation for Patients with Chronic Myeloid Leukemia in Advanced Stage

This is the first report to present a clinical comparison of unrelated cord blood transplantation (CBT) and HLA-matched sibling allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia (CML) in advanced stage (accelerated phase or blast crisis). A total of 32 consecutive patients with advanced CML received unrelated CBT (n = 16) or HLA-matched sibling allogeneic peripheral blood stem cell or bone marrow transplantation (allo-PBSCT/BMT) (n = 16) between 2002 and 2011. The median day to neutrophil engraftment and the median day to platelet engraftment were longer in the unrelated CBT group. The cumulative incidence of grades 1 to 2 acute graft-versus-host disease (aGVHD), grades 3 to 4 aGVHD, and chronic graft-versus-host disease did not differ significantly between the 2 cohorts. The cumulative incidence of transplantation-related mortality (TRM) at day +180 was higher in CBT group (37.5% versus 12.5%, P = .013). The risk of relapse was lower in CBT patients compared with that of allo-PBSCT/BMT patients (14.2% versus 42.7%, P = .03). The long-term survival in CBT group patients was slightly better than that of allo-PBSCT/BMT group, although the difference did not reach statistical significance: the 5-year overall survival for CBT patients and allo-PBSCT/BMT patients was 62.5% and 48.6%, respectively (P = .10), whereas the 5-year leukemia-free-survival rate was 50% and 40.5%, respectively (P = .12). Our comparisons suggest that patients with advanced CML receiving unrelated CBT had a lower relapse rate, a slightly better long-term survival, but a higher early TRM than those receiving HLA-matched related allo-PBSCT/BMT.

Rapid Recovery of CD4 Counts Following Low Dose Alemtuzumab Conditioning During HLA Matched Related Bone Marrow Transplant for Children with Haemoglobinopathies

AbstractAbstract 2335CMV viraemia and disease remains a major cause of morbidity and mortality following allogeneic bone marrow transplantation (BMT). We investigated the impact of low dose alemtuzumab conditioning in paediatric matched sibling allogeneic BMT for haemoglobinopathy on immune reconstitution (early and late CD3/4+, CD3/8+, CD3-/CD56+ cell recovery) and subsequent viral infections in 18 consecutive transplants (14 β thalassaemia major and 4 sickle cell anaemia). A secondary aim was to investigate the impact of immune reconstitution on graft versus host disease but due to the extremely low incidence of acute and chronic graft versus host disease with this protocol (acute grade II to IV 11.6% and chronic 4.6%) we were unable to assess this. Transplant protocol: following hypertransfusion to suppress endogenous haemopoiesis, patients were conditioned with oral busulfan 14 mg/kg (days -9 to -6), cyclophosphamide 200 mg/kg (days -5 to -2) and alemtuzumab 0.3 mg/kg (days -8 to -6). Graft versus host disease prophylaxis was provided with ciclosporin for six months and methotrexate 10 mg/m2 on days +4 and +7. All transplants used BM as source of stem cells. CMV PCR surveillance was undertaken twice weekly and CMV reactivation was treated with intravenous foscarnet or ganciclovir, followed by secondary prophylaxis with valganciclovir. Routine peripheral blood immunophenotyping of lymphocyte subsets was performed at 60-, 90-, 120-, 150- and 180- days post-BMT. Results:the median age of transplant recipients was 7 years (range 2 – 17 years) and median follow up 254 days (range 203–378). The median CD3/CD4+ cell count rose above 200 cells/μl by day 180 and above 300 cells/μl by day 254 following the withdrawal of immune suppression at six months (fig 1A), the median CD8+ cell count increased earlier, to >200 cells/μl by day 60 and 300 cells/μl by day 180 (fig 1B) and the median CD56+ cell count reached 200 cells/μl by day 60 and plateaued thereafter (fig 1C). Overall, CMV reactivation occurred in 13 patients (72.2%) after a median interval of 35 days following BM infusion (range day-1 to day +72): 10/13 patients (76.9%) in whom both recipient and donor were CMV positive (CMV +/+); 1/3 patients in whom recipient was CMV negative and donor CMV positive (CMV -/+); and in 1/1 who was CMV positive with a CMV negative donor (CMV +/−). Significantly there was no clinical CMV disease in any patient and with the use of oral valganciclovir there were no subsequent CMV reactivations. CMV reactivation occurred in patients with lower CD4+ cell counts at day 60 (67 cells/μl) compared with the CMV-unaffected group (a median CD4+ count 298 cells/μl; p= 0.0262). Four patients experienced other viral infections: HHV6 infection requiring foscarnet on day +85 (n=1), urinary BK virus not requiring treatment (n=2) and parainfluenza pneumonitis requiring ribavarin on day +12 (n=1). Conclusion:Low dose alemtuzumab conditioning is associated with rapid CD4+ cell recovery (CD4+ >200 cells/μl by day +180) in children undergoing allogeneic matched related donor BMT for haemoglobinopathy. Although there is a high frequency of CMV reactivation (72.2%) in patients with low CD4+ counts at day 60 (median CD4+ count 67 cells/μl), no clinical CMV disease was seen and subsequent reactivations of CMV were prevented by the use of valganciclovir secondary prophylaxis whilst awaiting full immune reconstitution. [Display omitted] [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Platform Presentations: Abstracts 101–153

Sickle Cell Disease (SCD) is the commonest inherited disorder in England, affecting 1 in 2000 births, the majority born in London and of Black African family origins. Newborn bloodspot screening for SCD has now been implemented across the whole of England. This review considers the neonatal screening pathway and aspects of out-patient and community care which should be delivered within comprehensive care networks. Morbidity and mortality during childhood has declined due to implementation of effective care programmes, which include infection and stroke prophylaxis. Children still suffer from complications of SCD affecting long-term health, quality of life, self esteem, school performance and attainment. Treatment options for long-term control of the disease include hydroxycarbamide, regular transfusion and sibling allogeneic bone marrow transplantation. The indications, evidence of efficacy and adverse effects of these treatments are discussed.

Congenital JAK2 V617F Polycythaemia Vera Cured with Sibling Allogeneic Bone Marrow Transplantation

Polycythaemia vera (PV) is extremely rare in young children. The Janus Kinase 2 V617F mutation is present in 95 % of adult PV patients. Testing is now widely available and has simplified the diagnostic workup. A previously healthy 7 month old girl was admitted to her local hospital with tonsillitis. Full blood count showed polycythaemia (Hb 19 g/dl) along with an elevated platelet (946 ×109/L) and white cell count (19.7 ×109/L). Oxygen saturations, arterial blood gases, chest x-ray, abdominal ultrasound and P50 were all normal. Serum erythropoietin was low. No mutations were identified in exons 7 and 8 of the EPO receptor gene, the Von Hipple Lindau tumour suppressor gene and the Prolyl hydroxylase domain 2 gene. Bone marrow aspirate and biopsy were showed hypercellularity, megakaryocyte hyperplasia and clustering along with erythroid hyperplasia. Cytogenetic analysis was normal. Spontaneous erythroid colonies were demonstrated. The JAK2 V617F mutation was found by polymerase chain reaction in her blood and in her Guthrie card taken at 2 days of age. Both parents and two of her siblings had normal full blood counts. Two further siblings have not had full blood counts. There is no known family history of myeloproliferative disorders. The JAK2 V617F mutation was not detected in the peripheral blood or the oral mucosa of either parent or in the oral mucosa of the patient. She was treated with regular venesection and aspirin 45mg OD was started when her platelet count rose above 1,500 × 109/L. Her clinical course and laboratory parameters remained stable with this treatment and no thromboembolic complications occurred. Due to the long term risks of malignant transformation and thromboembolism a sibling allogeneic bone marrow transplantation was performed with her 6 year old brother as a fully HLA matched, JAK2 V617F negative donor with a normal full blood count. A total nucleated count of 13 ×108 per kg recipient body weight, bone marrow was infused. The conditioning regimen was busulphan (4mg/kg/day × 5 days) and cyclophosphamide (50mg/kg/day × 4 days). Neutrophils rose to 2.6 ×109/L by day 24. No venous occlusive disease or graft versus host disease occurred. Complete donor chimerism and undetectable JAK2 V617F mutation have been observed from day + 14 to present. She remains in remission 15 months post transplant. She now has a normal full blood count and has not suffered any adverse sequelae. To the best of our knowledge this is the first report of prenatal JAK2 V617F PV. It further highlights the genotype-phenotype diversity that is seen amongst this group of JAK2 V617F positive myeloproliferative neoplasms. The frequency of the mutation in pediatric PV has been variably reported in the literature but this report proves that it can occur at all ages. The absence of the mutation in either parent or the oral mucosa of the child shows that this was likely an acquired somatic event that occurred in utero. The JAK2 V617F mutation is thought to be acquired in both familial and sporadic MPD. In a study of 22 families with PV the mutation was present in variable amounts in affected members and absent in unaffected members. Analysis of another single large family with PV showed the presence of JAK2 V617F in affected family members but not in an obligate carrier. This suggests that other genetic abnormalities, possibly inherited, precede the acquisition of the JAK2 V617F mutation. Inheritance of as yet unknown germline mutations may have predisposed towards the in utero acquisition of the somatic JAK2 V617F mutation in our particular case.Young children with PV face a considerable lifetime risk of arterial and venous thrombosis and of malignant transformation. Hemopoetic stem cell transplantation normalises the full blood count and eradicates the pre malignant clone thereby reducing these risks and should be considered early if a suitable donor is available.

The influence of cyclosporin alone, or cyclosporin and methotrexate, on the incidence of mixed haematopoietic chimaerism following allogeneic sibling bone marrow transplantation for severe aplastic anaemia

We previously reported a randomized trial comparing Cyclosporin-A (CsA) and short-term methotrexate versus CsA alone for graft-versus-host disease (GvHD) prophylaxis in 71 patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) from a human leucocyte antigen-identical sibling for severe aplastic anaemia (SAA). We found a better survival in the group receiving the two-drug prophylaxis regimen with no significant difference in the probability of developing GvHD between the two groups. The present study details chimaeric analysis and its influence on survival and GvHD occurrence in 45 of the original 71 patients in whom serial samples were available. Analysis was carried out in a blinded prospective manner. Seventy-two per cent achieved complete donor chimaerism (DC), 11% stable mixed chimaerism (SMC) and 17% progressive mixed chimaerism (PMC). The overall 5-year survival probability was 82% (+/-11%) with a significant survival advantage (P = 0.0009) in DC or SMC compared to those with PMC. Chronic GvHD was more frequent in DC patients, whereas no patient with SMC developed chronic GvHD. Graft failure occurred in 50% of the PMC group. This study demonstrates the relevance of chimaerism analysis in patients receiving HSCT for SAA and confirms the occurrence of mixed chimaerism in a significant proportion of recipients.

Marrow aplasia developing 13 years after HLA‐identical sibling allogeneic transplantation for chronic myeloid leukaemia: successful treatment with antithymocyte globulin and peripheral blood stem cell infusion from the original donor

Secondary or late graft failure has been defined as the development of inadequate marrow function after initial engraftment has been achieved. We describe a case of profound marrow aplasia occurring 13 years after sibling allogeneic bone marrow transplantation for chronic myeloid leukaemia (CML) in first chronic phase. Although the patient remained a complete donor chimera, thereby suggesting that an unselected infusion of donor peripheral blood stem cells (PBSC) or bone marrow might be indicated, the newly acquired aplasia was thought to be immune in aetiology and some immunosuppression was therefore considered appropriate. Rapid haematological recovery was achieved after the infusion of unselected PBSC from the original donor following conditioning with anti-thymocyte globulin (ATG).

Hematologic Recovery and Clinical Outcomes according to Cell Dose after HLA-matched Sibling Allogeneic Bone Marrow Transplantation

Hematologic Recovery and Clinical Outcomes according to Cell Dose after HLA-matched Sibling Allogeneic Bone Marrow Transplantation

Polymorphisms of interleukin-1alpha constitute independent risk factors for chronic graft-versus-host disease after allogeneic bone marrow transplantation.

The interleukin-1 (IL-1) family of cytokines is widely involved in inflammatory processes and diseases with an inflammatory component. Polymorphisms of the IL-1alpha, IL-1beta and IL-1Ra genes have been implicated in a number of autoimmune or inflammatory conditions, with polymorphism of the IL-1Ra gene showing association with severity of graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). We compared the clinical outcomes (GVHD and survival) of 115 patients after human leucocyte antigen (HLA)-identical sibling allogeneic BMT with their genotype for two polymorphisms present in the IL-1alpha gene, which have been implicated in immune-related pathology. Possession of allele 2 of the IL-1alpha-889 polymorphism and allele 2 of the IL-1alpha variable number tandem repeat (VNTR) polymorphism in the donor genotype was associated with the occurrence of chronic, but not acute GVHD. A local normal population was also genotyped for these polymorphisms, and subsequent analysis identified conserved haplotypes in this gene region. Haplotypes containing allele 2 at both IL-1alpha-889 and IL-1alpha VNTR loci were extremely uncommon, suggesting that both risk alleles would be inherited independently. Both loci could therefore function as independent disease association markers. The polymorphisms of the IL-1alpha gene could be used to predict chronic GVHD in HLA-matched sibling transplants alongside clinical risk factors.

Vitamin D receptor gene polymorphism associates with graft-versus-host disease and survival in HLA-matched sibling allogeneic bone marrow transplantation.

We investigated the role of polymorphism of the vitamin D receptor (VDR) gene in HLA-matched sibling BMT for polymorphisms previously associated with human disease pathology. In intron 8 of the VDR gene, the B and A alleles of the BsmI and ApaI RFLPs were found to associate with reduced aGVHD when present in the patient's genotype. Logistic regression analysis demonstrated that patient VDR genotype, along with previously identified IL-10(-1064) and IFN-gamma genotype to be risk factors for severe acute GVHD. The A allele also associates with increased likelihood of death when present in the donor genotype (AA vs Aa or aa, hazard ratio 2.03, P = 0.0232). In patients who received increased prophylaxis with multi-agent therapy, patients whose graft was from a donor with an AA genotype had a substantially worse survival than patients whose graft was from a donor with a non-AA genotype (hazard ratio 12.93, P < 0.0001). Analysis of VDR genotype in prospective BMT recipients could indicate patients at risk of severe aGVHD. Analysis of VDR genotype in prospective BMT donors may identify individuals who have greater transplant-related mortality, and also allow appropriately restricted use of increased immunosuppressive prophylaxis.

Rapid identification of minor histocompatibility antigen HA-1 subtypes H and R using fluorescence-labeled oligonucleotides.

Donor-recipient disparitiy of the minor histocompatibility antigen HA-1 is relevant for the development of graft-versus-host disease after HLA-matched sibling allogeneic bone marrow transplantation in HLA-A*0201-positive individuals. Two different alleles of HA-1 with a single amino acid polymorphism have been identified. Here we describe a time- and cost-efficient method for HA-1 typing of genomic DNA, using site-specific hybridization probes with the LightCycler. This method was compared with standard techniques as sequencing or allele-specific polymerase chain reaction (PCR) and proved to be specific, reliable and reproducible. We conclude that HA-1-subtyping using fluorescent-labeled oligonucleotides represents a attractive method for the screening of samples before allogeneic transplantation in HLA-A*0201-positive individuals.

Allogeneic bone marrow transplantation for agnogenic myeloid metaplasia. French Society of Bone Marrow Transplantation.

Agnogenic myeloid metaplasia is a rare indication for allogeneic bone marrow transplantation (BMT). We have retrospectively studied 12 patients allografted for this disease within the French BMT group. Prior to BMT, the mean age was 40 years (range 14-49). Diagnosis was based on the Polycythaemia Vera Study Group criteria. Before BMT, 10 patients had been splenectomized, eight required transfusions, and four had received at least two lines of chemotherapy. Cyclophosphamide and total body irradiation was the main conditioning regimen used (n=8). The donor was an HLA-identical sibling except in one case where there was one HLA-DR mismatch. Acute graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate and cyclosporine A. 11 patients engrafted with median times to achieve absolute neutrophil count > 0.5 x 10(9)/l and platelet count > 50 x 10(9)/l of 17 (range 12-44) and 29 (range 12-196) days respectively. One primary graft failure occurred. 10 patients developed grade II-IV acute GVHD, four developed extensive chronic GVHD. One patient relapsed 16 months post-BMT and was untreated and well 14 months later. Three patients died from the BMT procedure. In May 1996 the median follow-up was 25 months and the 4-year overall and event-free survivals were 71% and 59%, respectively. Thus, we conclude that extensive myelofibrosis is not associated with delayed engraftment, and that HLA-identical sibling allogeneic BMT can be considered in a small proportion of patients with agnogenic myeloid metaplasia.

PREVENTION OF INFECTIONS IN BONE MARROW TRANSPLANT RECIPIENTS

Bone marrow transplantation (BMT) is increasingly used in the treatment of hematologic malignancies, solid tumors, and congenital diseases. The number of patients receiving a BMT increased from approximately 5000 in 1989 to 12,000 in 1995. Infectious complications are the most common cause of morbidity and mortality in the peritransplant period in patients undergoing autologous BMT. Additionally, infectious complications are a serious cause of complications in recipients of matched sibling allogeneic BMT, unrelated BMT, and related mismatched BMT.

Unrelated donor bone marrow transplantation for children with relapsed acute lymphoblastic leukaemia in second complete remission.

Allogeneic sibling bone marrow transplantation (BMT) is the recommended treatment for relapsed childhood acute lymphoblastic leukaemia (ALL), but appropriate donors are only available in 30% of cases. Unfortunately, BMT from unrelated donors (UD) has been associated with high rates of severe graft-versus-host disease (GvHD) and transplant-related mortality (TRM). In an attempt to improve outcome in UD-BMT we have assessed the impact of T-cell depletion using CAMPATH-1 (anti-CD52) monoclonal antibodies in 50 consecutively referred patients with relapsed ALL in second remission. All were previously treated according to MRC protocols UKALL X and XI, and then given chemotherapy on MRC R1 from relapse until UD-BMT, 19 patients had relapsed on and 31 off therapy. Patients and donors were fully matched at HLA-A, -B, -DR and -DQ loci in 29 cases and mismatched in 21 (four mismatched for more than one antigen). Pre-transplant conditioning comprised CAMPATH-1G, cyclophosphamide and total body irradiation. Bone marrow was T-cell depleted in vitro using CAMPATH-1 antibodies. Additional GvHD prophylaxis consisted of cyclosporin A (42 cases), cyclosporin plus methotrexate (four) or none (four). 47 patients engrafted. The incidence of acute GvHD was very low: two patients with grade II disease in the matched group, four with grade II-IV in the mismatched group. Only four patients have chronic GvHD. The actuarial event-free survival (EFS) at 2 years is 53%, with no significant difference between the matched and mismatched group. Further leukaemic relapse was the most important cause of failure. These results are similar to the most favourable published reports for HLA-matched sibling BMT in relapsed ALL.

Donor leukocyte infusions in the treatment of chronic myeloid leukemia in relapse post bone marrow transplantation

A 25-yr-old Caucasian man presented in 1988 with Philadelphia chromosome (Ph) negative, bcr-abl rearranged, chronic phase chronic myeloid leukemia (CML). He was treated with human leukocyte antigen matched sibling allogeneic bone marrow transplantation but relapsed 5 yrs later. At this time he was given donor leukocyte infusions from the original bone marrow donor, seeking an immune anti-leukemic effect. This treatment induced graft versus host disease and severe bone marrow aplasia, requiring immunosuppression and repeat donor marrow infusion (without prior conditioning). Graft versus host disease was controlled and full donor hematopoiesis was restored, resulting in complete eradication of the leukemic clone at a molecular level. The patient remains in complete clinical and molecular remission and off all immunosuppression 24 mths later. This emphasizes a potentially powerful graft versus leukemia effect in CML.

27-Year-Old Woman With Pancytopenia

A 27-year-old woman had a 4-week history of progressive dyspnea on exertion, palpitations, light-headedness during activity, and frontal headache. She denied having fever, cough, chest pain, or vertigo. Hematologic studies showed a hemoglobin concentration of 5.0 g/dL, a mean corpuscular volume of 102.9 fL, a total leukocyte count of 4.3 x 109/L (differential: neutrophils, 1.35 x 109; lymphocytes, 2.54 x 109; mononuclear cells, 0.39 x 109; eosinophils, 0.01 X 109; and basophils, 0.01 X 109),and a platelet count of 115 X 109/ L. She was hospitalized for further assessment. The patient's past medical history was remarkable for a chronic generalized seizure disorder; the last tonic-clonic seizure had occurred 3 months before the current admission. She experienced absence seizures daily. One episode of streptococcal pharyngitis was treated with orally administered penicillin 4 months before the current examination. Medications included valproic acid, 1 g/day in divided doses (a regimen that had been used for 7 years), and felbamate, 1,200 mg three times daily (therapy that had been initiated 7 months before hospitalization). She used nonprescription aspirin preparations for headaches. The patient had no family history of hematologic disorders, and a complete blood cell count performed 8 months previously had shown normal results. Menses were normal, and no other overt source of blood loss was identified. The patient had never received chemotherapy or radiation treatment, and no exposure to toxins was elicited. Physical examination revealed a resting tachycardia of 110 beats/min and a normal blood pressure, respiratory rate, and temperature. Pallor was noted. A grade 2 (on the basis of 1 to 6) systolic murmur was heard over the precordium. No adenopathy, splenomegaly, or neurologic deficit was detected. Two painless ecchymoses, each less than 5 em in diameter, were seen over the left deltoid muscle and anterior aspect of the thigh. On admission, an electrolyte panel, liver