Unrelated Donor Bone Marrow Transplantation Research Articles

Impact of posttransplantation G-CSF on outcomes of allogeneic hematopoietic stem cell transplantation

Granulocyte colony-stimulating factor (G-CSF) is often administered after hematopoietic-cell transplantation (HCT) to accelerate neutrophil recovery, but it is unclear what impact G-CSF has on long-term transplantation outcomes. We analyzed within the database of the Center for International Blood and Marrow Transplant Research the impact of giving posttransplantation G-CSF on the outcomes of allogeneic HCT for acute myelogenous leukemia and chronic myelogenous leukemia in 2719 patients who underwent transplantation between 1995 and 2000. These included 1435 recipients of HLA-identical sibling bone marrow (BM), 609 recipients of HLA-identical peripheral-blood stem cells (PBSCs), and 675 recipients of unrelated donor BM transplants. Outcomes were compared between patients receiving or not receiving G-CSF within 7 days of HCT according to graft type. Median follow-up was more than 30 months (range, 2-87 months). G-CSF shortened the posttransplantation neutropenic period, but did not affect days +30 and +100 treatment-related mortality (TRM). Probabilities of acute and chronic graft-versus-host disease (GVHD), leukemia-free survival (LFS), and overall survival were similar whether or not G-CSF was given. Multivariate analyses confirmed that giving G-CSF did not affect the risk of GVHD, TRM, LFS, or survival. In conclusion, results of this study found no long-term benefit or disadvantage of giving G-CSF after transplantation to promote hematopoietic recovery.

A systematic review and meta analysis of unrelated donor umbilical cord blood transplantation versus unrelated donor bone marrow transplantation in adult and pediatric patients

Several studies have been performed to compare the results of unrelated donor bone marrow transplantation (UBMT) with unrelated donor cord blood transplantation (UCBT). In order to objectively analyze these data, we performed a systematic review and meta analysis of pooled data on comparative studies on unrelated donor BMT versus UCBT to evaluate if UCBT is equivalent to BMT in patients requiring a haematopoietic stem cell transplant. Combining the studies, 161 children and 331 adults undergoing UCBT (mostly 1-2 antigen mismatched), as well as 316 children and 646 adults undergoing UBMT (almost entirely fully matched with the recipient) were analyzed.

Favorable late outcomes following unrelated donor bone marrow transplantation when anti-thymocyte globulin is used as a part of conditioning

Favorable late outcomes following unrelated donor bone marrow transplantation when anti-thymocyte globulin is used as a part of conditioning

Advances in HLA: Practical Implications for Selecting Adult Donors and Cord Blood Units

HLA plays a critical role in hematopoietic cell ransplantation, but a full understanding of this role is onstantly in flux because of changing technologies nd burgeoning amounts of clinical transplantation esults. Today the clinician considering unrelated donor ransplantation must also consider stem cell source: an dult donor or an umbilical cord blood unit (CBU). In he context of cord blood, the task is further compliated by the strong interaction of cell dose. Each individual carries from 10 to 12 genes that ncode the HLA-A, HLA-B, HLA-C, HLA-DR, HLAQ, and HLA-DP molecules. Most of these genes are ighly polymorphic, ranging from 13 (HLA-DRB4) to 99 (HLA-B) alleles at a locus [1]. Most of the allelic ifferences result in changes in the HLA protein seuences, thus producing potential targets for allorecogition [2]. The frequency of alleles differs in different opulations: some are common in most populations, nd others are found predominantly in only 1 or a few opulations. The same is true for HLA haplotypes—the ollection of multiple HLA alleles within a short reion of chromosome 6—which are typically inherited s a single block of genetic information. Table 1 proides examples. DNA-based testing methods provide an accurate nd powerful approach to identify HLA diversity, and hese are replacing serologic testing [3,4]. DNA testng detects specific nucleotide differences that distinuish alleles or sets of alleles. The ability to distinuish among particular alleles at a locus (ie, the esolution) depends on the methodology, the set of ligonucleotide reagents used in the assay, or both. he choice of assay depends on the purpose of the yping, eg, initial testing of newly recruited volunteers r CBUs for a registry (low to intermediate resoluion) compared with testing of transplantation candiates and a few selected potential donors or CBUs high or allele-level resolution). C

A Case of Limbic Encephalitis Developed after Allogeneic Stem Cell Transplantation

Limbic encephalitis is a rare neurological syndrome, which develops after stem cell transplantation, and is characterized by a series of neurological symptoms, including retrograde amnesia, behavioral disturbance, and progressive intellectual deterioration and high signal intensity in the hippocampus on magnetic resonance imaging (MRI). Herein is described the case of a patient with limbic encephalitis, which developed after allogeneic bone marrow transplantation, and was possibly due to HHV-6 infection. An 18-year-old man, with acute lymphoid leukemia, who underwent HLA-matched unrelated donor bone marrow transplantation, developed a fever and chill accompanied by neurological symptoms, including behavioral disturbance and retrograde amnesia, during the bone marrow recovery phase. A brain MRI revealed bright signal-intensity in both hippocampi. Examination of his cerebrospinal fluid suggested viral encephalitis. Based on these findings, a diagnosis of viral limbic encephalitis was highly suspected. Tests for casual causes of viral limbic encephalitis, including the CMV, HZV and HSV-1 and 2, in serum or CSF were all negative. The encephalitis responded well to ganciclovir therapy.

High Disease Burden Is Associated with Poor Outcomes for Patients with Acute Myeloid Leukemia Not in Remission Who Undergo Unrelated Donor Cell Transplantation

Results were analyzed for 48 consecutive patients with acute myeloid leukemia not in remission who underwent unrelated donor bone marrow or stem cell transplantation between 1991 and February 2003 at 2 transplant centers. Forty-six were adults with a median age of 32 years (range, 4-58 years). Forty-two were HLA-A, -B, and -DR matched with their respective donors, and 6 were mismatched at 1 of these loci. The conditioning regimen was myeloablative in all cases: busulfan/cyclophosphamide/etoposide in 34 patients, busulfan/cyclophosphamide in 10 patients, and total body irradiation based in 4 patients. Median follow-up for survivors was 540 days (range, 145-2716 days). Only patients with <5000 peripheral blood blasts per microliter at the time of transplantation survived 2 years (18% versus 0%; P = .003). Similarly, patients with <20% blasts in the marrow at the time of transplantation had superior 2-year survival compared with those who had ≥20% (33% versus 5%; P = .04). Patients with <20% blasts who had ≥3 prior therapies also fared poorly. Cause of death was more commonly treatment related rather than relapse related. This study confirms that patients with acute myeloid leukemia not in remission can achieve prolonged survival with myeloablative conditioning and unrelated donor cell transplantation. However, sustained survival occurs only in patients with a low disease burden at the time of unrelated donor stem cell transplantation, and patients with a high disease burden may benefit from added counseling regarding the high risk of death due to both treatment-related toxicities and disease relapse.

Simultaneous Control of Third-Degree Graft-Versus-Host Disease and Prevention of Recurrence of Juvenile Myelomonocytic Leukemia (JMML) With 6-Mercaptopurine Following Fulminant JMML Relapse Early After KIR Mismatched Bone Marrow Transplantation

The authors describe a young boy with juvenile myelomonocytic leukemia (JMML) who relapsed 45 days after HLA and killer immunoglobulin-like receptor (KIR) mismatched unrelated donor bone marrow transplant (MMUD-BMT) and subsequently developed life-threatening graft-versus-host disease (GvHD). Treatment with 6-mercaptopurine (6-MP) appeared to control severe GvHD and possibly prevented recurrence of leukemic relapse.

Decision-making in adult thalassemia patients undergoing unrelated bone marrow transplantation: quality of life, communication and ethical issues

Bone marrow transplantation (BMT) represents a potentially curative treatment of thalassemia. For patients without an HLA-identical sibling donor, recourse to an unrelated donor is a practicable option but the candidates and their families are faced with a difficult decision. They can either choose to continue the supportive therapy, with no chance of definitive cure, or they accept the mortality risk of BMT in the hope of obtaining a definitive resolution of the disease. We investigated the communication strategies and the post transplantation quality of life (QoL) in 19 adult thalassemia patients surviving after an unrelated donor BMT. The patients were given two questionnaires: a questionnaire to evaluate pre-transplantation communication factors and the EORTC QLQ-C30 questionnaire to assess global QoL. All patients were satisfied with the communication modalities employed by the physicians. The global post transplantation QoL in our patient cohort was found to be good. The approach used in this study may offer a contribution to understanding the decision-making process leading to the choice of a treatment with a high mortality risk for a chronic, non-malignant disease. Finally, some ethical issues of this therapeutic approach are briefly addressed.

SPTBN1-FLT3 in Atypical Chronic Myeloid Leukemia Transforms Ba/F3 Cells to IL-3 Independence and Is Sensitive to Both Tyrosine Kinase Inhibitors and Immunotherapy.

We have identified a patient who presented with BCR-ABL negative chronic myeloid leukemia (CML) and an acquired 46XX, t(2;13;2;21) (p13;q12;q33;q11.2) in all bone marrow metaphases examined. Fluorescence in situ hybridization (FISH) using probes flanking the FLT3 gene at 13q12 suggested that this gene was disrupted. 5′-RACE PCR using primers to the region of FLT3 encoding the tyrosine kinase domain identified a novel in-frame mRNA fusion between exon 3 of SPTBN1 (spectrin, beta, non-erythrocytic 1 isoform 2, NM 178313) on chromosome 2p16 and exon 13 of FLT3 (NM 004119). Juxtaposition of SPTBN1 and FLT3 was confirmed by two color FISH and amplification of the genomic DNA breakpoint confirmed a fusion between intron 3 of SPTBN1 and intron 12 of FLT3. The SPTBN1-FLT3 fusion gene is predicted to be translated into a 570 amino acid chimeric protein that retains two coiled-coil domains from SPTBN1 and 424 amino acids from FLT3, including the entire tyrosine kinase domain. Since the t(2;13) is readily visible by cytogenetic analysis but has not been reported previously it seems likely that SPTBN1-FLT3 is uncommon. However to test if FLT3 might be involved more widely in BCR-ABL negative CML we analysed 40 cases by RT-PCR. Two cases were positive for the FLT3 internal tandem duplication (ITD) but mutation of residue D835 was not observed. Expression of the SPTBN1-FLT3 fusion transformed the interleukin 3 (IL-3)-dependent cell line Ba/F3 to growth factor independence and was accompanied by constitutive phosphorylation of the fusion protein and the downstream substrate ERK1/2. The growth of transformed cells was inhibited in a dose-dependent fashion by SU11567 and PKC142, but not by imatinib mesylate. The patient was initially treated with hydroxyurea and subsequently underwent an unrelated donor bone marrow transplant. She relapsed cytogenetically at 4 years but responded to donor lymphocyte infusion (DLI), achieving sustained cytogenetic and molecular (nested RT-PCR) remission. We conclude that SPTBN1-FLT3 is a rare abnormality in BCR-ABL negative CML that is responsive to both targeted signal transduction therapy and immunotherapy by DLI.

Unrelated Donor Bone Marrow Transplantation for Class I-II Thalassemia Pediatric Patients.

Allogeneic bone marrow transplantation (BMT) is the only treatment potentially able to cure patients with thalassemia major. When the donor is an HLA-identical sibling, the reported probability of survival with transfusion independence for young thalassemia patients at an early stage of disease ranges between 84% and 91%. Unfortunately, at least 70 percent of patients who might benefit from this therapy lack a compatible sibling. Aim of the study was to evaluate whether BMT from an HLA-matched unrelated volunteer can offer children with thalassemia major and limited iron overload a probability of cure comparable to that obtained when the donor is a compatible sibling. Fifty class I-II thalassemia patients (22 females and 28 males, age range 2–17 years, median 8) were transplanted from an unrelated volunteer, selected using stringent criteria of compatibility after high-resolution molecular typing of HLA loci. Twenty-three patients belonged to class I and 27 to class II of the Pesaro classification. All patients received cyclosporine-A (Cs-A) 3 mg/kg/day intravenously from day -2 to day +30 and short-term methotrexate (15 mg/m2 on day +1 and 10 mg/m2 on days +3, +6, +11) for graft-versus-host disease (GVHD) prophylaxis. Cs-A was switched to 6 mg/kg/day orally as soon as oral administration could be tolerated; starting from day +60 the dose was tapered and then discontinued. Twenty-seven out patients who were transplanted in 2 centers were also given anti-thymocyte globulin (3.5 mg/Kg) on days -3 and -2 because of evidence that serotherapy can lessen the risk of GVHD. Four patients were transplanted after a preparative regimen including busulfan (BU, 14 mg/kg) and cyclophosphamide (CY, 200 mg/kg). As 2 of these patients rejected the allograft and this raised concerns about the capacity of this preparative regimen to lead to sustained engraftment, the remaining 46 patients were given a modified conditioning regimen, either adding Thiotepa (TT) (10 mg/kg) to the same BU-CY combination, or employing a myeloablative therapy based on the use of oral BU, TT and fludarabine (160 mg/m2). The median duration of follow-up is 2.9 years (range: 4 months-10 years). Six patients had either primary (4 cases) or secondary (2 cases) graft failure; both these latter patients had sustained donor engraftment after a second allograft from the same donor. Three patients died, one of them due to graft failure. The cumulative incidence of acute GVHD was 33% (CI 22–49%), whereas that of developing chronic GVHD was 12% (CI 2–22%). The overall survival probability was 94% (CI 87–100%), whereas the 5-year Kaplan-Meier estimate of survival with transfusion independence was 88% (CI 78–97). These data indicate that, provided that selection of the donor is based on stringent criteria of HLA-compatibility, the results of transplantation from unrelated volunteers in class I-II thalassemia patients are comparable to those obtained when the donor is a compatible sibling.

Higher Rate of Thrombotic Thrombocytopenic Pupura (TTP) Associated with Graft Versus Host Disease (GVHD) and Unrelated Donor Bone Marrow Transplantation (BMT).

TTP is one of the complications of allogeneic hematopoietic stem cell transplantation (HSCT). In contrast to idiopathic cases, post-transplantation TTP may not be associated with severe von Willebrand factor-cleaving protease deficiency but rather a diffuse endothelial injury. Our aim was to define incidence, risk factors and mortality of TTP following allogeneic HSCT. 1312 patients with lymphoid malignancies (n=605), myeloid malignancies (n=688) or aplastic anemia (AA, n=18) who were treated with ablative preparative regimens (n=614) or reduced intensity regimens (n=697) followed by HSCT from an HLA matched related (MRD, n=694) or unrelated donor (MUD; n=461) and 1–3 antigen mismatched related (MMR, n=99) or unrelated donor (MMUD, n=57) between December 1997 and December 2004 were studied. Patients with prior allogeneic HSCT or graft failure were excluded. GVHD prophylaxis was tacrolimus-based in 1276 (97.3%) and cyclosporine based in 15 (1.1%) patients. Twenty patients did not receive GVHD prophylaxis per protocol. Anti-thymocyte-globulin (ATG) was added in 350 patients. Stem cell sources were bone marrow (n=626), peripheral blood (n=635) or cord blood (n=50).The following variables were evaluated: age, gender, primary diagnosis, disease status before HSCT, intensity of preparative regimen, stem cell source and acute GVHD(aGVHD) grade ≥2 (time dependent variable).Of the 1312 patients with a median follow-up from transplantation of 11.4 months (range, 5 days-7.2 years), 77 developed TTP (6%). The actuarial risk of developing TTP was 6.5% at 1 year. The median time of the onset of TTP was 67 days post HSCT (range, 11–1812) with 27 cases (35%) presenting after day 100. Female gender, lymphoid malignancies, unrelated or antigen mismatched related donor and aGVHD grade ≥2 were found to be independent risk factors. (Table1). Among the patients who had aGVHD grade≥2, the median time of interval between the onsets of two events was 25 days (range, 2–335 days). All patients were treated with therapeutic plasma exchange (PE). Of the 77 patients only 1 died of TTP (intracranial hemorrhage). The overall one-year survival after TTP was 29% and the most common cause of death were acute or chronic GVHD (n=35, 55%) and primary disease progression (n=10, 16%).Stem cell donors other than MRD, lymphoid malignancies and aGVHD≥2 have been established as risk factors associated with development of TTP and therapeutic PE has been shown to decrease TTP related mortality.Risk factors for TTP after allogeneic HSCTVariablessample sizeeventsHR95% CIpMale793331.0Female518442.21.3–3.60.002Myleoid malignancy688331.0Lymphoid malignancy605421.91.1–3.30.03AA1821.30.2–8.00.75MRD694281.0MUD461402.91.6–5.1<0.001MMR9972.40.9–6.00.06MMUD5721.70.4–7.60.5aGVHD ≥2370393.32.0–5.5<0.001

Multiple Transplant-Related Risk Factors for Hemolysis Including Major Kidd-Group Incompatibility Did Not Influence the Favourable Course of Unrelated Donor Bone Marrow Transplantation for Paroxysmal Nocturnal Hemoglobinuria.

The significance of additional transplant-related risk factors for hemolysis, including potentially severe hemolysis due to Kidd group incompatibility, is unknown in BMT from matched unrelated donors (MUD). We report MUD BMT for 35y old male PNH patient (pt) diagnosed 1,5y before, with CD59 defect on 95% of erythrocytes (Er), with refractory hemolysis (LDH 1886 U/l, haptoglobin 0.08 g/l) and IgG autoantibodies on Er, previously treated with steroids and multiple transfusions with increasing frequency. BMT-related risk factors for hemolysis were: major Kidd incompatibility (Jk(b)+ donor and detectable anti-Jk(b) alloantibodies in titer 2 in pt), minor AB0 incompatibility (pt B, donor 0 with anti-B titer 1:16) and different Rh (pt−, donor+). Other risk factors included CMV seronegativity of the donor and seropositivity of the pt, arterial hypertension, steroid-related diabetes mellitus and probable former thrombotic episode leading to nasal septum perforation. MUD was ten alleles HLA-matched 38y old male. Myeloablative conditioning consisted of Treosulfan, Fludarabine and Thymoglobulin. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin-A and methotrexate. Gancyclovir and IgG were used for CMV-reactivation prophylaxis. Transplanted bone marrow was depleted of Er on Fenwall CS3000 plus and contained 0.5x10(8) NC/kg, 2.1x10(6) CD34+ cells/kg and 12.5x10(6) CD3+ cells/kg. No serious complications were observed during the treatment and post-transplant aplasia. Filtered washed Er 0Rh-Jk(b)- were transfused 7x and single-donor platelets 7x. Following 11 days of absolute agranulocytosis full reconstitution of haematopoiesis was achieved with granulocyte count of 1.0x10(9)/l and platelets 50x10(9)/l on day +22, Hb 10 g/dl on day +26. Acute GVHD grade II was transiently present since day +21 and responded well to low-dose methylprednisolone. No chronic GVHD was observed. CMV reactivation with transient severe pancytopenia developed after day +70 and was overcome with ganciclovir, foscarnet and immunoglobulins. Hemolysis gradually decreased (LDH less than 400 U/L since day +5, normal haptoglobin >0.7 g/l since day +38). Anti-Jk(b) alloantibodies titer reached 0 on day +31 and since then they were detectable only with use of a micro-method. Full 100% donor chimerism was achieved on day +28 and was re-confirmed on days +71 and +99. Recipient-type population of erythrocytes gradually decreased (24%, 7% and 1% on days +30, +70 and +98, respectively). Complete eradication of PNH clone was confirmed by absence of complement inhibitor CD55 (DAF) and CD59 (MIRL) defects on 100% of erythrocytes and granulocytes in flow-cytometric evaluation performed on day +160. The patient stays at home without any signs of GVHD, hemolysis nor PNH over 9 months following BMT. We conclude that MUD BMT can be offered as an effective treatment option despite multiple transplant-related risk factors for hemolysis including Kidd group incompatibility.

Alloimmunisation of Patients Undergoing Bone Marrow Transplantation in the Setting of Leucodepleted Apheresis-Collected Single Donor Platelets.

Introduction: Immune platelet transfusion refractoriness often leads to requirements for specialised platelet products. Our patients are screened weekly for the presence of platelet antibodies during bone marrow transplantation (BMT) protocols and are routinely issued leucodepleted (LD) packed red cells and apheresis-collected leucodepleted single donor platelets (LDSDP).Aims: We assessed the alloimmunisation rate in BMT patients, the impact of this on transfusion requirements and addressed the value of continued routine platelet antibody (PAI) screening in the setting of LDSDP.Results: Routine PAI screens performed on 148 BMT patients over 33-months (January 2002–September 2004) were reviewed; 71 autologous, 55 sibling allogeneic and 22 matched unrelated donor (MUD) BMT patients. Thirteen patients were alloimmunised (antibody specificity anti-HLA (11 patients) and anti-HPA/platelet glycoprotein (2 patients)). The overall alloimmunisation rates were 8.8% (sibling allogeneic 14.5%, MUD 9.1% and autologous 4.2%). Alloimmunisation rates for women were 4.15 times higher than for male patients. Risk factors for secondary alloimmunisation were present in 92.3%. Seven of 9 alloimmunised women had children, 1 of 2 nulliparous women and all 4 male patients had extensive transfusion histories (all 5 were also transfused at other centres where LDSDP were not standard). Alloimmunisation was detected earlier in females, usually on first PAI screen and before transfusion. Alloimmunised patients required specialised platelet products (crossmatched, HLA, directed donations or frozen-thawed SDP). These measures resulted in improved post platelet transfusion increments.Conclusions: Alloimmunisation continues to occur despite use of leucodepleted transfusion products. Evidence supporting secondary alloimmunisation was present in the great majority of patients with more female patients alloimmunised largely due to their parity. Secondary alloimmunisation is not prevented by transfusion of leucodepleted blood products, however early detection of alloimmunisation assists transfusion decisions. There is indication from this data that platelet antibody could be limited to a PAI screen at presentation (together with HLA typing) in patients who have been transfused or pregnant with a repeat PAI performed following transfusion. Further testing could be delayed until platelet transfusion refractoriness is suspected.

Non-Myeloablative vs. Conventional Allogeneic Hematopoietic Stem Cell Transplantation for Lymphoma.

Non-myeloablative allogeneic stem cell transplantation (NMT) is increasingly used as an alternative to conventional bone marrow transplantation (BMT). Limited NMT data is available for lymphoma patients (pts). Most series include all hematological malignancies and only a minority with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL). Therefore, we reviewed the Cleveland Clinic BMT Program experience with lymphoma pts and specifically compared the outcome between NMT and BMT. Between July 2, 1985 and December 7, 2004, 67 pts received a matched related (n=47) or unrelated (n=20) donor BMT (n=46) or NMT (n=21) for HL (n=11), aggressive NHL (n=32), indolent NHL (n=23), or unknown NHL (n=1). Pts with lymphoblastic, Burkitt, or atypical Burkitt-like lymphoma were excluded. Compared to BMT pts, NMT pts were older, had longer time from diagnosis to transplant (tx), and were more likely to have a normal LDH and be in remission (CR/PR) at tx. The median follow-up of surviving BMT and NMT pts was 73.8 (range 11.8–106.7) and 20.6 (range 2.8–44.0) months, respectively. 18 (39%) BMT and 5 (24%) NMT pts progressed, and 9 (20%) BMT and 2 (10%) NMT pts died from lymphoma. The incidence of grade 2–4 acute GVHD was not different between the BMT and NMT groups. Among all pts, the risk of lymphoma progression was significantly higher in pts with compared to pts without GVHD (Figure 1). The overall survival for NMT pts was significantly better than for BMT pts (P=.019). Among 15 pts that previously received high dose therapy with autologous stem cell transplant (ASCT), all 7 BMT pts died a median of 1 (range 1–14) month post-BMT while 4/8 NMT pts remained alive 8, 21, 29, and 33 months post-NMT. By multivariate analysis, BMT (HR 7.74, 95% CI 2.49–24.0, P<.001), HL (HR 6.52, 95% CI 2.04-20-85, P=.002), prior ASCT (HR 3.33, 95% CI 1.20–9.25, P=.021), and increasing age by decade (HR 1.7, 95% CI 1.11–2.62, P=0.14) were associated with a significantly higher mortality while CR/PR at tx was associated with a significantly lower mortality (HR 0.44, 95% CI 0.21–0.93, P=.032). Restricting the multivariate analysis to the 56 NHL pts identified no significant independent prognostic factors. Finally, excluding the 15 pts with prior ASCT showed that BMT, >3 prior chemotherapy regimens, tumor >10 cm at diagnosis, older age, and no remission at tx were all associated with a significantly higher mortality. We conclude that: 1) lymphoma progression and lymphoma- or transplant-related death beyond 2 years are uncommon; 2) BMT after failed ASCT is uniformly fatal while NMT (even after failed ASCT) may lead to long-term survival; 3) GVHD (with its presumed graft vs. lymhoma effect) is important for long-term, progression-free survival; 4) compared to BMT, NMT is associated with a better OS (although pt selection may account for some of the observed difference), and 5) both NMT and BMT are appropriate options for selected NHL pts. Whether NMT or BMT offers any benefit compared to ASCT for HL pts is unclear. [Display omitted]

Unrelated donor bone marrow transplantation for β-thalassemia major: an experience from China

Although related bone marrow transplantation (BMT) is effective for thalassemia, less than 30% of patients have sibling donors. Here, we report unrelated BMT in nine thalassemic children using a high-resolution HLA typing technique to identify donors. HLA mismatches between donors and recipients were 0, 1 and 2 in 2, 5 and 2 cases, respectively. The results showed that white blood cells, platelets and hemoglobin all returned to normal at various time points, and blood transfusion was eliminated from 13 to 62 days after transplantation. Full engraftment was achieved in eight patients while ABO blood types were replaced with that of donors in five of the six ABO mismatched recipients. Acute skin GVHD was found in seven patients and acute liver GVHD in one. One patient with acute intestinal GVHD eventually developed chronic GVHD. One patient died of pulmonary hemorrhage in spite of having a fully functional graft. We conclude that this is the first successful application of unrelated BMT for thalassemia major in Chinese people and that the results will certainly expand donor resources and greatly enhance the survival and quality of life of thalassemic patients.

Unrelated donor bone marrow transplantation with treosulfan-based myeloablative conditioning for paroxysmal nocturnal hemoglobinuria- successful treatment despite multiple transplant-related risk factors for hemolysis including major Kidd group incompatibility

Unrelated donor bone marrow transplantation with treosulfan-based myeloablative conditioning for paroxysmal nocturnal hemoglobinuria- successful treatment despite multiple transplant-related risk factors for hemolysis including major Kidd group incompatibility

Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): a multi-centre, randomised phase II–III trial

Graft-versus-host disease (GVHD) reduces the efficacy of unrelated donor bone marrow transplantation in patients with lymphohaemopoietic malignancy. A multi-centre, randomised trial was undertaken to determine the effects of ex-vivo T-cell depletion versus methotrexate and cyclosporine immunosuppression on 3-year disease-free survival. Between Mar 1, 1995, and Oct 31, 2000, 405 patients with lymphohaemopoietic malignancy, from 15 participating centres, were randomly assigned to undergo transplantation with either T-cell depleted marrow and cyclosporine A (TCD arm; n=201) or methotrexate and cyclosporine A after transplantation of T-replete marrow (M/C arm; n=204). The primary outcome was 3-year disease-free survival and was analysed by intention to treat. Five patients died before transplantation. Seven in the TCD arm received T-replete grafts. Disease-free survival at 3 years was 27% (95% CI 21-33) and 34% (27-40) in recipients of TCD and M/C, respectively (p=0.16). TCD was associated with significantly more rapid neutrophil recovery (15 days vs 20 days, p<0.0001), less grade III-IV acute GVHD (18%vs 37%, p<0.0001), reduced grade III-IV toxicities (19%vs 29%, p=0.017), reduced duration of initial hospitalisation, but higher risk of chronic myelogenous leukaemia relapse (20%vs 7%, p=0.009) and cytomegalovirus infection (28%vs 17%, p=0.023) than was M/C. Disease-free survival at 3 years did not differ between TCD and M/C groups. Relapse and opportunistic infection are important obstacles to successful unrelated donor bone marrow transplantation, irrespective of the method of GVHD prophylaxis used.

Successful bone marrow transplantation for life threatening xanthogranuloma disseminatum in neurofibromatosis type‐1

A 2-yr and 9-month-old female patient with neurofibromatosis type-1 presented with hepatomegaly, anemia, thrombocytopenia, and croupy cough and diagnosed with xanthogranuloma disseminatum (XD). She failed chemotherapy consisting of steroids, 6-mercaptopurine and methotrexate. A partial response to HLH-94 therapy that included etoposide and cyclosporine A was initially observed. However, she continued to have significant organ dysfunction without further improvement at 6 months of therapy. She then received matched unrelated donor bone marrow transplantation (BMT) following carmustine, etoposide, cytarabine and melphelan conditioning with complete resolution of symptoms. BMT is an option in therapy-resistant, life threatening XD cases.

Unrelated Donor Marrow Transplantation for B-Cell Chronic Lymphocytic Leukemia After Using Myeloablative Conditioning: Results From the Center for International Blood and Marrow Transplant Research

To determine the role of myeloablative conditioning and unrelated donor (URD) bone marrow transplantation in the treatment of patients with advanced B-cell chronic lymphocytic leukemia (CLL). A total of 38 CLL patients received a matched URD transplant using bone marrow procured by the National Marrow Donor Program. The median age was 45 years (range, 26 to 57 years), the median time from diagnosis was 51 months, and the median number of prior chemotherapy regimens was three. Fifty-five percent of patients were chemotherapy refractory and 89% had received fludarabine. Conditioning included total-body irradiation in 92% of patients. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate with cyclosporine or tacrolimus for 82% of patients. Twenty-one patients (58%) achieved complete response and six (17%) achieved partial response. Incidences of grades 2 to 4 acute GVHD were 45% at 100 days and incidences of chronic GVHD were 85% at 5 years. Eleven patients are alive and disease free at a median of 6 years (range, 3.0 to 9.0 years). Five-year overall survival, failure-free survival, disease progression rates, and treatment-related mortality (TRM) were 33%, 30%, 32%, and 38% respectively. These data demonstrate that lasting remissions can be achieved after URD transplantation in patients with advanced CLL. High TRM suggest that myeloablative conditioning and HLA-mismatched donors should be avoided in future protocols, and it is mandatory to investigate transplant strategies with a lower morbidity and mortality, including the use of nonmyeloablative regimens.

Unrelated donor bone marrow transplantation for 100 pediatric patients: a single institute's experience

In all, 100 unrelated donor bone marrow transplantations (UD-BMT) were performed in our institute between October 1993 and January 2003. Of 93 evaluable patients, 73 patients had hematological malignancy, 13 had nonmalignancy and seven had lymphoproliferative disease. The estimated 9-year event-free survival (EFS) rate was 57.1+/-5.5% in all patients. In the following analyses of the patients with hematological malignancy, the standard group had significantly better EFS than the high-risk group (61.5+/-7.0 vs 35.6+/-9.7%, P=0.02), and the EFS rate of the tacrolimus (FK-506)+methotrexate (MTX)+/-methylprednisolone prophylactic group for graft-versus-host disease was superior to that of the FK-506 without MTX group (75.7+/-8.0 vs 55.8+/-7.6%, P=0.02). When we compared the EFS rates of the FK506+MTX+/-methylprednisolone (mPSL) group and the HLA-matched related donor BMT group in our institute, these were almost similar (75.7+/-8.1 vs 68.4+/-9.3%). Therefore, UD-BMT using FK-506+MTX+/-mPSL is a safe and useful method for children with hematological malignancy who require allogeneic BMT.