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Results for “National Marrow Donor Program”

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PubMed1996

Large-scale DRB and DQB1 oligonucleotide typing for the NMDP registry: progress report from year 2.

DNA typing of HLA class II alleles of the DRB1/3/4/5 and DQB1 loci using sequence-specific oligonucleotide probes and polymerase chain reaction amplified DNA has been used for the large-scale typing of donors for the National Marrow Donor Program unrelated donor registry. The results of quality control analysis for the second year of the project (10/1/939/30/94) show the typing continues to be highly accurate, specific, and reliable. The average percent of correctly classified HLA oligotypes (groups of alleles defined by a hybridization pattern with a panel of sequence-specific oligonucleotide probes) based on 9,244 DRB1 and 7,244 DQB1 assignments was 99.8% (range 99.4%100.0%) for DRB1/DRB3/DRB4/DRB5 and 99.8% (range 99.6%100.0%) for DQB1. This level of accuracy is particularly remarkable because the 4,636 DRB quality control samples were tested blindly and could not be distinguished from 57,580 donor samples tested at the same time by the laboratories.

Alleles↗

PubMed1997

Analysis of HLA-A and -B serologic typing of bone marrow registry donors using polymerase chain reaction with sequence-specific oligonucleotide probes and DNA sequencing.

Unrelated volunteer donors (69) recruited by the National Marrow Donor Program were HLA typed by DNA-based methods for both the HLA-A and -B loci. Each donor had been previously typed by serology by at least two independent laboratories. Of the 69 samples, all serologic laboratories were in concordance for HLA-A in 62 typed samples and for HLA-B in 48 typed samples. Of the serologically concordant samples, 5 samples typed for HLA-A and 7 samples typed for HLA-B received DNA and serology types differing in their level of resolution. One sample typed for HLA-A and 3 samples typed for HLA-B by DNA methods gave different results from their serologic assignments. Of the samples exhibiting disparities among the different serologic typing laboratories, the DNA-defined types of 7 samples typed for HLA-A and 18 samples typed for HLA-B were consistent with at least one of the serologic assignments. The DNA types for the remaining 3 HLA-B typed samples did not agree with the serologic assignments and their alleles were subsequently sequenced. One of these sequences was a previously undefined allele, B*1537. Sharing of polymorphic sequences among HLA allelic products creates difficulties for consistent serologic assignments of some types complicating the process of identifying potential donors from bone marrow registries. Thus, the use of DNA-based typing techniques for characterization of donor class I types should allow a more consistent definition of types and should speed the donor selection process.

Bone Marrow Transplantation↗

PubMed1997

Accurate typing of HLA-A antigens and analysis of serological deficiencies.

We are reporting the results of HLA-A typing by PCR-SSOP complemented by PCR-SSP of samples obtained from the National Marrow Donor Program (NMDP). These samples were a representative group from 2486 tested in duplicate by serology. A total of 390 samples gave HLA-A discrepant results. Comparing the molecular typing results of 238 samples (samples with available DNA) with the serological typing results, 54 homozygotes and 184 heterozygotes produced a total of 422 assignments by molecular methods. We found assignment discrepancies in 147/422 (35%) in laboratory 1 and 144/422 (34%) in laboratory 2 (a combined group of 4 NMDP laboratories; laboratory 1 is not included). The serological discrepancies found were of 3 categories: a) false negatives, b) incomplete typing (discrepancies due to the level of resolution within a cross-reactive or CREG group) and c) false positives. Major problems were identified using serology for typing HLA-A antigens: a) inability to identify all WHO-recognized specificities, more frequently in non-Caucasians or in HLA-A specificities known to be found more frequently in non-Caucasians for laboratory 1 and incorrect assignments of A19 specificities in laboratory 2, b) incorrect assignments in cells with poor viability and c) false-positive assignments in homozygotes. We propose a possible strategy to type HLA-A specificities with two steps: a) a minimum of serology for typing specificities for common CREG groups: A1, A2, A3, A11, A9, A10, A28, A19. However, a given laboratory can determine the level of serological assignments needed as a first step. And b) molecular methods to identify splits: A23, A24, A29, A30, A31, A32, A33, A34, A36, A66, A74 and A80. The technique described is useful for large-scale bone marrow donor typings for cells with poor viability, and for resolving ambiguous results including false-positive assignments of homozygous cells.

DNA↗

PubMed2004

HLA-Cw1214 allele arisen via recombination between HLA-Cw070201 and HLA-Cw*120201.

Allelic polymorphism of the major histocompatibility complex arises mostly from gene conversion. Intralocus gene conversion usually involves limited fragments of DNA, whereas recombination involving large fragments of DNA is considered to be a rare event. During routine sequencing-based typing of donors for the National Marrow Donor Program, a new HLA-C allele was identified in a Caucasian donor. The allele, HLA-Cw*1214, proved to be the product of recombination between HLA-Cw*070201 and HLA-Cw*120201. Exons 1, 2, the 3' end of exon 3 and exon 4 (with one mismatch) belong to HLA-Cw*120201, whereas part of exon 3 belongs to HLA-Cw*070201. Sequencing with primers based in exon 2 and exon 3 showed that intron 2 of the new allele also belonged completely to HLA-Cw*1202. The recombination event apparently occurred within exon 3 with the first point of recombination somewhere between codons 92 and 134 and the second one between codons 157 and 181.

Alleles↗

PubMed2005

Emerging new alleles suggest high diversity of HLA-C locus.

Human leukocyte antigen (HLA)-C has only recently emerged as an important transplantation antigen and as a receptor for natural killer cells. Over the last few years, sequence-based typing (SBT) revealed the true diversity of HLA-C locus; however, the frequency at which new alleles are detected still remains high. During routine SBT of 3500 samples for the National Marrow Donor Program, we have identified 20 new HLA-C alleles reported in this article in 26 individuals. New variants have been characterized by direct sequencing of polymerase chain reaction product obtained by allele-specific amplification of potential new alleles. Most of the new alleles carry coding substitutions of residues located within the antigen-binding groove. The substitutions are predominantly located in the alpha2-helix which is consistent with the unique to HLA-C conservation of alpha1-helix. Seven new alleles, or 35%, have been identified in African Americans, two of them in three and four individuals each, suggesting that these alleles may not be rare. This observation reflects the fact that the minority groups, previously under-represented in the HLA research pools subjected to SBT, now begin to emerge as a main source of new HLA-C alleles. This study further confirms that HLA-C locus is at least as polymorphic as HLA-A and HLA-B.

Alleles↗

PubMed2005

The recombinant HLA-B*5518 allele supports the evidence of conserved haplotype association of rare alleles.

Allelic polymorphism of the major histocompatibility complex arises mostly from gene recombination. Intralocus gene recombination usually involves short fragments of DNA leading most commonly to single-nucleotide substitutions and rarely involves large fragments. Here, we report a new recombinant human leukocyte antigen (HLA)-B*5518 allele that has arisen via recombination of a large fragment of DNA spanning more than 70 nucleotides. During routine HLA typing of potential volunteer donors for the National Marrow Donor Program((R)), a new HLA-B allele was identified in two donors from Guam. The allele, B*5518, appears to be a product of recombination between B*5502 and B*40. Exons 1, 3, and 4 of the new allele belong to B*5502, whereas part of exon 2 belongs to one of B*40 alleles. Introns 1 and 2 appear to belong to B*55, suggesting that the recombination event may have occurred within the homologous parts of exon 2.

Alleles↗

PubMed2005

The HLA Dictionary 2004: a summary of HLA-A, -B, -C, -DRB1/3/4/5 and -DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR and -DQ antigens.

This report presents serological equivalents of HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5 and -DQB1 alleles. The dictionary is an update of that published in 2001. The data summarize equivalents obtained by the World Health Organization Nomenclature Committee for Factors of the HLA System, the International Cell Exchange (UCLA), the National Marrow Donor Program (NMDP), recent publications and individual laboratories. This latest update of the dictionary is enhanced by the inclusion of results from studies performed during the 13th International Histocompatibility Workshop and from neural network analyses. A summary of the data as recommended serological equivalents is presented as expert assigned types. The tables include remarks for alleles, which are or may be expressed as antigens with serological reaction patterns that differ from the well-established HLA specificities. The equivalents provided will be useful in guiding searches for unrelated haematopoietic stem cell donors in which patients and/or potential donors are typed by either serology or DNA-based methods. The serological DNA equivalent dictionary will also aid in typing and matching procedures for organ transplant programmes whose waiting lists of potential donors and recipients comprise mixtures of serological and DNA-based typings. The tables with HLA equivalents and a questionnaire for submission of serological reaction patterns for poorly identified allelic products will be made available through the WMDA web page (http://www.worldmarrow.org) and, in the near future, also in a searchable form on the IMGT/HLA database.

Alleles↗

PubMed2005

KIR reconstitution is altered by T cells in the graft and correlates with clinical outcomes after unrelated donor transplantation.

Although unrelated hematopoietic cell transplantation (HCT) is curative for many hematologic malignancies, complications and relapse remain challenging obstacles. Natural killer (NK) cells, which recover quickly after transplantation, produce cytokines and express killer immunoglobulin-like receptors (KIRs) that regulate their cytotoxicity. Some clinical trials based on a KIR ligand mismatch strategy are associated with less relapse and increased survival, but results are mixed. We hypothesized that T cells in the graft may affect NK cell function and KIR expression after unrelated transplantation and that these differences correlate with clinical outcomes. NK cell function was evaluated using 77 paired samples from the National Marrow Donor Program Research Repository. Recipient NK cells at 100 days after both unmanipulated bone marrow (UBM) and T-cell depleted (TCD) transplants were compared with NK cells from their healthy donors. NK cells expressed fewer KIRs and produced more interferon gamma (IFN-gamma) after UBM compared to TCD transplants. Multivariate models showed that increased NK cell IFN-gamma production correlated with more acute graft-versus-host disease (GVHD), and decreased KIR expression correlated with inferior survival. These results support the notion that T cells in the graft affect NK cell reconstitution in vivo. Understanding these mechanisms may result in strategies to improve clinical outcomes from unrelated HCT.

Adolescent↗

PubMed2007

HLA mismatching within or outside of cross-reactive groups (CREGs) is associated with similar outcomes after unrelated hematopoietic stem cell transplantation.

The National Marrow Donor Program maintains a registry of volunteer donors for patients in need of a hematopoietic stem cell transplantation. Strategies for selecting a partially HLA-mismatched donor vary when a full match cannot be identified. Some transplantation centers limit the selection of mismatched donors to those sharing mismatched antigens within HLA-A and HLA-B cross-reactive groups (CREGs). To assess whether an HLA mismatch within a CREG group ("minor") may result in better outcome than a mismatch outside CREG groups ("major"), we analyzed validated outcomes data from 2709 bone marrow and peripheral blood stem cell transplantations. Three-hundred and ninety-six pairs (15%) were HLA-DRB1 allele matched but had an antigen-level mismatch at HLA-A or HLA-B. Univariate and multivariate analyses of engraftment, graft-versus-host disease, and survival showed that outcome is not significantly different between minor and major mismatches (P = .47, from the log-rank test for Kaplan-Meier survival). However, HLA-A, HLA-B, and HLA-DRB1 allele-matched cases had significantly better outcome than mismatched cases (P < .001). For patients without an HLA match, the selection of a CREG-compatible donor as tested does not improve outcome.

Alleles↗

PubMed2002

Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse.

Chronic graft-versus-host disease (cGVHD) is the leading cause of late treatment-related deaths among recipients of allogeneic bone marrow and blood transplants. However, cGVHD is also associated with fewer relapses. We sought to determine whether severity of cGVHD predicts the magnitude of these effects. One impediment to such an analysis is the current limited/extensive grading system for cGVHD because this classification was designed to identify patients likely to benefit from systemic immune suppression and does not capture the severity of multiorgan involvement. We, therefore, first developed a grading system predictive for survival by using data from 1827 HLA-matched sibling allotransplant recipients reported to the International Bone Marrow Transplant Registry (IBMTR). We found Karnofsky performance score, diarrhea, weight loss, and cutaneous and oral involvement to be independent prognostic variables, from which we generated a grading scheme. We tested this scheme, the limited/extensive classification system, and a classification based on clinical impression of overall cGVHD severity (mild/moderate/severe) in parallel analyses of 1092 HLA-matched sibling transplant recipients from the IBMTR and 553 recipients of unrelated donor marrow from the National Marrow Donor Program. Presence of cGVHD was associated with fewer relapses (relative risk [RR], 0.5-0.6) but more treatment-related mortality (RR, 1.8-2.8) in the 3 analyses. No grading scheme correlated cGVHD severity with relapse rates, but all schemes predicted treatment-related mortality. Survival and disease-free survival of the most favorable cGVHD group in each scheme were similar, or better, than those of patients without cGVHD; these patients may not need aggressive or extended immune suppression.

Adolescent↗

PubMed2001

Unrelated marrow transplantation for adult patients with poor-risk acute lymphoblastic leukemia: strong graft-versus-leukemia effect and risk factors determining outcome.

Between 1988 and 1999, 127 patients with poor-risk acute lymphoblastic leukemia (ALL) received a matched unrelated donor transplant using marrow procured by National Marrow Donor Program (NMDP) collection centers and sent out to 46 transplant centers worldwide. Poor risk was defined by the presence of the translocations t(9;22) (n = 97), or t(4;11) (n = 25), or t(1;19) (n = 5). Sixty-four patients underwent transplantation in first remission (CR1), 16 in CR2 or CR3, and 47 patients had relapsed ALL or primary induction failure (PIF). Overall survival at 2 years from transplant was 40% for patients in CR1, 17% in CR2/3, and 5% in PIF or relapse. Treatment-related mortality (TRM) and relapse mortality, estimated as competing risk factors, were 54% and 6%, respectively, in CR1, 75% and 8% in CR2/3, and 64% and 31% in PIF or relapse. Currently 23 CR1 patients are alive and free of disease with a median follow-up of 24 months (range, 3-97). Multivariable analysis showed that CR1, shorter interval from diagnosis to transplantation, DRB1 match, negative cytomegalovirus (CMV) serology (patient and donor), and presence of the Philadelphia chromosome, t(9;22), were independently associated with better disease-free survival (DFS). Transplantation in CR and presence of t(9;22) were associated with lower risk of relapse. Shorter interval from diagnosis to transplantation, DRB1-match, negative CMV, higher marrow cell dose, and Karnofsky score of 90 or higher were associated with less TRM. These results indicate that, despite a relatively high TRM, the low relapse rate resulted in a 37% +/- 13% DFS for CR1 patients, comparing favorably to results obtained with chemotherapy alone and matching results following HLA-identical sibling transplantation.

Actuarial Analysis↗

PubMed2001

The effect of pretransplant interferon therapy on the outcome of unrelated donor hematopoietic stem cell transplantation for patients with chronic myelogenous leukemia in first chronic phase.

Various therapeutic options are available for patients with chronic myelogenous leukemia. Allogeneic stem cell transplantation, though often curative, is associated with high nonrelapse mortality and long-term morbidity, particularly when cells from unrelated donors are used. Many physicians and patients opt for a trial of interferon-alpha (IFN)-based therapy first, reserving transplantation for patients with inadequate response or intolerance to IFN. Data were analyzed on 740 patients receiving unrelated donor transplants for chronic myelogenous leukemia in first chronic phase provided by the International Bone Marrow Transplant Registry and the National Marrow Donor Program to see whether IFN pretreatment compromised transplantation outcome. A total of 489 (66%) had received IFN prior to transplantation; 251 (34%) had not. Disease characteristics in the 2 groups were similar at diagnosis but at the time of transplantation, hematologic parameters and weight were lower in IFN patients and the interval between diagnosis and transplantation was longer. After adjustment for baseline covariates, no effect of IFN exposure was found on overall survival, leukemia-free survival, nonrelapse mortality, engraftment, relapse, or acute or chronic graft-versus-host disease. Evaluation of effects based on duration of therapy and time off IFN prior to transplantation was limited by missing data and confounding with IFN intolerance and disease responsiveness. In conclusion, no evidence was found for an independent adverse effect of IFN pretreatment on the outcome of subsequent unrelated donor transplantation.

Acute Disease↗

PubMed2001

Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age.

The National Marrow Donor Program (NMDP) maintains a registry of approximately 4 million volunteer unrelated donors for patients in need of a stem cell transplant. When several comparably HLA-matched volunteers are identified for a patient, various criteria are used to select a donor. A retrospective analysis of 6978 bone marrow transplantations facilitated by the NMDP from 1987 to 1999 was conducted to study the effects of various donor characteristics on recipient outcome. The evaluation addressed possible effects of donor age, cytomegalovirus serologic status, ABO compatibility, race, sex, and parity on overall and disease-free survival, acute and chronic graft-versus-host disease (GVHD), engraftment, and relapse. Age was the only donor trait significantly associated with overall and disease-free survival. Five-year overall survival rates for recipients were 33%, 29%, and 25%, respectively, with donors aged 18 to 30 years, 31 to 45 years, and more than 45 years (P =.0002). A similar effect was observed among HLA-mismatched cases (28%, 22%, and 19%, respectively). A race mismatch between recipient and donor did not affect outcome. The cumulative incidences of grade III or IV acute GVHD were 30%, 34%, and 34%, respectively, with donors aged 18 to 30 years, 31 to 45 years, and more than 45 years (P =.005). The corresponding incidences of chronic GVHD at 2 years were 44%, 48%, and 49% (P = 0.02). Recipients with female donors who had undergone multiple pregnancies had a higher rate of chronic GVHD than recipients with male donors (54% versus 44%; P <.0001). The use of younger donors may lower the incidence of GVHD and improve survival after bone marrow transplantation. Age should be considered when selecting among comparably HLA-matched volunteer donors.

Adolescent↗

PubMed2002

Allogeneic bone marrow transplantation for chronic myelogenous leukemia: comparative analysis of unrelated versus matched sibling donor transplantation.

Allogeneic bone marrow transplantation (BMT) offers the only curative therapy for chronic myelogenous leukemia. We compared prospectively collected results of 2464 unrelated donor (URD) transplantations with 450 HLA-identical, matched sibling donor (MSD) transplantations performed at collaborating National Marrow Donor Program institutions. A total of 63% of URDs were matched at HLA-A, -B, and at -DRB1 alleles; all MSDs were genotypically identical at major histocompatibility loci. URD recipients were younger (median 36 vs 39, P =.001) than MSDs and underwent BMT later after diagnosis (median 17 [0-325 months] vs 7 [1-118 months], P =.001) and less often in chronic phase (CP) (67% vs 82%, P =.001). Multivariate analysis demonstrated a significantly increased risk of graft failure and acute graft versus host disease after URD BMT. The risk of hematologic relapse was low after either matched URD or MSD transplantations. We observed significantly though modestly poorer survival and disease-free survival (DFS) after URD transplantations. However, for those undergoing transplantation during CP within 1 year from diagnosis, 5-year DFS was similar or only slightly inferior after matched URD versus MSD transplantation (age < 30: URD 61% +/- 8% vs MSD 68% +/- 15%, P =.18; 30-40: URD 57% +/- 9% vs MSD 67% +/- 10%, P =.05; > 40: URD 46% +/- 9% vs MSD 57% +/- 9%, P =.02). Delay from diagnosis to BMT in CP patients led to substantially poorer 5-year DFS after matched URD than MSD BMT (CP 1-2 years: URD 39% +/- 6% vs MSD 63% +/- 12%; beyond 2 years: URD 33% +/- 7% vs MSD 50% +/- 20%). Outcome of matched URD BMT for early CP chronic myelogenous leukemia yields survival and DFS approaching that of MSD transplantation. However, delay may compromise URD outcomes to a greater extent. Improvements in URD and MSD transplantation are still needed, and results of newer, nontransplantation therapies should be evaluated against the established curative potential of URD and MSD marrow transplantation.

Adolescent↗

PubMed2005

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.

PURPOSE: 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). PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Adult↗

PubMed2003

Amotosalen: Allogeneic Cellular Immunotherapies system, INTERCEPT Plasma System, INTERCEPT Platelet System, S 59.

Adis CommentsCerus Corporation is developing a variety of pathogen-inactivation systems, based on its Helinx technology. Three of the systems include amotosalen [S 59] as the inactivation compound. Amotosalen is a light-activated, DNA-, RNA-crosslinking psoralen compound, which is used to neutralise pathogens. The systems that utilise amotosalen are called the INTERCEPT Platelet System, the INTERCEPT Plasma System and the Allogeneic Cellular Immunotherapies (ACIT) system. The INTERCEPT Platelet System and INTERCEPT Plasma System are two of the systems that make up Cerus' INTERCEPT Blood Systems. The other system is the INTERCEPT Red Blood Cell System, which contains S 303 as the inactivation compound rather than amotosalen. Cerus' Helinx technology is able to prevent replication of DNA or RNA that is present in pathogens but not in the blood components being treated (e.g. platelets and plasma). When added to the blood components, the inactivation agent (in this case amotosalen) crosses the membrane or cell wall of the pathogen. When activated by light, amotosalen binds to the nucleic acid of the pathogen and prevents replication. This process prevents infection. INTERCEPT Platelet System: Cerus developed its INTERCEPT Platelet System, in collaboration with Baxter Healthcare, for use in blood centres. Platelets are an essential component of the coagulation process and may be required by patients undergoing surgery, cancer chemotherapy, transplantation or with bleeding disorders. The system is made up of an illuminator device, a compound absorption device and a processing kit containing amotosalen. In October 2002, the two companies announced that CE Mark approval had been received for the illuminator device for the INTERCEPT trade mark Blood System. Application of this technology to platelets is the first to be approved. As it is a new technology, the system is currently undergoing process validation in accordance with European Blood Bank GMP requirements. This validation process is currently being conducted in Denmark, France, Germany, Sweden and the UK. Marketing approval applications for the INTERCEPT Platelet System have also been submitted in Australia and Canada. In addition, the regulatory submission process has begun in the US. A phase III trial (EuroSPRITE) has been conducted in 103 patients in Europe with pooled random donor platelets. The platelets were collected using the buffy coat process. Another two 20-patient clinical trials have also been conducted in Europe, as well as a 40-patient trial using platelets collected by an apheresis collection system. Cerus has also conducted a phase III trial (SPRINT) in the US. The trial was conducted in 671 patients and used platelets collected by Baxter's apheresis collection system. INTERCEPT Plasma System: Cerus is also developing the INTERCEPT Plasma System in collaboration with Baxter Healthcare. The system also combines amotosalen, an illumination device and a compound absorption device. The two companies are currently preparing regulatory applications for the INTERCEPT Plasma System for the US. This application will be followed by a submission for CE Mark designation in Europe. Patients undergoing surgery, or transplantation, or with bleeding disorders, may require transfusions of plasma, often to control bleeding. The type of plasma is stored in frozen form and is called fresh frozen plasma (FFP). The INTERCEPT Plasma System is currently in phase IIIc development in the US. Patient enrolment in the trial is still ongoing. The trial is comparing INTERCEPT trade mark Plasma System treated versus untreated FFP in 30 patients with thrombotic thrombocytopenic purpura. Allogeneic Cellular Immunotherapies system: Cerus is also investigating the potential of its Helinx technology to improve the outcome of bone marrow transplantation procedures (used to treat leukaemia and lymphoma) through the treatmatment for many forms of leukaemia and is most effective when the donor is very closely matched to the patient for the major human leucocyte antigen (HLA) groups. As part of the transplant procedure, patients receive donor T cells to improve engraftment of the bone marrow transplant and strengthen the patient's immune system. However, donor T cells expose the patient to a high risk of contracting graft-versus-host disease (GVHD) caused by the proliferation of donor T cells, which attack the patient's healthy tissue. GVHD has a high mortality rate. Cerus' ACIT system has been developed to decrease the stringency of matching donors to patients and to inhibit the ability of donor T cells to cause GVHD. Light-activated amotosalen binds and permanently crosslinks DNA, preventing replication and thus stopping proliferation of donor T cells. Phase I development is currently being conducted in this area in the US using amotosalen as the neutralising agent. Cerus completed a phase I study investigating the safety and tolerability of its ACIT system in 2001. The study was conducted in patients receiving closely matched allogeneic bone marrow transplants for leukaemia. The company is currently collaborating with the National Marrow Donor Program in order to conduct further clinical studies in patients receiving bone marrow transplants from unmatched donors. Cerus has development, manufacturing and marketing agreements with Baxter covering the INTERCEPT Blood Systems, which includes the INTERCEPT Platelet system, the INTERCEPT Plasma System, and the INTERCEPT Red Blood Cell System. Under the terms of the agreements the two companies usually share the very early development activities. Cerus then conducts preclinical and clinical trials, while Baxter is responsible for the development of the systems disposables and devices. Following commercialisation Cerus will supply amotosalen and Baxter will supply the other components of the system and market, sell and distribute the system In January 2001, Cereus announced that it has entered into a collaborative agreement with the Pharmaceutical Division of Kirin Brewery in Japan to develop and market products for stem cell transplantation based on Cerus' proprietary Helinx technology. Under terms of the agreement, Cerus and Kirin will jointly develop the products. Cerus has received an initial license fee of US dollar 1 million. In addition it may receive up to US dollar 11 million in future payments upon achievement of development milestones. Kirin will also fund all development expenses for the Asia-Pacific region and a portion of Cerus' development activities aimed at obtaining product approval in the US. Kirin will market the products in the Asia-Pacific region, including Japan, China, Korea and Australia, and Cerus will receive a specified share of product revenues. Cerus will retain marketing rights in the rest of the world, including the US and Europe.

Anti-Infective Agents↗

PubMed1997

Allogeneic bone marrow transplantation for hematological malignancies--controversies and recent advances.

Today more than 80000 allogeneic bone marrow transplantations (BMT) have been performed worldwide. The major indications are hematological malignancies such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and myelodysplastic syndromes. Unrelated donors are increasingly used and there are around 4 million volunteer donors available in different registers, the largest being the National Marrow Donor Program. Molecular typing has improved the typing technique which has resulted in a decreased risk of graft-versus-host disease (GVHD), lower transplant-related mortality (TRM) and improved leukemia-free survival (LFS). Using HLA-identical siblings, patients with AML in first complete remission (1 CR) and high-risk ALL in 1 CR are clear indications for BMT. However, if an HLA-identical sibling is not available, it is not known today if an unrelated bone marrow or autografting is the best option for all patients with acute leukemia in 1 CR. Because BMT is the only curable treatment for CML, a search for an unrelated donor should start as soon as it is evident that an HLA-identical sibling is not available. BMT within a year from diagnosis is of major importance for outcome. Allogeneic peripheral blood progenitor cells (PBPC) have been used as an alternative to bone marrow. Preliminary studies indicate a faster engraftment, but prospective randomized trials are necessary to establish the role of allogeneic PBPC. Umbilical cord blood has also been used as a source of allogeneic hematopoietic stem cells. Using cord blood from HLA-identical siblings, engraftment seems to be delayed, but the probability of GVHD is low. Preliminary data using unrelated cord blood cells are encouraging. GVHD has an important antileukemic effect. Recently, a graft-versus-myeloma and a graft-versus-breast-cancer effect has been demonstrated. In patients who relapse after BMT, donor lymphocytes can induce remission, especially in patients with CML. With molecular techniques it is possible to detect relapse at an early stage, so called minimal residual disease. Liposomal amphotericin B has few side-effects and decreased the death rate by invasive fungal infection in BMT recipients. Early diagnosis and treatment of cytomegalovirus (CMV) infection with new antiviral drugs have dramatically reduced the incidence and mortality in CMV disease. Cyclosporine combined with methotrexate is today the most widely used immunosuppressive regimen and has decreased GVHD and improved survival. However, several new immunosuppressive drugs need to be explored in clinical BMT. Immune modulation by for instance cytokines and cytokine inhibititors is a new exciting development.

Bone Marrow Transplantation↗

PubMed1996

Unrelated donor bone marrow transplantation for hematological malignancies-current status.

We have explored the efficacy and toxicity of hematopoietic stem cell transplantation from unrelated donors for hematologic malignancies and other disorders. While most marrow donors have been identified through the National Marrow Donor Program in cooperation with many international registries, the recent development of unrelated donor umbilical cord blood (UCB) banks has allowed us to also evaluate this stem cell source. Analysis of the first 211 URD BMT performed at the University of Minnesota shows an overall survival of 33%, with older recipient age and transplant from a donor with a major HLA-A or B mismatch independently associated with poorer survival. Analysis of engraftment of URD marrow shows increasing risk of delayed or incomplete engraftment with increasing HLA disparity between URD and recipient. GVHD is increased in recipients of URD marrow compared with recipients of related donor marrow. Malignant relapse, however, is less frequent in URD marrow recipients, perhaps due to an increased graft-versus-leukemia effect. Formal assessment shows quality of life in long term URD BMT survivors (beyond 2 years) is excellent, and not different from that seen in sibling marrow recipients. Data from patients receiving unrelated donor UCB transplantation at the University of Minnesota indicate that UCB is an acceptable alternate source of stem cells, at least for young recipients, and may be associated with a reduced incidence of GVHD. Ongoing studies at the University of Minnesota include examination of the applicability of unrelated UCB transplantation to adult recipients, and of the degree of HLA-incompatibility which can be tolerated in UCB transplantation. Studies to identify the optimal GVHD prophylaxis for URD BMT, and to examine the role of class II matching in transplant outcome are in progress.

Bone Marrow Transplantation↗