Biomedical subjects

K Cwynarski

Publications and source records attributed to K Cwynarski.

13 recordsLinked to original sources

PubMed2003

Strongyloidiasis pre and post autologous peripheral blood stem cell transplantation.

Hyperinfection with strongyloides stercolis occurs in the setting of chronic strongyloides infection in conjunction with immune suppression. Although malnutrition remains the major secondary cause worldwide in the developed world, iatrogenic immune suppression is an important precipitant. Autologous stem cell transplantation recipients are significantly immunocompromised albeit temporarily. Despite the increasing use of haemopoetic stem cell transplantation, hyperinfection with strongyloides has rarely been reported. We describe two cases of patients transplanted with chronic strongyloidiasis. In one case eradication therapy was given prior to the transplant which was uncomplicated. In the second case strongyloidiasis was diagnosed post transplant which was complicated by infection and respiratory compromise. Fatal hyperinfection subsequently developed after corticosteroid therapy was started for a disease progression in the CNS.

Aged↗

PubMed2002

Minor H antigens: genes and peptides.

In this review, we describe the evidence from which the existence of non-MHC histocompatibility (H) antigens was deduced, the clinical setting of bone marrow transplantation in which they are important targets for T cell responses, and the current understanding of their molecular identity. We list the peptide epitopes, their MHC restriction molecules and the genes encoding them, of the human and murine minor H antigens now identified at the molecular level. Identification of the peptide epitopes allows T cell responses to these antigens following transplantation of MHC-matched, minor H-mismatched tissues to be enumerated using tetramers and elispot assays. This will facilitate analysis of correlations with HVG, GVH and GVL reactions in vivo. The potential to use minor H peptides to modulate in vivo responses to minor H antigens is discussed. Factors controlling immunodominance of T cell responses to one or a few of many potential minor H antigens remain to be elucidated but are important for making predictions of in vivo HVG, GVH and GVL responses and tailoring therapy after HLA-matched BMT and DLI.

Amino Acid Sequence↗

PubMed2001

Early detection of BCR-ABL transcripts by quantitative reverse transcriptase-polymerase chain reaction predicts outcome after allogeneic stem cell transplantation for chronic myeloid leukemia.

The reverse transcriptase-polymerase chain reaction (RT-PCR) has become widely used for monitoring minimal residual disease after allogeneic stem cell transplantation (SCT) for chronic myeloid leukemia (CML). However, most of these studies were performed using qualitative RT-PCR, and the interpretation of the results obtained has been conflicting. The correlation of a quantitative RT-PCR test performed early after SCT (at 3 to 5 months) and long-term outcome of CML patients surviving for more than 6 months was studied. Between January 1991 and June 1999, data from 138 CML patients who received allografts were evaluated. Early RT-PCR results were classified as (1) negative if there were no BCR-ABL transcripts detected (n = 61), (2) positive at low level if the total number of BCR-ABL transcripts was less than 100 per microg RNA and/or the BCR-ABL/ABL ratio was less than 0.02% (n = 14), or (3) positive at high level if transcript levels exceeded the thresholds defined above (n = 63). Three years after SCT the cumulative incidence of relapse was 16.7%, 42.9%, and 86.4%, respectively (P =.0001). The relationship between BCR-ABL transcript level and probability of relapse was apparent whether patients had received sibling or unrelated donor SCT and also whether or not the transplantation was T cell depleted. The results suggest that quantitative RT-PCR performed early after SCT is useful for predicting outcome and may help to define the need for further treatment.

Actuarial Analysis↗

PubMed2001

Direct visualization of cytomegalovirus-specific T-cell reconstitution after allogeneic stem cell transplantation.

Cytomegalovirus (CMV) remains an important cause of morbidity and mortality after allogeneic stem cell transplantation (SCT), but cytotoxic T lymphocytes (CTL) may play a critical role in controlling CMV reactivation. Fluorescent HLA-peptide tetramers containing immunodominant peptides from CMV were used to prospectively monitor the recovery of CMV CTL in recipients of allogeneic transplants from siblings (n = 13) or unrelated donors (n = 11). In patients given allografts from a sibling when both the patient and donor were seropositive for CMV before SCT, recovery of CMV-specific CTL was rapid and reached up to 21% of all CD8(+) T cells. Early reconstitution of CMV-specific immunity was not observed if either the donor or recipient was seronegative for CMV. In recipients of transplants from volunteer unrelated donors, recovery of CMV-specific CTL was delayed in comparison to that in recipients of transplants from siblings and no CTL were observed within the first 100 days after SCT. CTL numbers were increased after episodes of CMV reactivation but were suppressed by prednisolone therapy. Recovery of CMV-specific CTL to levels greater than 10 x 10(6)/L was associated with protection from CMV disease. It was concluded that use of HLA-peptide tetramers to quantify CMV CTL is valuable for studying T-cell responses after allogeneic SCT. It should allow prediction of CMV reactivation in individual patients and assist in the development of adoptive T-cell immunotherapy.

Adolescent↗

PubMed2001

Immune haemolytic anaemia following T cell-depleted allogeneic bone marrow transplantation for chronic myeloid leukaemia: association with leukaemic relapse and treatment with donor lymphocyte infusions.

Immune haemolytic anaemia (IHA) is a recognised complication after allogeneic stem cell transplantation (SCT) and occurs more frequently if marrow cells have been subjected to T cell depletion (TCD). Among 58 consecutive patients who underwent TCD-allogeneic SCT from volunteer unrelated donors for the treatment of CML at the Hammersmith Hospital during a 3-year period (1 March 1996 to 28 February 1999) we identified nine cases of IHA. All patients had a strongly positive direct and indirect antiglobulin test and in eight patients the serological findings were typical of warm-type haemolysis often with antibody specificities within the Rh system. All nine cases had clinically significant haemolysis and were treated initially with prednisolone and immunoglobulin. The onset of IHA coincided with the occurrence of leukaemic relapse in six cases, and the presence of host haemopoiesis confirmed by lineage-specific chimerism in all four cases studied. Five patients received donor lymphocyte infusions (DLI); in three molecular remission and the restoration of full donor chimerism coincided with resolution of haemolysis. We conclude that in the context of leukaemic relapse, DLI is an effective therapy for IHA following allografts involving TCD.

Adolescent↗

PubMed2001

Stem cell transplantation for chronic myeloid leukaemia: the role of infused marrow cell dose.

INTRODUCTION: Allogeneic stem cell transplantation is a potentially curative option for patients with CML. The optimal donor is an HLA-identical sibling but transplants using unrelated volunteers can also be successful. The factors influencing survival after allogeneic SCT for CML are reasonably well defined. Recently however, the Seattle group have emphasised the influence of a high marrow cell dose on outcome following volunteer unrelated donor SCT for high risk acute leukaemia. MATERIALS AND METHODS: We have sought to define factors impacting on transplant related mortality (TRM) in a population of CML patients after allografting with matched sibling or alternative stem cell donors at a single centre over a 20-year period, with emphasis on infused marrow cell dose. Factors entered into a multivariate analysis were: recipient age, recipient CMV serostatus, disease phase, donor sex, cell dose and frequency of CTLP reactivity. RESULTS: In multivariate analysis four factors had an adverse effect on TRM when using a VUD: low marrow cell dose (<3.65 x 10(8) TNC/kg, relative risk 2.05, CI 1.08-3.90, P = 0.029), late disease phase (relative risk 1.68, CI 1.03-2.74, P = 0.038), patient CMV seropositivity (relative risk 1.98, CI 1.25-3.13, P = 0.004) and high frequency of CTLP (relative risk 1.93, CI 1.18-3.13, P = 0.008). For HLA-identical sibling donor transplants the only factor that adversely impacted on TRM was late disease phase (P = 0.0004 in univariate analysis). CONCLUSION: High infused cell dose is a new modifiable factor associated with reduced TRM following allogeneic SCT using an unrelated donor for the treatment of CML. The data support the recommendation that bone marrow harvest teams should aim to collect the highest possible number of nucleated cells for recipients of unrelated donor transplants.

Adult↗

PubMed2001

Minor H antigens: genes and peptides.

In this review, we describe the evidence from which the existence of non-MHC histocompatibility (H) antigens was deduced, the clinical setting of bone marrow transplantation in which they are important targets for T-cell responses, and the current understanding of their molecular identity. We list the peptide epitopes of the human and murine minor H antigens now identified at the molecular level, their MHC restriction molecules and the genes encoding them. Identification of the peptide epitopes allows T-cell responses to these antigens following transplantation of MHC-matched, minor H-mismatched tissues to be enumerated using tetramers and elispot assays. This will facilitate analysis of correlations with host-versus-graft (HVG), graft-versus-host (GVH) and graft-versus-leukaemia (GVL) reactions in vivo. The potential to use minor H peptides to modulate in vivo responses to minor H antigens is discussed. Factors controlling immunodominance of T-cell responses to one or a few of many potential minor H antigens remain to be elucidated but are important for making predictions of in vivo HVG, GVH and GVL responses and tailoring therapy after HLA-matched bone marrow transplantation and donor lymphocyte infusion.

Alleles↗

PubMed2001

Cytomegalovirus seropositivity adversely influences outcome after T-depleted unrelated donor transplant in patients with chronic myeloid leukaemia: the case for tailored graft-versus-host disease prophylaxis.

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after haematopoietic stem cell transplantation from matched unrelated donors (MUD). The role of T-cell depletion (TCD) as a strategy to prevent GVHD is controversial because of the associated increased risk of leukaemic relapse, graft failure and delayed immune reconstitution. The demonstration that donor lymphocyte infusion (DLI) is effective salvage therapy if patients relapse after transplantation for chronic myeloid leukaemia (CML) prompted us to examine the proposal that TCD may be a form of GVHD prophylaxis particularly suited to this disease in patients undergoing MUD transplantation. We analysed the outcome of 106 consecutive patients with CML in first chronic phase who underwent MUD transplantation. Patients were conditioned with cyclophosphamide and total body irradiation (TBI), and received in vivo TCD, using CD52 monoclonal antibody, as GVHD prophylaxis. Donor lymphocytes were infused at the time of leukaemic relapse. The projected survival at 5 years for all patients was 52.6%. The probability of developing severe acute GVHD (grade 3 or 4) was 14.5%. The only significant predictor of overall survival in univariate and multivariate analysis was patient cytomegalovirus (CMV) serostatus: in CMV-negative patients survival at 5 years was 60% vs. 42% in CMV-positive patients (P = 0.006). The use of TCD was associated with an increased risk of relapse (62% probability at 5 years after transplant), but 80% of patients who received DLI achieved molecular remission that was durable in all but two cases. In vivo TCD, in conjunction with DLI at relapse, is a valuable GVHD prophylactic regimen in CMV-seronegative recipients of MUD allografts, but in CMV-seropositive patients this approach is associated with an increased non-relapse mortality. Consequently, GVHD prophylactic regimens in MUD transplantation should be tailored according to the patient and donor pretransplant characteristics.

Adolescent↗

PubMed2001

Immune neutropenia associated with anti-human neutrophil antigen-2a (NB1) antibodies following unrelated donor stem cell transplantation for chronic myeloid leukaemia: perpetuation by granulocyte colony-stimulating factor.

A case of immune neutropenia following unrelated stem cell transplantation for chronic myeloid leukaemia is described. The neutropenia developed following herpes zoster viral infection and was associated with antibodies to the human neutrophil antigen (HNA)-2a (formerly known as NB1). The neutropenia was prolonged, profound and unresponsive to granulocyte colony-stimulating factor (GCSF). The neutrophil count recovered after GCSF was discontinued. HNA-2a has been reported to be upregulated following GCSF administration. In the present case, it appears that the immune neutropenia may have been perpetuated by GCSF administration.

Adult↗

PubMed2001

Pharmacokinetics of CAMPATH-1H in BMT patients.

BACKGROUND: CAMPATH-1 (CD52)Abs are used in stem-cell transplantation for prevention of GvHD and rejection. The humanized Ab CAMPATH1H has recently replaced the rat Ab CAMPATH-1G. There was a concern whether it might have a longer half-life in vivo and, possibly, cause prolonged immunosuppression post-transplant. METHODS: Serum samples were collected pre- and post-transplant from patients receiving CAMPATH-1H at 10 mg/day according to two protocols: (A) from Day -5 to Day +4 (total dose, 100 mg), (B) from Day -10 to Day -6 (total dose, 50 mg). The Ab concentrations were measured using an immunofluorescence assay. RESULTS: Lymphocytes were substantially depleted by the second day of treatment and were below 0.1 x 10(9)/L by the day of transplant and for at least 1 month post-transplant. By Day 90 there was a greater recovery in Group B, to a median of 0.32 x 10(9)/L compared with 0.25 x 10(9)/L in Group A. By Day 180, both groups had recovered to approx 0.52 x 10(9)/L. Serum concentrations of CAMPATH-1H on the day of transplant were well above the level necessary for opsonization of lymphocytes. The peak Ab concentration was 6.1 micro g/mL in Group A and 2.5 micro g/mL in Group B. CAMPATH-1H could be detected in Group A for 23 days post-transplant, significantly longer than in Group B (11 days). The terminal half-life in the two groups was similar (range 15-21 days) and contrasts with the half-life of < 1 day previously estimated for CAMPATH-1G. There were no cases of graft failure and the incidence of GvHD was similar in the two groups. DISCUSSION: The humanized Ab CAMPATH-1H appears to persist in the circulation for longer than the original rat Ab CAMPATH-1G. This might contribute to delayed lymphocyte recovery and prohibit the use of early donor-lymphocyte infusions. A short course of treatment given early pre-transplant is likely to be preferable to the extended course given both pre- and post-transplant.

Adult↗

PubMed2000

Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia.

An analysis was performed of the response to treatment with donor lymphocyte infusions (DLI) and the survival in 66 consecutive patients who relapsed after primary treatment by allogeneic stem cell transplantation for BCR-ABL-positive chronic myeloid leukemia. The transplant donor was an HLA-identical sibling (n = 35) or a "matched" unrelated volunteer (n = 31). Fifty-seven patients were transplanted in chronic phase, eight in accelerated phase, and one in second chronic phase. The recognition of relapse was based on precise molecular, cytogenetic, or hematologic criteria. The median interval from transplant to relapse was 12 months (range 3-85). The median interval from relapse to initiation of DLI was 9.4 months (range 1-70). Patients received DLI from their original transplant donors on a bulk-dose (n = 34) or on an escalating-dose (n = 32) regimen. Patients were monitored serially by hematologic, cytogenetic, and molecular criteria. Molecular remission was defined by the finding of negative results by nested primer reverse transcriptase polymerase chain reaction (RT-PCR) for BCR-ABL transcripts on two consecutive occasions, subject to satisfactory controls. Forty-four patients (67%) achieved molecular remission. Patients who had relapsed to advanced phase disease and patients with short intervals between transplant and relapse had significantly lower probabilities of achieving molecular remission. Of the 44 patients who achieved molecular remission, 4 reverted to a PCR-positive status at 15, 18, 37, and 87 weeks after remission. The probability of survival for patients who achieved molecular remission was significantly better than for those who failed to do so (95% versus 53% at 3 years post-DLI, P = .0001). We conclude that the majority of molecular remissions after DLI are durable, and thus the majority of responding patients may prove to have been cured. (Blood. 2000;96:2712-2716)

Adult↗

PubMed2000

Estimating leukemia-free survival after allografting for chronic myeloid leukemia: a new method that takes into account patients who relapse and are restored to complete remission.

A significant number of patients who relapse after allogeneic stem cell transplantation (SCT) for chronic myeloid leukemia (CML) will achieve sustained remissions after treatment with interferon-alpha, second transplants, or donor lymphocyte infusions (DLI) from the original stem cell donor. Because leukemia-free survival (LFS) is at present defined as survival without evidence of relapse at any time posttransplant, patients who relapse but are then restored to complete remission are treated as failures when estimating LFS. We have established a new category of LFS, termed current LFS (CLFS), which we define as survival without evidence of leukemia at the time of most recent assessment. To gauge the contribution of treatment for relapse to the efficacy of allogeneic SCT in the management of CML in chronic phase, we compared conventional LFS and CLFS in 189 consecutive patients who underwent SCT over a 7-year period with a minimum follow-up of 3 years. Patients with sibling donors (n = 111) received cyclosporine and methotrexate as prophylaxis for graft versus host disease; patients with unrelated donors (n = 78) also received Campath-1G or 1H as intravenous T-cell depletion. The 5-year LFS defined conventionally was 36% (CI: 29% to 43%) versus a 5-year CLFS of 49% (CI: 36% to 62%). This new method of defining LFS confirms the view that appropriate "salvage" therapy, principally DLI, makes a major contribution to the capacity of allogeneic SCT to produce long-term LFS in patients who receive SCT for CML and emphasizes the importance of redefining LFS to take account of successful treatment of relapse.

Adolescent↗

PubMed2000

Fusion of H4/D10S170 to the platelet-derived growth factor receptor beta in BCR-ABL-negative myeloproliferative disorders with a t(5;10)(q33;q21).

We have studied a patient who presented with clinical features suggestive of chronic myeloid leukemia in accelerated phase. BCR-ABL transcripts were undetectable by reverse transcription-PCR, but a novel reciprocal translocation, t(5;10)(q33;q21.2), was seen by standard cytogenetic analysis. Chromosome band 5q33 contains the gene encoding the platelet-derived growth factor beta receptor (PDGFbetaR), the receptor tyrosine kinase that is disrupted by the t(5;7), t(5;12), and t(5;14) in myeloid disorders, resulting in the fusion of PDGFbetaR to HIP1, TEL/ETV6, and CEV14, respectively. Southern analysis with PDGFbetaR cDNA revealed novel bands in patient but not control DNA after digestion with several restriction enzymes, indicating that this gene is also targeted by the t(5;10). Fluorescence in situ hybridization analysis of chromosome 5 indicated that a small inversion at 5q33 had taken place in addition to the interchromosomal translocation. The site of the chromosome 10 breakpoint fell within YAC 940e4. Because all PDGFbetaR fusions described thus far result in splicing to a common exon of this gene, we performed 5'-rapid amplification of cDNA ends PCR on patient RNA. Several clones were isolated in which PDGFbetaR fused in frame to H4/D10S170, a previously described ubiquitously expressed gene that is fused to the ret protein tyrosine kinase to form the PTC-1 oncogene in approximately 20% of papillary thyroid carcinomas. The presence of H4-PDGFbetaR chimeric mRNA in the patient was confirmed by reverse transcription-PCR; reciprocal PDGFbeta1R-H4 transcripts were not detected. We conclude that t(5;10)(q33;q21.2) is a novel translocation in BCR-ABL-negative chronic myeloid leukemia and that this abnormality results in an H4-PDGFbetaR fusion gene. This finding further strengthens the association between myeloproliferative disorders and deregulated tyrosine kinases.

Amino Acid Sequence↗