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D I Marks

Publications and source records attributed to D I Marks.

At least 19 recordsLinked to original sources
PubMed2006

Alternative donor transplants for adult acute lymphoblastic leukaemia: a comparison of the three major options.

Myeloablative sibling-matched allogeneic transplantation for adult acute lymphoblastic leukaemia provides the best outcome, but most patients lack a suitable, related histocompatible donor. We reviewed three haematopoietic stem cell donor sources used for alternative donor transplantation pointing out drawbacks of these approaches including inherent selection bias. Matched unrelated donor allografts most often are performed in Philadelphia chromosome-positive disease and in second complete remission (CR2); a nearly 30% event-free survival (EFS) can be anticipated in select patients. Transplants using haploidentical donors are most successful if undertaken in CR1 and CR2 and appear to produce EFS rates of about 25%. Limited umbilical cord blood transplant data suggest efficacy, but marked patient and treatment heterogeneity hamper conclusions. Each of these three strategies has unique potential benefits and disadvantages. The growing use of minimal residual disease detection may identify subgroups of patients unlikely to be cured by chemotherapy alone; these patients are candidates for upfront high-dose chemoradiotherapy and cellular immunotherapy. These three approaches are plagued by treatment-related mortality and relapse rates as high as 40%, but advances in technology and supportive care may make each stem cell source more feasible and efficacious.

Adult↗
PubMed2005

Granulocyte transfusions for treating infections in patients with neutropenia or neutrophil dysfunction.

BACKGROUND: Transfusions of granulocytes have a long history of usage in clinical practice to support and treat severe infection in high risk groups of patients with neutropenia or neutrophil dysfunction. However, there is considerable current variability in therapeutic granulocyte transfusion practice, and uncertainty about the beneficial effect of transfusions given as an adjunct to antibiotics on mortality. OBJECTIVES: To determine the effectiveness of granulocyte transfusions compared to no granulocyte transfusions for treating infections in patients with neutropenia or disorders of neutrophil function in reducing mortality. SEARCH STRATEGY: Randomised controlled trials (RCTs) were searched for in the Cochrane Central Register of Controlled Trials (CENTRAL) in 2003. Searching was also undertaken on the OVID versions of Medline and Embase using an RCT search filter strategy. SELECTION CRITERIA: RCTs involving transfusions of granulocytes, given therapeutically, to patients with neutropenia or disorders of neutrophil dysfunction. DATA COLLECTION AND ANALYSIS: Two reviewers completed data extraction independently. Relative risk (RR) with 95% confidence intervals (CI) using the random effects model were reported for dichotomous outcomes. Pre-specified subgroup analyses were done and reported eg granulocyte dose. MAIN RESULTS: Eight parallel RCTs were included with 310 total analysed patient episodes. Different policies were applied for the schedule of transfusion, method of granulocyte procurement and process of donor selection including leucocyte compatibility. Each study used different criteria for neutropenia (range < 0.1 to < 1.0 x 10(9)/L) and definition of infection requiring treatment. For mortality, which was extracted from six trials, the summary RR = 0.64 in favour of transfusion (95% CI 0.33, 1.26), but with evidence of significant statistical heterogeneity (Chi-square 11.3 and I(2) = 56%). The data for the combined RR for mortality for the four studies transfusing higher granulocyte doses greater than 1x10(10) indicated a significant summary RR= 0.37 (95% CI 0.17, 0.82); Chi-square 3.9, I(2) 23%. Data on rates of reversal of infection could be extracted from four studies, and the combined RR was 0.94 (95% CI 0.71, 1.26), again with evidence of heterogeneity. In addition to the observed clinical diversity between all studies, uncertainty about the quantitative and qualitative analyses for these studies is compounded by methodological deficiencies. AUTHORS' CONCLUSIONS: Currently, there is inconclusive evidence from RCTs to support or refute the generalised use of granulocyte transfusion therapy in the most common neutropenic patient populations, that is caused by myeloablative chemotherapy with or without haematopoietic stem cell support. Contemporary well designed prospective trials are required to evaluate the efficacy of this intervention in these patient populations and to establish definitively whether it has clinical benefit. In such studies, average numbers of collected granulocytes for adults should be (at least) greater than 1x10(10).

Cause of Death↗
PubMed2005

Early emergence of PNH-like T cells after allogeneic stem cell transplants utilising CAMPATH-1H for T cell depletion.

CAMPATH-1H (C-1H) is widely used in vivo and / or in vitro for T cell depletion in hematopoietic SCT. This humanised monoclonal antibody is specific for CD52, a marker coexpressed on the majority of human lymphocytes with CD48 and other glycosylphosphatidyl-inositol (GPI) anchored proteins. We detected CD52 / CD48 dual expression on >99% of CD3(+) lymphocytes from normal individuals and all 15 post-SCT patients whose transplants did not utilise C-1H. By contrast, 23 / 26 patients with transplants involving C-1H (in vivo, in vitro or both) exhibited populations lacking CD52 expression that accounted for 49.7% (4.2-86.2%) of the CD3+ lymphocytes (median and range) in samples evaluated at a median of 2 months post-SCT. Most CD52- cells also lacked CD48 expression. These GPI- T cells were of either donor or mixed donor / recipient origin. They were predominant in the early months after SCT at times of profound lymphopenia and inversely correlated with the recovery of the absolute lymphocyte count (r= - 0.663, P<0.0001). The presence of CD52- cells has been correlated previously with clinical outcome after CAMPATH therapy for both malignant and nonmalignant diseases.

Adolescent↗
PubMed2005

Rotavirus as a significant cause of prolonged diarrhoeal illness and morbidity following allogeneic bone marrow transplantation.

Infective diarrhoea is common among allogeneic stem cell transplant (SCT) recipients, frequently caused by viruses and may be difficult to differentiate from acute graft-versus-host disease (GVHD). Viral pathogens may directly or indirectly impact upon transplant-related mortality. Rotavirus is one of the most common causes of diarrhoea worldwide, but one of the least studied causes of diarrhoea post SCT. In this retrospective study we describe 21 cases of confirmed rotavirus infection in allogeneic SCT recipients. Most of these cases may occur in clusters during the winter and spring period. Symptoms of rotaviral infection were diarrhoea (95%), vomiting (62%), abdominal pain (38%), weight loss and loss of appetite in 38 and 29% of the cases, respectively. Possible extraintestinal manifestations of rotavirus infection were observed. The duration of the symptoms in this series ranged from 4 days to 4 months with median of 15 days. Patients with rotavirus infection were invariably lymphopenic and/or on immunosuppression for GVHD. Of the patients diagnosed with rotavirus, 86% required hospitalisation. In 57% of the cases, other viral pathogens were isolated near to the rotavirus infection period. Rotavirus infection is an important cause of prolonged diarrhoea post SCT, causing significant morbidity and frequently requiring hospitalisation.

Adolescent↗
PubMed2005

Management of chronic myeloid leukaemia in relapse following donor lymphocyte infusion induced remission: a retrospective study of the Clinical Trials Committee of the British Society of Blood & Marrow Transplantation (BSBMT).

Donor lymphocyte infusion (DLI) can restore remission in a high percentage of patients with chronic myeloid leukaemia (CML) who relapse after allogeneic stem cell transplant (SCT). Subsequent relapses after a DLI-induced remission do occur and the optimal management of these patients is not defined. A retrospective study of the practice of UK transplant centres was conducted. In all, 13 patients from seven centres were identified: all were treated for relapse post allogeneic SCT with DLI and achieved either a complete cytogenetic (n=5) or molecular (n=8) remission. All patients subsequently had a second relapse, at molecular (n=7), cytogenetic (n=4) and haematological (n=2) levels. Further DLI was used in the treatment of 11 patients, imatinib mesylate in three and chemotherapy in two. The two patients with haematological relapse died of blastic disease. The remaining 11 patients achieved either a complete cytogenetic (n=2) or molecular (n=9) remission. Nine patients remain in molecular remission at a median follow-up of 29 months, seven of whom had received DLI alone as treatment for second relapse, one DLI plus imatinib and one imatinib alone. Toxicity following DLI for second relapse was low. Longer follow-up will be required to see if these second DLI-induced remissions will be durable.

Adult↗
PubMed2004

Influence of cytomegalovirus (CMV) sero-positivity on CMV infection, lymphocyte recovery and non-CMV infections following T-cell-depleted allogeneic stem cell transplantation: a comparison between two T-cell depletion regimens.

We compared the incidence and outcome of preemptively treated cytomegalovirus (CMV) infection, lymphocyte recovery and non-CMV infections between two different TCD modalities, one employing CD34+ selection and T-cell add-back (TCAB), preceded by Campath-1H in vivo (CD34+/TCAB group, n=29), and the other using grafts incubated with Campath-1H in vitro (Campath-1H in vitro group, n=32). The probabilities of CMV reactivation and recurrence were 67 and 83.6% in the CD34+/TCAB group and 42.9 and 20% in the Campath-1H group (P=0.07 and 0.02). Donor sero-positivity reduced CMV reactivation in the Campath-1H group, but not in the CD34+/TCAB group. The durations of positive PCR/antigenemia positivity and antiviral therapy were also significantly longer in the CD34+/TCAB group. However, only two patients developed CMV disease in each group. The mean absolute lymphocyte counts (x 10(9)/l) at 30 days (0.27 vs 0.4, P=0.03) and 100 days (0.77 vs 1.4, P=0.01) were significantly lower in the CD34+/TCAB group along with a higher incidence of non-CMV infections in CMV at-risk patients, but not in the CMV low-risk group. These findings suggest that the modality of TCD should be tailored according to the CMV risk status, and CMV sero-positive patients should receive a less extensively T-cell-depleted graft and a CMV sero-positive graft if possible.

Adoptive Transfer↗
PubMed2004

Gram-negative bacteraemia (GNB) after 428 unrelated donor bone marrow transplants (UD-BMT): risk factors, prophylaxis, therapy and outcome.

Gram-negative infection is an important cause of morbidity and mortality after unrelated donor-bone marrow transplantation (UD-BMT). We performed a retrospective case-control study to examine the risk factors, prophylaxis, therapy and outcome of Gram-negative bacteraemia (GNB) in 428 patients undergoing UD-BMT. The incidence of GNB was 3.6% in children and 19% in adults. Of the adults, 11% developed GNB >60 days post UD-BMT. Predisposing risk factors for GNB included 'high-risk' disease status, chronic graft-versus-host disease and use of systemic steroids. Fever, a raised C-reactive protein (CRP) and hypotension were common findings at presentation. Patients were routinely given prophylactic ciprofloxacin: resistance to this antibiotic was seen in 33% of isolates. We identified an age-matched control group undergoing UD-BMT over the same time period as the study group. Gram-positive bacteraemia was significantly more common in cases than controls. Mortality from GNB was 17% in children and 24% in adults. We conclude that GNB is a common complication of UD-BMT with a high associated mortality. Patients should be educated further to present rapidly with symptoms suggestive of infection.

Adolescent↗
PubMed2004

Granulocyte transfusions in the G-CSF era. Where do we stand?

The efficacy of granulocytes transfusions (GTX) in either the prevention or treatment of neutropenic sepsis has been a controversial issue. Early studies employing steroid mobilised GTX showed variable, dose-dependent results and significant pulmonary toxicity was reported. With the introduction of the recombinant myeloid growth factor, granulocyte-colony stimulating factor (G-CSF), the quantity of granulocytes that could be harvested was substantially increased leading to renewed interest in the clinical application of GTX. The administration of G-CSF to normal donors leads to significantly higher pre-harvest neutrophil counts and consequently larger granulocyte harvests. Infusion of G-CSF stimulated GTX results in measurable increases in the recipients' neutrophil count and may reduce the duration and severity of neutropenia. However, the efficacy of these GTX in treating or preventing established neutropenic sepsis remains to be established in prospective controlled clinical trials.

Granulocyte Colony-Stimulating Factor↗
PubMed2004

Second transplant for acute and chronic leukemia relapsing after first HLA-identical sibling transplant.

Treatment options for persons with leukemia relapsing after allogeneic transplantation are limited. We analyzed the outcome of 279 patients with acute and chronic leukemia, who relapsed after HLA-identical sibling transplantation and received a second allogeneic transplant. The influence of potential risk factors on treatment-related mortality (TRM), relapse, treatment failure (relapse or death) and overall survival after second transplantation were assessed using proportional-hazards regression. The cumulative incidences (95% confidence interval) of relapse and TRM at 5 years were 42 (36-48)% and 30 (24-36)%, respectively. The 5-year probabilities of both overall and leukemia-free survival were 28 (23-34)%. In multivariate analyses, risks of treatment failure and mortality were lower in younger patients (< or =20 years) and patients who relapsed after 6 months from first transplantation. Risks of relapse were lower in patients who relapsed after 6 months from first transplantation and in complete remission prior to second transplantation. Risks of relapse were higher after reduced-intensity conditioning regimens. Any potential advantage of using a different matched related donor for a second transplantation is not supported by these data. Although age, disease status and conditioning regimen are important, duration of remission after first transplantation appear to be the most important determinant of outcome.

Adolescent↗
PubMed2003

Early lymphocyte recovery is an important determinant of outcome following allogeneic transplantation with CD34+ selected graft and limited T-cell addback.

We evaluated the outcome of 29 patients (age 22-60 years), who received a CD34+selected related (n=16) or unrelated graft (n=13) with limited T-cell addback (TCAB) (median 5.9 x 10(4)/kg) following full-intensity conditioning for haematological malignancies. In all, 16 patients (55%) had either advanced disease or previous transplants. The cumulative incidences of grade 2-4 acute GVHD were 15.4 and 19.2% and that for chronic extensive GVHD were 35 and 37% in related and unrelated graft recipients, respectively. The strongest predictor of nonrelapse mortality and overall survival was the absolute lymphocyte count (ALC) at 30 days; patients with ALC<0.35 x 10(9)/l having an NRM and OS of 59.2 and 24.7%, compared to 10 and 90% in those with a higher ALC. Patients with acute leukaemia had poorer survival and this was associated with a lower ALC as well. Thus, TCAB with a CD34+ selected graft resulted in a comparable outcome in both older and younger patients, but the survival was strongly influenced by early lymphocyte recovery.

Adult↗
PubMed2003

Should we T cell deplete sibling grafts for acute myeloid leukaemia in first remission?

There is controversy regarding the best approach to the management of patients with acute myeloid leukaemia (AML) in first remission (CR1). The impact of matched related allogeneic transplant in CR1 on the overall survival is equivocal, but what is not in doubt is a significant reduction in the relapse risk, compared to both autologous transplants and intensive chemotherapy, which is because of the allogeneic or the graft-versus-leukaemia (GVL) effect. Yet, this does not always translate to improved survival. T cell depletion (TCD) can reduce deaths related to graft-versus-host disease (GVHD) and its therapy, but might increase the relapse risk. The existing literature suggests that TCD is associated with a disease-free survival (DFS) of 53-80% and is associated with a lower relapse risk than anticipated (0-30%). We discuss the evolution of TCD in allogeneic transplantation and its relevance in AML-CR1 with regard to GVHD, DFS, immune reconstitution and GVL effect. It is possible that by reducing TRM related to GVHD and extramedullary toxicities, particularly in the older patients, TCD might improve the impact of allogeneic transplantation in AML-CR1, provided the immune reconstitution and the relapse risk are not adversely affected. Randomised studies are underway to address these issues.

Acute Disease↗
PubMed2002

The use of zanamivir to treat influenza A and B infection after allogeneic stem cell transplantation.

The use of zanamivir in seven patients with influenza (three A and four B) post allograft is described. Inhaled zanamivir (10 mg twice daily) was continued from the diagnosis of influenza until excretion of virus ceased (median duration 15 days, range 5 to 44 days). There was no toxicity attributable to zanamivir and rapid resolution of influenza symptoms was seen. There was no mortality due to influenza in the seven patients. The good outcome of 30 previous patients with influenza post transplant is described. A randomised multicentre study would be required to demonstrate efficacy.

Adolescent↗
PubMed2001

The clinical features, risk factors and outcome of thrombotic thrombocytopenic purpura occurring after bone marrow transplantation.

In this study, we retrospectively analysed the clinical features, risk factors and outcome of 22 patients with thrombotic thrombocytopenic purpura (TTP) occurring after allogeneic stem cell transplantation. All but two of these patients received stem cells from unrelated donors (UDs), two-thirds were female, three-quarters were adults and leukaemia was the major reason for transplant. The incidence of TTP was 20 out of 332 patients (6%) with UD transplants and two out of 104 recipients (2%) of matched sibling allografts (P = 0.16). In order to ascertain basic demographic risk factors for the development of TTP, we compared the 22 patients with 434 patients who did not develop TTP. Compared with patients who did not develop TTP, patients with TTP were nearly three times older (P < 0.001) and were more than twice as likely to be female (P = 0.001). Because > 90% of patients were recipients of UD marrow, we then compared the 20 UD-bone marrow transplantation (BMT) patients with 60 randomly selected UD-BMT patients who did not develop TTP. On univariate analysis, age and female gender were again significant risk factors, as was grade II-IV acute graft-versus-host disease (GvHD) (P = 0.002), and there was a trend towards an association with chronic GvHD (P = 0.083). However, after logistic regression analysis, only age and sex remained significant (P < 0.001 and 0.009 respectively). We report an 86% mortality with only three survivors out of 22 patients, and one of these remains thrombocytopenic and red cell transfusion dependent, possibly in part because of graft hypoplasia. Six out of 17 patients responded to plasmapheresis, but the majority of them ultimately succumbed because of TTP, often in association with GvHD or fungal infection.

Adolescent↗
PubMed2001

Allogeneic transplantation for leukaemia using unrelated donors.

This chapter describes the current role of unrelated donor stem cell transplantation (UD-SCT) in the management of leukaemia. The available data are scant and incomplete and there are few randomized studies comparing UD-SCT with alternative therapies. Patients with many of the leukaemias require prolonged follow-up after allogeneic SCT to determine whether they are cured; the registry-based comparisons that have been initiated reflect the results achievable some years ago and may not help us in deciding what is best in 2001. In addition, new therapies such as ST1571, even though the long-term outcome of patients treated with this agent is uncertain, may affect which patients with chronic myeloid leukaemia we decide to recommend for transplant. The focus here is on acute and chronic myeloid leukaemia, acute lymphoblastic leukaemia and chronic lymphocytic leukaemia, as well as the myelodysplastic syndromes. Patient selection, conditioning strategies, comparison with other therapies, timing of transplant and the major causes of treatment failure are discussed, and there is an exploration of where improvement will come from.

Disease Management↗
PubMed2000

T cell-depleted unrelated donor bone marrow transplantation for acute myeloid leukemia.

The outcome for 39 patients with acute myeloid leukemia (AML) in remission who had CAMPATH 1M T cell-depleted unrelated donor bone marrow transplantations (BMTs) is described. Conditioning was mainly with cyclophosphamide (120 mg/kg) and total body irradiation (TBI) (14.4 Gy), but 5 patients received busulfan in place of TBI and 200 mg/kg cyclophosphamide. All patients received cyclosporin, and short-course methotrexate was given to recipients of mismatched grafts. The patient population was predominantly pediatric (median age, 10 years), but one third of the patients was aged 15 years or above. Twenty-five patients were in second complete remission (CR2), and 14 had high-risk CR1 disease (primarily failed remission induction or antecedent myelodysplastic syndrome, often with complex cytogenetic abnormalities). Both recipient and donor were cytomegalovirus seronegative in 15 of 37 cases (38%); 51% of patients were matched for HLA class I and II. Grade II to IV acute graft-versus-host disease (GVHD) occurred in 24% of patients; chronic GVHD occurred in 5 of 31 evaluable patients (16%), 4 extensive and 1 limited. Relapse occurred in 5 cases (13%); 1 of these 5 patients survives, 24 months after a second unrelated donor transplantation. Two of these relapses were associated with secondary graft failure (incidence rate, 5%). All patients engrafted primarily. Severe viral infection was the major transplant-associated complication, with 12 episodes in 9 patients, 5 of them lethal. Twenty-five patients survive at a median follow-up of 44 months (range, 2-102 months), with estimated actuarial overall and disease-free survival rates at 44 months of 61% (SE 8%) and 57% (SE 8%), respectively. Nineteen patients are more than 2 years post-BMT and may be cured. The functional status of long-term survivors is excellent, with 19 of 21 patients who survive 6 months or more in full-time employment or full-time students. These encouraging results suggest that in patients lacking a sibling donor, unrelated donor BMT for AML in remission achieves survival figures as good as or better than those reported on patients with autologous stem cell transplantation, and that T-cell depletion of grafts is associated with a low relapse rate and an excellent functional status. However, only a randomized study comparing unrelated donor BMT and auto-grafting will resolve which of these treatment strategies is better for patients with AML.

Acute Disease↗
PubMed2000

Outcome and clinical course of 100 patients with adenovirus infection following bone marrow transplantation.

We conducted a retrospective review of the clinical features and outcome of adenovirus infection in 572 consecutive patients transplanted in a single centre over a 10 year period. One hundred patients (17%) had a total of 105 episodes of adenovirus infection diagnosed at a median of 18 days post transplant (range 2-150 days). The incidence was higher in children than adults (21% vs 9%, P < 0.001) and in unrelated donor vs matched sibling donor transplants (26% vs 9%, P < 0.001). Diarrhoea and fever were the most common presenting features. Reflecting these symptoms, the most common site of isolation was the stool. Serotypes 1, 2 and 7 were the most frequently seen (total of 41/68 or 60% of evaluable cases). In six patients (6%) adenovirus infection was the direct cause of death occurring at a median of 72 days post transplant (range 18-365 days). Five of these six patients had pulmonary involvement and four had associated graft-versus-host disease (GVHD). Three further patients were considered to have severe adenoviral disease (total incidence 9%). Isolation of virus from multiple sites correlated with a poor outcome (P < 0.001). Comorbid viral infection was common in this group with 50% of all patients having other viruses isolated (predominantly polyoma virus and cytomegalovirus). We conclude that adenovirus is commonly isolated after bone marrow transplant and is a cause of significant morbidity but was a rare cause of mortality (6/572 = 1%) in our patient group as a whole. The relative infrequency of severe infection will make it difficult for the transplant physician to decide which patients should receive experimental antiviral drugs such as ribavirin and cidofovir or immunomodulatory therapy with donor white cell infusions.

Adenovirus Infections, Human↗
PubMed2000

Diagnosis of invasive aspergillosis in bone marrow transplant recipients by polymerase chain reaction.

A nested polymerase chain reaction (PCR) test targeting Aspergillus spp. large ribosomal subunit genes was evaluated retrospectively on 175 serum samples from 37 bone marrow transplant recipients, 70% of whom received grafts from unrelated donors. Six patients had proven infection, seven had probable infection, and three had possible infection, using the revised EORTC case definitions. These 16 patients were all PCR positive (57 out of 93 samples tested). Two additional patients who did not fulfil current diagnostic criteria, but in whom invasive aspergillosis (IA) was thought clinically probable, were also PCR positive (five out of nine samples). Invasive aspergillosis was unlikely in the remaining 19 patients, four of whom were PCR positive on a single occasion (four out of 70 samples). Three samples were inhibitory to PCR. Sensitivity of PCR in diagnosing patients with IA was 100%, specificity was 79% and positive predictive value was 80%, using the criterion of a single positive result. If two positive results were required, these values were 81%, 100% and 100% respectively. The median duration of infection documented by PCR was 36 days (range 3-248 days) in 17 out of 18 patients (94%) who did not survive. Positive PCR results predated the institution of antifungal therapy in two-thirds of patients. Four patients became PCR positive during pretransplant conditioning therapy.

Adolescent↗