Does reduced-intensity allogeneic transplantation confer a survival advantage to patients with poor prognosis chronic lymphocytic leukaemia? A case-control retrospective analysis.

BACKGROUND: Reduced-intensity conditioning (RIC) allogeneic haemopoietic cell transplantation (allo-HCT) is increasingly considered as a therapeutic option for younger patients with poor-risk chronic lymphocytic leukaemia (CLL). In this retrospective analysis, we assessed the outcomes of CLL patients undergoing RIC allo-HCT compared with a group of matched controls that were candidates for transplantation but did not have a suitable donor or refused the procedure. PATIENTS AND METHODS: Cases comprised 37 patients who underwent RIC allo-HCT. Haemopoietic cell grafts were harvested from HLA-matched siblings (27) and unrelated donors (7). Controls consisted of 43 patients from the same institutions who received conventional therapy only. Matching variables were age at diagnosis and time to first CLL-specific therapy. RESULTS: Both patient groups were well balanced in terms of cytogenetics by FISH, CD38 and ZAP-70 expression, and immunoglobulin heavy-chain variable region mutational status. Median overall survival was 113 months for HCT patients and 85 months for controls when calculated from time of diagnosis (P = 0.072) and 103 and 67 months, respectively, when calculated from time of first therapy (P = 0.041). CONCLUSION: RIC allo-HCT is a reasonable option for patients with high-risk CLL. However, these results require confirmation before the procedure can be recommended outside clinical trials.

Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial.

BACKGROUND: Previous studies of patients with chronic lymphocytic leukaemia reported high response rates to fludarabine combined with cyclophosphamide. We aimed to establish whether this treatment combination provided greater survival benefit than did chlorambucil or fludarabine. METHODS: 777 patients with chronic lymphocytic leukaemia requiring treatment were randomly assigned to fludarabine (n=194) or fludarabine plus cyclophosphamide (196) for six courses, or chlorambucil (387) for 12 courses. The primary endpoint was overall survival, with secondary endpoints of response rates, progression-free survival, toxic effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number NCT 58585610. FINDINGS: There was no significant difference in overall survival between patients given fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Complete and overall response rates were better with fludarabine plus cyclophosphamide than with fludarabine (complete response rate 38%vs 15%, respectively; overall response rate 94%vs 80%, respectively; p<0.0001 for both comparisons), which were in turn better than with chlorambucil (complete response rate 7%, overall response rate 72%; p=0.006 and 0.04, respectively). Progression-free survival at 5 years was significantly better with fludarabine plus cyclophosphamide (36%) than with fludarabine (10%) or chlorambucil (10%; p<0.00005). Fludarabine plus cyclophosphamide was the best combination for all ages, including patients older than 70 years, and in prognostic groups defined by immunoglobulin heavy chain gene (V(H)) mutation status and cytogenetics, which were tested in 533 and 579 cases, respectively. Patients had more neutropenia and days in hospital with fludarabine plus cyclophosphamide, or fludarabine, than with chlorambucil. There was less haemolytic anaemia with fludarabine plus cyclophosphamide (5%) than with fludarabine (11%) or chlorambucil (12%). Quality of life was better for responders, but preliminary analyses showed no significant difference between treatments. A meta-analysis of these data and those of two published phase III trials showed a consistent benefit for the fludarabine plus cyclophosphamide regimen in terms of progression-free survival. INTERPRETATION: Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.

Single versus double volume exchange transfusion in jaundiced newborn infants.

BACKGROUND: Double volume exchange transfusion is commonly used in newborns with severe jaundice in order to prevent kernicterus and other toxicity related to hyperbilirubinemia. Most commonly, exchange transfusions are used in infants with rhesus hemolytic disease. OBJECTIVES: To compare the effectiveness of single volume exchange transfusion (SVET) with that of double volume exchange transfusion (DVET) in producing survival without disability and reducing bilirubin levels in newborn infants with severe jaundice. SEARCH STRATEGY: MEDLINE, EMBASE (Excerpta Medica online), The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), SCISEARCH (Science Citation Index), Reference lists from the articles identified in the search of the databases, and from review articles were searched through March 2006. Personal communication with experts in the field was used to identify unpublished data. SELECTION CRITERIA: All Randomised and quasi randomised control trials comparing single volume and double volume exchange transfusions in jaundiced newborn infants were included. DATA COLLECTION AND ANALYSIS: Safety and efficacy of single and double volume exchange compared with regards to long term neurodevelopment, reduction in bilirubin levels and other complications during exchange transfusion. Data was evaluated separately with regards to the cause of jaundice. Relative risk (RR) and weighted mean difference (WMD) were calculated for dichotomous and continuous variables respectively. 95% confidence intervals were used and a fixed effects model was assumed. MAIN RESULTS: Only one study fulfilled the criteria (Amato 1988). 20 full term babies requiring exchange transfusion for hemolytic jaundice due to ABO incompatibility were randomly allocated to receive single or double volume exchange transfusion. Base line characteristics of both groups were similar with regards to birth weight 3260 (SD 390) g vs. 3350 SD (410) g, gestational age 39 (SD 1) week vs. 40 (SD 0.8) week, immediate pre exchange bilirubin level 199 (SD 33) micromol/L vs. 216 (SD 55) micromol/L. Both groups were treated equally apart from the volume of blood used for exchange transfusion. Total bilirubin levels immediately after exchange transfusion were not significantly different in either group. No long term neurodevelopmental outcome was examined in this study. AUTHORS' CONCLUSIONS: There was insufficient evidence to support or refute the use of single volume exchange transfusion as opposed to double volume exchange transfusion in jaundiced newborns. A change from the current practice of double volume exchange transfusions for severe jaundice in newborns infant, cannot be recommended on current evidence.

Deletions at 11q identify a subset of patients with typical CLL who show consistent disease progression and reduced survival.

Eighty-four patients with typical chronic lymphocytic leukemia (CLL) (by morphological and immunophenotypic criteria) on whom karyotypes were available were studied. Binet stage at diagnosis and follow-up were defined. Survival was calculated from diagnosis. Fifty-one percent of patients had a karyotypic abnormality, the commonest being abnormalities at 13q14 (16%); these patients did not have significantly different survival from patients with normal karyotype. The second commonest abnormality was del(11q) (13%); these patients had significantly worse survival when compared both with patients with normal karyotype (P < 0.0001) and with other patients with karyotypic abnormality (P = 0.0012). All patients with del(11q) had progressed to stage C at follow-up while only 20% of the other patients had shown any disease progression (P < 0.0001). Del(11q) may identify a subset of patients with typical CLL who have worse survival and consistent disease progression and in future may help define a group of patients with CLL who could benefit from earlier or more intensive therapy.

Primary care management of early stage chronic lymphocytic leukaemia is safe and effective.

BACKGROUND: Chronic lymphocytic leukaemia (CLL) is the commonest leukaemia in western society. Most patients are detected incidentally at an early stage and require 'watch and wait' follow-up. In the UK, management of Stage A0 CLL varies with some centres advising regular outpatient haematology follow-up, whereas others recommend management within primary care. The safety and effectiveness of these two management options are currently unknown. METHODS: An observational retrospective cohort study in outpatient Haematology clinics at Queen Elizabeth Hospital Birmingham (QEH) and Birmingham Heartlands Hospital (BHH) and primary care practices in West Midlands, UK. All patients diagnosed with stable stage A0 CLL since 2002 at BHH or QEH were identified. At BHH, patients were discharged to primary care follow-up, whilst QEH patients remained under haematology for follow-up. Evidence of disease progression, need for treatment and overall mortality was documented. RESULTS: Two hundred and forty-six Stage A0 CLL patients were identified. One hundred and five (43%) patients were discharged to primary care, whilst 141 (57%) patients were followed up in haematology outpatient clinics. No difference in mortality or need for treatment was found between the two groups. Of those discharged, 93 (66%) remained in primary care. CONCLUSION: The management of stable-stage A0 CLL within primary or secondary care leads to equivalent clinical outcomes. The prevalence of early-stage CLL is expected to increase with the ageing population and management within primary care should be considered as a potentially effective approach.

Will mixed chimerism cure autoimmune diseases after a nonmyeloablative stem cell transplant?

BACKGROUND: Mixed chimerism after allogeneic bone marrow transplantation has been shown to cure a number of genetic disorders in both the clinical and experimental settings. Although encouraging results have been reported from animal experiments, the role of mixed chimerism in eliminating autoimmune disorders is not clear. METHODS: A 50-year-old man with extensive psoriasis received an allogeneic transplant from his brother after nonmyeloablative conditioning with fludarabine, melphalan, and Campath-1H for relapsed non-Hodgkin's lymphoma. The chimerism status and the immunological recovery after the transplant were serially monitored. RESULTS: Twenty-one months after the transplant, the patient continues to be in complete remission from psoriasis and lymphoma with stable mixed chimerism (30% to 40% donor cells), despite significant recovery of T-cell subsets and antigen-specific response. CONCLUSIONS: If mixed chimerism can be achieved safely with novel low-intensity conditioning regimens and results in sustained remission of autoimmune diseases, allogeneic transplantation may become a realistic therapy in the management of some patients with autoimmune disease.

Respiratory virus infections in adult T cell-depleted transplant recipients: the role of cellular immunity.

BACKGROUND: Little is known about the role of cellular immunity in respiratory virus infections after bone marrow transplantation. METHODS: Forty allograft recipients T-cell depleted with Campath antibodies were evaluated for respiratory virus infections in an active surveillance program with early initiation of antiviral therapy. RESULTS: Eighteen episodes of respiratory virus infection were detected in nine patients (22%) at a median of 95 days, with lower respiratory involvement in 44%. Fourteen episodes were treated with antiviral therapy for 7 to 46 days, with 11% mortality. Respiratory virus infections were more common in patients receiving Campath 100 mg in vivo, but delayed CD4+ recovery was the most significant risk factor. CONCLUSIONS: Respiratory virus infections are common and often recurrent in patients with severe CD4+ T lymphopenia. However, the mortality was low, which may have been due to early institution of antiviral treatment or reduced inflammatory damage to the lungs due to severe lymphopenia.

Polyoma viruria following T-cell-depleted allogeneic transplants using Campath-1H: incidence and outcome in relation to graft manipulation, donor type and conditioning.

Haemorrhagic cystitis (HC) is an important cause of morbidity following stem cell transplantation (SCT) and has been associated with polyoma virus infection. We studied the incidence and outcome of polyoma virus infection in 58 T-cell-depleted SCT patients. T-cell depletion was carried out using Campath-1H, either 10 or 20 mg in vitro (n=33) or 50 or 100 mg in vivo (n=25) following conventional (n=35) or nonmyeloablative conditioning (n=23). A total of 21 patients (36%) had polyoma viruria at a median of 35 days (5-114); 30% among patients receiving Campath in vitro and 44% among those given in vivo. The only risk factor for polyoma viruria was graft-versus-host disease GVHD grade >or=2. The onset of polyoma viruria coincided with Cytomegalovirus (CMV) reactivation in all six patients who reactivated both viruses. Prolonged viruria (defined as polyoma viruria >2 weeks) was documented in 10 patients (17%) and this was associated with GVHD >or=grade 2. HC occurred in four patients. Prolonged viruria was associated with HC only in patients receiving unrelated donor grafts following conventional conditioning. HC was not observed following nonmyeloablative conditioning despite a higher incidence of prolonged viruria. Thus, HC was uncommon in patients with polyoma viruria following T-cell depletion with Campath, particularly after reduced intensity conditioning.

Listeria meningitis after bone marrow transplantation.

Over the past decade infections from food-borne Listeria monocytogenes have become an important cause of septicaemia and meningitis and immunocompromised patients are at particular risk. We report three cases of Listeria meningitis occurring post-BMT. The patients were aged 53, 51 and 56 years and presented 4, 7 and 90 months post-transplant, respectively. The first patient had undergone allogeneic BMT for myelodysplasia and the other two patients had ABMT for AML in second and first CR, respectively. All the patients presented with classical features of meningitis and L. monocytogenes was cultured from cerebrospinal fluid. All made a full recovery with appropriate antibiotic therapy. We have not seen cases of meningitis due to other organisms in our transplant programme and the cases represent a risk of one episode per 59 surviving patient years. None of the patients was receiving prophylactic post-BMT antibiotics and the episodes may strengthen the case for using prophylactic penicillin. Recent epidemics of septicaemia and meningitis caused by L. monocytogenes-contaminated milk and cheese suggest that these patients should be informed about potential sources of infection.

Fulminant adenovirus hepatitis following unrelated bone marrow transplantation: failure of intravenous ribavirin therapy.

Fulminant hepatic failure due to adenovirus infection is a rare complication following stem cell transplantation. We report this complication in an unrelated bone marrow transplant recipient 30 weeks post-transplant. Treatment with intravenous ribavirin was started within 36 h of admission, but he succumbed to unusually fulminant hepatic failure. Adenovirus type 2 was isolated from stool surveillance samples and from post-mortem liver samples. Adenovirus DNA was detected by PCR in blood and sputum samples at admission and was identified in post-mortem liver tissue by electron microscopy. Implications of the failure of ribavirin therapy are discussed.

Clostridium difficile infection in allogeneic stem cell transplant recipients is associated with severe graft-versus-host disease and non-relapse mortality.

We retrospectively evaluated 75 allogeneic stem cell transplant recipients to ascertain the incidence, risk factors and outcome of infection with Clostridium difficile. Ten patients (13%) had Clostridium difficile infection at a median of 38 days (range day -6 to day +72) following the transplant. There was no difference in the duration or severity of diarrhoea in patients with Clostridium difficile infection compared to the uninfected patients and no relationship to the prior antibiotic or chemotherapy usage, age, gender, underlying disease, donor type, CMV serostatus, total body irradiation or time to engraftment. The incidence of viral infections was increased in patients infected with Clostridium difficile (7/10 vs 15/65, P = 0.005, odds ratio 7.7), but the strongest association was with GVHD >grade 2 (5/10 vs 6/65 uninfected patients, P = 0.004, odds ratio 9.8). Patients infected with Clostridium difficile also suffered a higher non-relapse mortality with 7/10 patients succumbing to either GVHD or infections, compared to 19/65 patients in the uninfected group (P = 0.02, odds ratio 5.6). Thus Clostridium difficile infections in our study had a strong association with GVHD and increased non-relapse mortality. It is possible that Clostridium difficile toxin might predispose to increased severity of GVHD leading to an adverse outcome.

Adenovirus infections following haematopoietic cell transplantation: is there a role for adoptive immunotherapy?

Adenovirus has been recognised as an important pathogen in BMT recipients, especially in patients with GVHD and those receiving T cell-depleted allografts. We report adenovirus infections from an ongoing surveillance study in four patients after a non-myeloablative transplant and their improved outcome following withdrawal of immunosuppression in two patients and donor lymphocyte infusion for relapsed disease in the others. We discuss the control of adenovirus infections following immune manipulations and the feasibility of adoptive immunotherapy for post-transplant adenovirus infections.

Philadelphia-positive T-ALL in a patient with follicular lymphoma.

Follicular lymphoma is a B cell malignancy prone to transformation into a large cell diffuse histology. This progression may be multi-clonal as determined by IgH rearrangement. Similar multi-clonal occurrences have been described in immunocompromised patients. However, the lymphoma cells remain predominantly of B cell type. Rarely, composite lymphomas with diffuse T cell histology have been reported arising from follicular lymphoma. The development of T cell leukaemia in a patient with a pre-existing B cell malignancy is an extremely rare event. The occurrence of T cell acute lymphoblastic leukaemia (T-ALL) following follicular lymphoma (FL) has not previously been reported. We report a case of Philadelphia positive (Ph+) T cell ALL developing in a patient who previously had FL which may give some insight into the cell of origin and the defects responsible for malignant transformation of the lymphocytes.

Percutaneous insertion of subclavian Hickman catheters.

We have assessed the percutaneous insertion of Hickman catheters implanted directly into the subclavian vein; 116 catheters were inserted in 86 patients. The catheters were all inserted by members of the haematology staff. The majority of the catheters were inserted under local anaesthetic in a haematology ward with filtered positive pressure ventilation. X-ray screening was not routinely used. The average patient age was 45 years and the average platelet count was 155 x 10(9)/l. Sixty-seven per cent of the catheters either remain in situ or have been removed electively or at death. The remainder have been removed for a variety of reasons (infection 10%, suspected infection 8%, accidental dislodgement 7%, thrombosis 4%, catheter blockage 3%, catheter fracture 0.9%). The only complication specific to direct subclavian puncture was pneumothorax (4%). This disadvantage may be offset by rapid insertion, a cosmetically superior result and the avoidance of surgical and operating theatre time.

Enterovirus infections following T-cell depleted allogeneic transplants in adults.

Anecdotally, enteroviruses have been reported to cause serious complications post BMT, but the exact impact of these viruses in the post transplant period has not been reported. We prospectively evaluated stool, urine and throat samples for enteroviruses by viral culture together with relevant body fluids by RT-PCR in 64 allograft recipients receiving grafts T-cell depleted by Campath-1H, following both conventional and reduced-intensity conditioning. Seven patients (10.4%) developed nine episodes of enterovirus infections at a median of 146 days post transplant. Four episodes were associated with symptomatic illnesses, which could be attributable to enteroviruses. There was no mortality directly related to enteroviruses. There was no correlation between dose and mode of Campath-1H use, lymphocyte recovery, IgG and IgA levels and enterovirus isolation. Although enteroviruses tended to be more frequent in TBI-based conventional conditioning recipients, the only significant risk factor for enterovirus infection was unrelated donor graft. The low incidence of the severe enterovirus infections could have been related to a low lymphocyte count in this cohort in the absence of GVHD, particularly CD4+ count, which has been implicated in tissue damage in experimental animals. Further studies are needed to define its impact in different allograft settings.

Gonadal function and psychosexual adjustment in male long-term survivors of bone marrow transplantation.

Gonadal function and psychosexual adjustment were evaluated in 29 male patients after autologous and allogeneic BMT (mean post-BMT time 35.6 months). Patients were divided into groups according to their interval from transplant in order to evaluate gonadal function throughout the post-BMT years. Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were normal throughout the post-BMT years. Follicle-stimulating hormone (FSH) and luteinising hormone (LH) were increased throughout the years after BMT, suggesting moderate compensated hypogonadism. Hyperprolactinaemia was observed only in the 2nd year post-BMT and testosterone levels were normal, suggesting that Leydig cells can withstand alkylating agents or TBI. Psychosexual functioning in BMT survivors was compared with that of a group of mixed-diagnosis cancer patients (n = 30) and a group of healthy young subjects (n = 119). Long-term BMT survivors had similar psychosexual adjustment to that of other cancer patients who had received less intensive chemotherapy. Half the patients were dissatisfied with their current sex life. Major problems included impotence/erectile difficulties (37.9%), low sexual desire (37.9%) and altered body image (20.7%). However, both BMT survivors and cancer patients had significantly higher psychosexual dysfunction compared with healthy subjects. The type of chemotherapy, TBI (either single-dose or fractionated), type of transplant and post-BMT time did not correlate with either gonadal or psychosexual functioning.

Quality assurance of CD34+ cell estimation in leucapheresis products.

In order to examine the feasibility of an external quality assurance (QA) scheme for CD34+ cell enumeration and to identify causes of the differences between laboratories for CD34 counts, we carried out a pilot QA exercise in two parts. There were eight participating laboratories in the initial study and each performed CD34 counts using their in-house method. A series of 12 samples of cryopreserved peripheral blood progenitor cells (PBPC) were analysed by each of the eight laboratories. A very wide range of values for all the samples was found for the different in-house methods. For the second part of the study, 12 laboratories analysed a different set of 12 PBPC samples and each used the same anti-CD34 antibody (HPCA-2 PE), anti-CD45 antibodies to identify leucocytes, and counted a minimum of 50,000 events. These measures have reduced the interlaboratory variation in results but this variation is still too high to allow us to realistically compare values between centres. Overall, most centres performed comparably, but there was one centre in part one of the study which gave results that were significantly different from the other centres.

Isolation of viruses from stools in stem cell transplant recipients: a prospective surveillance study.

We prospectively examined stool specimens for enteric viruses in 75 stem cell transplant recipients (autologous 48, allogeneic 27) to determine the frequency and significance of these infections. Only six patients (8%) had a positive isolate. Five of these were allograft recipients (18%) compared to one autograft recipient (2%) (P = 0.02). Unrelated donor BMT recipients were at the highest risk for a viral isolate (OR = 10.5). Adenovirus was the commonest isolate (four patients). One patient each had an echovirus, enterovirus and small round structured virus identified. No correlation was found between the severity of gastro-intestinal symptoms and detection of a viral pathogen. There was no correlation with GVHD or CMV status. The only risk factor identified for isolation of an enterovirus was allogeneic BMT from an unrelated donor. There was a negative correlation with PBSC grafts. All the patients infected with an enteric virus had concomitant infection with other pathogens, compared to only 18% of uninfected patients (P = 0.001). The non-relapse mortality of the infected patients was 50% and only 7% in the uninfected patients (P = 0.01, OR = 12.5), although the isolated virus was the direct cause of death in one patient only. This study indicates a low rate of enteric virus isolation in recipients of PBSC grafts, both autologous and allogeneic. However, unrelated donor BMT is associated with a higher risk of enteric virus infection and an adverse outcome. Bone Marrow Transplantation (2000) 25, 277-282.

Pre-emptive oral ribavirin therapy of paramyxovirus infections after haematopoietic stem cell transplantation: a pilot study.

Infections with the paramyxoviruses, respiratory syncytial virus (RSV) and parainfluenza virus (PIV) can result in serious morbidity and mortality after haemopoietic stem cell transplant (HSCT). Once pneumonia develops, the outcome of these infections is often poor despite anti-viral therapy. Aerosolised ribavirin has been evaluated as pre-emptive therapy for post-transplant RSV infections with some success. Due to the financial and logistic burden involved with the use of aerosolised ribavirin, we explored the efficacy and toxicity of oral ribavirin for pre-emptive therapy of post-transplant RSV and PIV infections in a dose escalating schedule (15-60 mg/kg/day). Five episodes each of RSV and PIV were treated in seven patients. Five patients were receiving treatment for GVHD and two acquired the infection in the pre-engraftment period. All the episodes of RSV infection improved with oral ribavirin with dose escalation to 30-45 mg/kg in three of them. On the other hand, only two of the five PIV infections improved with oral ribavirin. Of the three non-responders, two infections were acquired in the pre-engraftment period with one death from PIV pneumonia. Reversible anaemia was the only side-effect noted in patients treated for over 2 weeks. Thus, the use of oral ribavirin was well tolerated in the post-transplant period with no untoward toxicities. There was a trend towards better response in RSV infections, which needs to be further explored in controlled studies.

Cidofovir as primary pre-emptive therapy for post-transplant cytomegalovirus infections.

Pre-emptive antiviral therapy for CMV infection following allogeneic stem cell transplantation is an effective strategy for preventing CMV disease. This entails the logistic difficulty of daily intravenous therapy with ganciclovir or foscarnet to clinically asymptomatic patients. Cidofovir (CDV) is effective against CMV in vitro and has the practical advantage of weekly administration. However, there are limited data on the pre-emptive use of CDV in CMV infections. We carried out a pilot study exploring the efficacy and toxicity of CDV as primary pre-emptive therapy for CMV infections monitored by PCR-based assays. CDV was used at 5 mg/kg with probenecid and hydration, weekly for a maximum of 4 weeks, followed by fortnightly maintenance treatment. Four patients were treated with CDV and two of them responded. Both the non-responders developed CMV disease. There was no renal toxicity noted in any of the patients, but three patients had severe vomiting and one developed uveitis, which precluded maintenance treatment in the two responders. Following failure of CDV, foscarnet was effective in controlling the CMV infection in both patients, although the infection recurred in both. Thus, larger randomised studies are required before CDV can be recommended as a primary pre-emptive therapy for post-transplant CMV infections.