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.

Evidence for a GVL effect following reduced-intensity allo-SCT in ALL: a British Society of Blood and Marrow Transplantation study.

Myeloablative allo-SCT decreases relapse incidence (RI) in ALL. Reduced intensity conditioning (RIC) may extend allo-SCT to older and less fit patients. Sixty-nine ALL patients reported to the BSBMT underwent fludarabine-based RIC allo-SCT, 38 from unrelated donors (UD). Forty-four patients received alemtuzumab. ALL was in CR in 64 patients (93%). This was a second or third SCT in 23 patients. Two-year OS and PFS were 36% and 32%, respectively. In multivariate analysis male recipients demonstrated better OS and PFS (hazard ratio (HR) = 0.42, P = 0.008 and HR = 0.45, P = 0.012, respectively). Two-year TRM was 29%: higher with younger age (HR = 0.97/year, P = 0.041), female recipient (HR = 2.55, P = 0.049) and increasing grade of acute GVHD (HR = 1.87, P = 0.001). Two-year RI was 38% and was lower in patients with acute and chronic GVHD (HR = 0.62 per increasing grade, P = 0.035 and HR = 0.52, P = 0.025, respectively). Long-term ALL-free survival is achievable following fludarabine-based RIC allo-SCT. The association between GVHD and decreased RI suggests the presence of a GVL effect.

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.

Midazolam in conjunction with local anaesthesia is superior to Entonox in providing pain relief during bone marrow aspirate and trephine biopsy.

AIM: To compare intravenous titrated midazolam 5-10 mg and inhaled Entonox in addition to local anaesthesia in order to identify which agent provides optimum pain relief. METHODS: Randomised, controlled trial. 49 patients were recruited, of which 46 were evaluable. 24 and 22 patients were recruited into the Entonox and midazolam arms, respectively. Patient experiences as well as staff observations were recorded with questionnaires after recovery from the procedure and 24 hours later. RESULTS: 45% and 59% of the patients in the midazolam arm could recollect the procedure after 15 minutes and 24 hours, respectively, compared to 96% and 88% who received Entonox. Midazolam provided a more comfortable experience (p<0.01) and improved pain relief (p = 0.01) compared to Entonox immediately after the procedure; this further improved when recalled 24 hours later. Nausea, dizziness and hallucinations were observed with both treatments, but dizziness was significantly more frequent with Entonox (p = 0.048). Clinically relevant respiratory depression (O(2) saturation <90%) occurred in 19% of patients in the midazolam arm; sedation was reversed with flumazenil. CONCLUSION: Midazolam in conjunction with local anaesthesia provides rapid and reversible sedation as well as effective pain relief during bone marrow biopsy, and is superior to Entonox; however, care must be taken to monitor respiratory function.

Outcome of second allogeneic transplants using reduced-intensity conditioning following relapse of haematological malignancy after an initial allogeneic transplant.

Disease relapse following an allogeneic transplant remains a major cause of treatment failure, often with a poor outcome. Second allogeneic transplant procedures have been associated with high TRM, especially with myeloablative conditioning. We hypothesized that the use of reduced-intensity conditioning (RIC) would decrease the TRM. We performed a retrospective national multicentre analysis of 71 patients receiving a second allogeneic transplant using RIC after disease relapse following an initial allogeneic transplant. The majority of patients had leukaemia/myelodysplasia (MDS) (N=57), nine had lymphoproliferative disorders, two had myeloma and three had myeloproliferative diseases. A total of 25% of patients had unrelated donors. The median follow-up was 906 days from the second allograft. The predicted overall survival (OS) and TRM at 2 years were 28 and 27%, respectively. TRM was significantly lower in those who relapsed late (>11 months) following the first transplant (2 years: 17 vs 38% in early relapses; P=0.03). Two factors were significantly associated with a better survival: late relapse (P=0.014) and chronic GVHD following the second transplant (P=0.014). These data support our hypothesis that the second RIC allograft results in a lower TRM than using MA. A proportion of patients achieved a sustained remission even when relapsing after a previous MA transplant.

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.

Stem cell transplantation for chronic lymphocytic leukaemia.

Early results of autologous stem cell transplantation (ASCT) in chronic lymphocytic leukaemia (CLL) suggested a significant proportion of patients remained disease-free for years, raising the possibility of cure. More recent studies have shown no evidence of a plateau in the survival curves indicating that, at best, ASCT may only prolong disease-free survival. Problems remain over progenitor cell mobilization and one study has raised anxieties about post-transplant myelodysplasia. The impact of ASCT in CLL will only be properly ascertained in a randomized clinical trial and this in underway in Europe. Initial results of conventional allogeneic transplantation (allo-SCT) were very disappointing, with an unacceptably high mortality, but did show that cure was possible in some patients. The introduction of reduced intensity conditioning has limited the early transplant-related mortality but it remains too early to determine what proportion of patients will be cured. In view of these uncertainties, is important that reduced intensity allo-SCT for CLL is conducted in the context of a clinical trial. Finally, CLL is very heterogeneous condition and great deal more is becoming understood about the prognostic factors. These will become important in allowing patients and their physicians a choice in balancing the risks of various treatment options.

Neurological complications following alemtuzumab-based reduced-intensity allogeneic transplantation.

We report the incidence, characteristics and outcome of neurological complications occurring following reduced-intensity conditioning (RIC) in 85 patients who received a related/unrelated donor stem cell transplantation following therapy with alemtuzumab, fludarabine and melphalan. Six patients (probability 8.9%) developed severe neurological complications at a median of 151 days (24-334 days). Five of them presented with progressive peripheral sensori-motor radiculo-neuropathy and/or myelitis, preceded by one or more viral reactivation/infection. Despite treatment with immunoglobulins/plasmapheresis/steroids, four died of respiratory failure due to progressive peripheral neurophathy. Viral infection was identified as the only risk factor for the development of neurological complications. Patients who are treated with alemtuzumab-based RIC may have a lower risk of developing regimen-related neurological complications, but are more susceptible to develop peripheral radiculo-neuropathy or myelitis. This phenomenon may be possibly related to viral infection associated with delayed immunological recovery or immunological dysregulation caused by alemtuzumab-induced T-cell depletion.

A randomised study comparing peripheral blood progenitor mobilisation using intermediate-dose cyclophosphamide plus lenograstim with lenograstim alone.

We conducted a prospective randomised study to compare the efficiency of out-patient progenitor cell mobilisation using either intermediate-dose cyclophosphamide (2 g/m(2)) and lenograstim at 5 micrograms/kg (Cyclo-G-CSF group, n=39) or lenograstim alone at 10 micrograms/kg (G-CSF group, n=40). The end points were to compare the impact of the two regimens on mobilisation efficiency, morbidity, time spent in hospital, the number of apheresis procedures required and engraftment kinetics. Successful mobilisation was achieved in 28/40 (70%) in the G-CSF group vs 22/39 (56.4%) for Cyclo-G-CSF (P=0.21). The median number of CD34+ cells mobilised was 2.3 x 10(6)/kg and 2.2 x 10(6)/kg for G-CSF and cyclo-G-CSF arms following a median of two apheresis procedures. Nausea and vomiting and total time spent in the hospital during mobilisation were significantly greater after Cyclo-G-CSF (P<0.05). Rapid neutrophil and platelet engraftment was achieved in all transplanted patients in both groups. In conclusion, G-CSF at 10 micrograms/kg was as efficient at mobilising progenitor cells as a combination of cyclophosphamide and G-CSF with reduced hospitalisation and side effects and prompt engraftment. When aggressive in-patient cytoreductive regimens are not required to both control disease and generate progenitor cells, the use of G-CSF alone appears preferable to combination with intermediate-dose cyclophosphamide.

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.

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.

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.

The diagnosis and management of acute myeloid leukaemia.

Significant advances have been made in the management of AML in younger patients in the last 20 years, and it is easier to identify individual risk groups and stratify treatment accordingly. Results remain discouraging in the elderly, except for the minority with favourable risk factors, and new approaches are needed for most of these patients.

Purification of cytomegalovirus-specific CD8 T cells from peripheral blood using HLA-peptide tetramers.

Cytomegalovirus (CMV) reactivation and disease remains an important clinical problem for patients after allogeneic stem cell transplantation. Impaired cellular immune control of viral replication is responsible for viral reactivation, and transfer of CMV-specific T cells from transplant donors can be effective in providing protection. Recent reports have indicated that the frequency of CMV-specific CD8(+) T cells in the peripheral blood of healthy donors is surprisingly high. Here we demonstrate that by using a combination of human leucocyte antigen (HLA) Class I-peptide tetramers and magnetic selection it is possible to select CMV-specific T cells from CMV antibody-positive individuals to high purity. Reliable purification of CMV-specific T cells up to 99.8% of CD8(+) cells was possible within hours, even when starting with a precursor frequency of < 0.1% of peripheral blood CD8(+) T cells. CMV-specific T cells remained functional after the selection process. This novel form of antigen-specific T-cell selection should facilitate the selection of T cells for cellular immunotherapy to treat or prevent CMV disease after transplantation. In addition, this technique could potentially be applied to many antigens including against other infective agents and tumour-specific antigens.

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.

Accelerated telomere shortening following allogeneic transplantation is independent of the cell source and occurs within the first year post transplant.

Telomere shortening has been documented in the blood cells of recipients of allogeneic bone marrow transplants compared with their donors. Allogeneic peripheral blood progenitor cells (PBPCs) have been increasingly used as an alternative to bone marrow. Their advantages include earlier engraftment and immune reconstitution following transplantation. We have measured telomere length of neutrophils and T cells in fully engrafted recipients of allogeneic bone marrow (n = 19) and allogeneic PBPC (n = 17) and also measured sequential telomere length in four patients after transplantation. Overall, significant telomere shortening occurred in recipients in neutrophils (0.3 kb, P < 0.001) and T cells (0.2 kb, P = 0.045). The data demonstrate that first, the degree of shortening was the same for BM and PBPC transplants and was not related to the time taken to engraft neutrophils and platelets and second, telomere shortening occurs in the first year post transplant without further shortening during the period of observation. These data suggest that the superiority of engraftment seen in PBPC transplants is independent of telomere shortening and other mechanisms such as homing or seeding may be more important.

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.