Health-related quality of life after chemotherapy with or without rituximab in primary central nervous system lymphoma patients: results from a randomised phase III study.

BACKGROUND: The impact of rituximab on health-related quality of life (HRQoL) in primary central nervous system lymphoma patients is not well known. We determined the impact of rituximab added to standard high-dose methotrexate-based treatment on HRQoL in patients in a large randomised trial. PATIENTS AND METHODS: Patients from a large phase III trial (HOVON 105/ALLG NHL 24), randomly assigned to receive standard chemotherapy with or without rituximab and followed by 30 Gy whole brain radiotherapy (WBRT) in patients ≤60 years, completed the EORTC QLQ-C30 and QLQ-BN20 questionnaires before and during treatment, and up to 24 months of follow-up or progression. Differences between treatment arms over time in global health status, role functioning, social functioning, fatigue, and motor dysfunction were assessed. Differences ≥10 points were deemed clinically relevant. The effect of WBRT on HRQoL was analysed in irradiated patients. RESULTS: A total of 160/175 patients eligible for the HRQoL study completed at least one questionnaire and were included. Over time, scores improved statistically significantly and were clinically relevant in both arms. Between arms, there were no differences on any scale (range: -3.8 to +4.0). Scores on all scales were improved to a clinically relevant extent at 12 and 24 months compared with baseline in both arms, except for fatigue and motor dysfunction at 12 months (-7.4 and -8.8, respectively). In irradiated patients (n = 59), scores in all preselected scales, except motor dysfunction, remained stable up to 24 months compared with shortly after WBRT, overall mean difference ranging between 0.02 and 4.570. CONCLUSION: Compared with baseline, treatment resulted in improved HRQoL scores. The addition of rituximab to standard chemotherapy did not impact HRQoL over time. WBRT did not result in deterioration of HRQoL in the first 2 years.

Lymphocyte reconstitution following autologous stem cell transplantation for progressive MS.

BACKGROUND: Autologous stem cell transplantation (ASCT) for progressive multiple sclerosis (MS) may reset the immune repertoire. OBJECTIVE: The objective of this paper is to analyse lymphocyte recovery in patients with progressive MS treated with ASCT. METHODS: Patients with progressive MS not responding to conventional treatment underwent ASCT following conditioning with high-dose cyclophosphamide and antithymocyte globulin. Lymphocyte subset analysis was performed before ASCT and for two years following ASCT. Neurological function was assessed by the EDSS before ASCT and for three years post-ASCT. RESULTS: CD4+ T-cells fell significantly post-transplant and did not return to baseline levels. Recent thymic emigrants and naïve T-cells fell sharply post-transplant but returned to baseline by nine months and twelve months, respectively. T-regulatory cells declined post-transplant and did not return to baseline levels. Th1 and Th2 cells did not change significantly while Th17 cells fell post-transplant but recovered to baseline by six months. Neurological function remained stable in the majority of patients. Progression-free survival was 69% at three years. CONCLUSION: This study demonstrates major changes in the composition of lymphocyte subsets following ASCT for progressive MS. In particular, ablation and subsequent recovery of thymic output is consistent with the concept that ASCT can reset the immune repertoire in MS patients.

Prognostic nomogram for diffuse large B-cell lymphoma incorporating the International Prognostic Index with interim-positron emission tomography findings.

BACKGROUND/AIMS: Results from interim-positron emission tomography (PET) studies in diffuse large B-cell lymphoma (DLBCL) patients are varied. We evaluated the prognostic value of interim-PET in our centre. To improve concordance, interim-PET was combined with the International Prognostic Index (IPI). METHODS: We retrospectively reviewed 100 new consecutive DLBCL patients treated with immunochemotherapy from 2005 to 2010. Twenty-four patients did not receive interim-PET and were excluded. Interim-PET images were re-examined using a qualitative assessment technique. Progression-free survival (PFS) and overall survival (OS) were analysed by the Cox proportional hazards model and prognostic accuracy was assessed using Harrell's C statistics (C). RESULTS: Eleven patients were positive, and 65 were negative at interim-PET. The 2-year OS and PFS were 70.8% and 60.0%, respectively, in the PET-negative group, 36.4% and 36.4% for the PET-positive group (log-rank P-value 0.0008 for PFS, 0.0001 for OS). The IPI and interim-PET were minimally correlated. On Cox regression analysis, both were significant indicators of PFS (P < 0.001 and P = 0.002 respectively). The prognostic accuracy for PFS of a negative PET result was limited (C = 0.63), as it was for IPI (C = 0.75), but with the two indicators combined, the predictive accuracy was improved (C = 0.81). A nomogram, predictive for relapse-free survival at 2 years, was constructed. CONCLUSION: In DLBCL patients treated with immunochemotherapy, the IPI and interim-PET provide independent prognostic information. In combination, a more powerful predictive model may be created as a nomogram. This can be refined in prospective trials and may help clinical decision making.

When the safety net of treatment has been removed: patients' unmet needs at the completion of treatment for haematological malignancies.

OBJECTIVE: To determine patients' information, emotional and support needs at the completion of treatment for a haematological malignancy. METHODS: A self-report questionnaire was mailed to 113 adult patients. RESULTS: Sixty-six questionnaires were returned. The most frequently endorsed patient needs related to care co-ordination and help to manage the fear of recurrence. The most frequently endorsed unmet needs included managing the fear of recurrence, the need for a case-manager and the need for communication between treating doctors. Predictors of unmet needs included younger patients (p=0.01), marital status (p=0.03) and employment (p=0.03). Almost two-thirds of patients (59%) reported they would have found it helpful to talk with a health care professional about their experience of diagnosis and treatment at the completion of treatment and endorsed significantly more need in the arenas of Quality of Life (p=0.03) and Emotional and Relationships (p=0.04). CONCLUSION: This study provides valuable data on haematological cancer patients' needs in the first 12 months of finishing treatment. It appears that many needs emerge or remain unresolved at this time. PRACTICE IMPLICATIONS: An opportunity for patients to talk with a health professional about making the transition from active treatment to extended survivorship may be helpful.

Thrombotic microangiopathy from Australian brown snake (Pseudonaja) envenoming.

BACKGROUND: Australian brown snake (genus Pseudonaja) envenoming causes a venom-induced consumptive coagulopathy (VICC). A proportion of cases go on to develop thrombotic microangiopathy characterized by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and acute renal failure (ARF). AIM: The aim of the study was to define better the natural history and empirical treatments for thrombotic microangiopathy in brown snake envenoming. METHODS: A review of brown snake bites recruited to the Australian Snakebite Project (ASP), a national multicentre study of snake envenoming was undertaken. Serial data are recorded on clinical effects and laboratory results, including measurement of venom concentrations. We describe cases of thrombotic microangiopathy and compare these to cases without thrombotic microangiopathy. RESULTS: From 32 cases of brown snake envenoming with severe VICC, four (13%) developed thrombotic microangiopathy, we also included two cases of thrombotic microangiopathy from prior to ASP. All six developed severe thrombocytopenia (<20 x 10(-9)/L), worst 3 days after the bite and resolving over a week, MAHA with fragmented red blood cells on the blood film and five developed anuric ARF requiring dialysis and lasting 2-8 weeks. All six received antivenom, which was delayed compared with other brown snake-envenoming cases. Four were treated with plasmapheresis. The severity and recovery of the thrombocytopenia, anaemia and renal function were similar with and without plasmapheresis. The median length of stay for MAHA cases was 14 days (interquartile range (IQR) 12-14) compared to 1.8 days (IQR 1.3-2) for all other cases. CONCLUSION: Thrombotic microangiopathy resulting from brown snake bite appears to have a good prognosis and management should focus on early antivenom therapy and supportive care including dialysis. The role of plasmapheresis is yet to be defined.

Symptomatic hypocalcaemia and renal impairment associated with bisphosphonate treatment in patients with multiple myeloma.

We report three cases of severe hypocalcaemia associated with i.v. bisphosphonate treatment in patients with multiple myeloma. All patients had symptomatic hypocalcaemia, including a tonic-clonic seizure and tachyarrhythmia in one case. Two cases were associated with the development of acute renal failure, whereas the third patient had pre-existing renal impairment. We recommend that bisphosphonates be used with caution in patients with myeloma and renal impairment, that vitamin D deficiency be corrected prior to treatment (to reduce the risk of hypocalcaemia) and that serum calcium and renal function be monitored during treatment.

Baseline characteristics of the transient pattern electroretinogram in non-human primates: inter-ocular and inter-session variability.

This study assessed the inter-ocular and inter-session variability of the transient pattern electroretinogram (PERG) in a group of non-human primates. The transient PERG was measured both eyes of 29 non-human primates, and again after three months in 23 eyes of 23 of these animals. Signals were elicited using a contrast (90%, 75 cdm(-2)) reversing (5 reversals sec(-1)) checkerboard pattern (0.56 cpd). PERGs were also measured for stimuli of varied spatial frequency (n=8, 0.07-2.22 cpd), contrast (n=4, 20-100%), mean luminance (n=4, 4.7-75 cdm(-2)) and defocus (n=5, +1, +2, +3 diopters). The inter-eye and inter-session limits-of-agreement (LOA; 95%) were determined for each PERG parameter. Variability was also compared with previous studies using the coefficient-of-variability (COV). Pharmacological blockade of the inner retinal contributions to the PERG measured under these conditions was conducted in one animal using intravitreal injection of tetrodotoxin (approximately 6 microM) and N-methyl-D-aspartic acid (approximately 6 microM). The N95 component of the primate transient PERG showed spatial tuning, with a peak between 0.14 and 0.28cpd. This spatial tuning was not as apparent for the P50 component. A linear relationship between P50 and N95 amplitude was found with contrast and mean luminance. Both components were attenuated with the introduction of +2 diopters or more of defocus. The inter-session COV for the P50 and N95 components were 23.8 and 19.2%, respectively, while the LOA were 58 and 46%, respectively. The N95:P50 ratio had smaller inter-session variability, was robust to changes in contrast, mean luminance and defocus, and was effective for characterization of inner-retinal dysfunction after pharmacologic block.

Depth of penetration of scanning laser Doppler flowmetry in the primate optic nerve.

OBJECTIVES: To estimate the measuring depth of the blood flow and to establish the vascular contributions to these measurements with scanning laser Doppler flowmetry (SLDF) of the primate anterior optic nerve. METHODS: Optic nerve blood flow in each eye of 8 monkeys was measured using SLDF before and following surgical occlusion of the central retinal artery (n = 4) or posterior ciliary arteries (n = 4). The regional blood flow in both eyes was determined using a nonradioactive microsphere method. RESULTS: The blood flow in the nerve fiber layer (NFL), including the prelaminar region, was measured with microspheres after central retinal artery occlusion; it was significantly reduced (-83%) with no significant change in the combined laminar and retrolaminar regions. The blood flow measured with SLDF had a 51% reduction. After posterior ciliary artery occlusion, the blood flow in the NFL was measured with microspheres and was not significantly affected (+2%); neither was that measured with SLDF (-12%). However, there was a 51% reduction in the laminar and retrolaminar regions when microspheres were used. The mean +/- SD tissue thickness of the NFL was 359 +/- 16 microm and 353 +/- 54 microm in each group. CONCLUSIONS: Scanning laser Doppler flowmetry measures blood flow principally in the NFL of the anterior optic nerve, which is primarily supplied by the central retinal artery. Blood flow in the laminar and retrolaminar regions makes a small contribution to the SLDF measurement, with an NFL thickness between 300 and 400 microm. CLINICAL RELEVANCE: Scanning laser Doppler flowmetry is used for the noninvasive evaluation of ocular microcirculation in diseases such as glaucoma. Because of the dual blood flow supply in the optic nerve and the limited penetration power of the laser, the instrument primarily measures the microcirculation on the surface of the optic nerve, which is largely supplied by the central retinal artery rather than the ciliary arteries.

Allogeneic stem-cell transplantation for lymphoproliferative disorders using BEAM-CAMPATH (+/- fludarabine) conditioning combined with post-transplant donor-lymphocyte infusion.

BACKGROUND: We report our updated experience of allogeneic transplantation in lympho-proliferative disorders using a reduced-intensity conditioning regimen combining BEAM (plus fludarabine in three cases) with pre-transplant CAMPATH. Post-transplant donor lymphocytes have been infused for persisting disease or relapse, and both chimerism and minimal residual disease have been monitored utilizing molecular techniques. METHODS: Thirty patients with median age 47.6 years underwent allogeneic transplantation for relapsed or high-risk lymphoproliferative disease using HLA-identical (sibling n = 25, unrelated n = 2) or one antigen mismatched sibling donors (n = 3). Twenty-one had NHL, three had HD and six had CLL/PLL. Stem-cell source was PBSC (n = 24), BM (n = 5) or both (n = 1) with a median CD34 dose of 4.5 x 10(6)/kg. GvHD prophylaxis was with CYA and MTX. RESULTS: Engraftment was prompt in the majority of patients, with a median of 15 days to both ANC > 0.5 and platelets > 20. There have been three transplant-related deaths secondary to viral pneumonitis or bacterial pneumonia. Seven patients developed Grade I-II acute GvHD post-transplant. Of 28 evaluable patients, 18 achieved a CR at assessment 2-3 months post-transplant and a further patient converted from PR to CR following DLI, to give an overall CR rate of 68%. Three patients had early progressive disease and six have relapsed from CR or progressed from PR (two of whom have achieved CR following DLI therapy). Overall survival is 67% and event-free survival 48% at 3 years. With a median follow-up of 1.3 years 57% of patients are currently alive and lymphoma-free. A molecular remission has been achieved in nine of 12 informative patients. DISCUSSION: These encouraging results show that this reduced-intensity conditioning regimen is effective, with a low-toxicity profile compared with conventional TBI-based conditioning, and certainly merits further evaluation in this setting.

Preliminary experience of allogeneic stem cell transplantation for lymphoproliferative disorders using BEAM-CAMPATH conditioning: an effective regimen with low procedure-related toxicity.

Autologous transplantation has an established role in the treatment of lymphoproliferative disorders, but allogeneic transplantation remains controversial. In an attempt to reduce the high procedure-related mortality reported with allografting in lymphoma, we have used BEAM (BCNU, etoposide, cytarabine and melphalan), a standard conditioning regimen for autologous transplantation. As BEAM may be insufficiently immunosuppressive to permit durable engraftment in the allogeneic setting, patients received additional pretransplant immunosuppression with the anti-CD52 antibody CAMPATH-1G from day -5 to day -1. Twelve patients (median age 46 years) underwent allogeneic transplantation for lymphoma (n = 11) or chronic lymphocytic leukaemia (n = 1) from HLA-identical (n = 9) or mismatched (n = 3) sibling donors. Cyclosporin A and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. One patient died of progressive lymphoma at day +12, the remaining 11 patients engrafted rapidly, with eight demonstrating full donor chimerism. One patient had an episode of rejection and received a further stem cell infusion with sustained recovery. Only one patient developed GVHD (grade I). The low incidence of acute GVHD may be in part related to persisting levels of in vivo CAMPATH-IG at the time of transplantation. Of 11 evaluable patients, nine achieved complete remission (CR), and a further patient achieved CR after donor lymphocyte infusion at 5 months. Our preliminary experience is that this regimen was well tolerated with a low risk of GVHD and appears no more toxic than a BEAM autograft. Further follow-up is required to see whether the low incidence of GVHD impacts upon relapse risk.

The effect of the serotherapy regimen used and the marrow cell dose received on rejection, graft-versus-host disease and outcome following unrelated donor bone marrow transplantation for leukaemia.

Unrelated donor (UD) transplantation is the only potentially curative therapy for many leukaemia patients but is associated with a high mortality and morbidity. We sought to identify factors that could be optimised to improve outcome following UD transplantation in adults. Data was retrospectively analysed on 55 patients sequentially receiving UD transplants for CML or acute leukaemia (AL), all of whom received serotherapy for the prevention of GVHD and rejection. All patients received standard conditioning regimens. The first 28 patients transplanted also received combined pre- and post-transplant serotherapy with Campath 1G (days -5 to +5) and standard dose CsA plus MTX as GVHD prophylaxis (protocol 1). The subsequent 27 patients received a 5-day course of pre-transplant serotherapy alone either with ATG (CML patients) or Campath 1G (AL patients) on days -5 to -1 inclusive, with high-dose CSA plus MTX (protocol 2). The incidence of acute GVHD was low with no patient receiving either protocol developing > grade 2 disease. The use of protocol 2 and the administration of a bone marrow cell dose above the median (2.17 x 10(8)/kg) were the most important factors predicting engraftment (P = 0.03 and P = 0.001, respectively) but this only remained significant for cell dose in multivariate analysis (P = 0.03). Overall survival for the group was 45% at 3 years and was influenced by both age (P = 0.02) and disease status at transplantation (P = 0.001). Receiving a cell dose above the median was also associated with a trend towards better survival (P = 0.08), due primarily to a reduction in the TRM to 8.2% compared with 54.5% in those receiving a lower cell dose (P = 0.002). We conclude that pre-transplant serotherapy alone is highly effective at preventing acute GVHD following UD BMT and that additional post-transplant serotherapy does not confer any benefit. Furthermore, a high marrow cell dose infused has a major effect in reducing transplant related mortality following UD BMT.

Generation of anti-idiotype immune responses following vaccination with idiotype-protein pulsed dendritic cells in myeloma.

Myeloma cells produce immunoglobulin which is unique to the malignant clone and presents antigenic determinants, or idiotypes, which may function as a tumour-specific antigen. The availability of significant quantities of idiotype protein in the serum makes immunotherapeutic strategies utilizing this protein to generate an anti-idiotype immune response an attractive prospect. We treated two patients with advanced refractory myeloma with a series of four vaccinations using autologous idiotype-protein pulsed dendritic cells combined with adjuvant GM-CSF. The vaccinations were well tolerated with a mild fever post-vaccination in one patient. An idiotype-specific T-cell proliferative response developed in both patients. This T-cell response was associated with the production of gamma-interferon, indicating a TH-1-like response. Furthermore, one patient developed anti-idiotype IgM antibodies. However, no idiotype-specific cytotoxic T-cell response could be demonstrated. Further investigation is warranted to define the optimal conditions for dendritic cell culture and priming to maximize the anti-tumour immune response.

Low incidence of human herpesvirus 8 in stem cell collections from myeloma patients.

Human herpesvirus 8 is a gammaherpesvirus which may be implicated in the pathogenesis of multiple myeloma. Viral DNA sequences have been found in the bone marrow, peripheral blood and leukapheresis products of myeloma patients. These findings have significant implications for the use of leukapheresed cells in the transplantation and immunotherapy of myeloma. The studies suggest the cell which harbours the virus may be dendritic in origin. We have previously reported that dendritic cells cultured for use in the clinical setting do not harbour HHV-8. In this study, we examined the leukapheresis products of a larger cohort of myeloma patients for the presence of HHV-8 using a highly sensitive PCR technique. A strong association between HHV-8 and myeloma was not confirmed, with only 4% of the patient samples positive for viral sequences. While further study is needed, the current use of apheresis cells and their cultured progeny in the treatment of myeloma should not be compromised.

Dendritic cells cultured from mononuclear cells and CD34 cells in myeloma do not harbour human herpesvirus 8.

Dendritic cells (DC) are antigen-presenting cells with the potential to be a powerful adjuvant in the immunotherapy of haematological malignancy, including myeloma. Recently, human herpesvirus 8 (HHV-8) infection of dendritic cells in the long-term bone marrow stromal cultures of patients with myeloma has been reported. This finding is of great potential importance regarding oncogenesis in myeloma in addition to having significant implications for the use of DC in the immunotherapy of this disease. Therefore DC generated from mobilized blood mononuclear cells (MO-DC) and purified CD34+ cells (CD34-DC) of myeloma patients were examined for the presence of HHV-8 using a sensitive PCR technique. HHV-8 was not demonstrated in MO-DC or CD34-DC and we conclude that these cells remain a suitable vehicle for investigation in the immunotherapy of myeloma.

Collection and recruitment of CD34+ cells during large-volume leukapheresis.

Although sufficient progenitor cells for hematopoietic rescue following high-dose therapy may be obtained in a single leukapheresis, the majority of patients require multiple procedures. In an attempt to minimize the number of leukapheresis and maximize collection efficiency, we undertook large-volume leukapheresis in 17 patients with a variety of hematologic malignancies. Twenty-four procedures were performed over a 6-h period, with a mean of 21 L of blood processed. By employing a modified collection set, three separate 2-h collection bags were analyzed for a number of variables. CD34+ cells are collected at a steady rate throughout the procedure, with no evidence of exhaustion of progenitor cells. There was evidence of progenitor cell recruitment, with 1.4-fold more CD34+ cells in the collected product than were present in the blood at the beginning of the procedure. Initiation of leukapheresis was based on the blood CD34+ count, and this value was strongly correlated with the number of CD34+ cells in the collected product. The procedure is safe and relatively simple and minimizes the number of leukaphereses required to collect adequate progenitors for autologous transplantation.

Exacerbation of coagulopathy with concurrent bone marrow necrosis, hepatic and renal dysfunction secondary to all-trans retinoic acid therapy for acute promyelocytic leukemia.

A 22-year-old female presented with acute promyelocytic leukemia (APL). Treatment with all-trans retinoic acid (ATRA) resulted in a severe exacerbation of the coagulopathy 5 days after its introduction. This was complicated by bone marrow necrosis, parenchymal liver damage and acute tubular necrosis. Temporary cessation of the drug and subsequent dose reduction was effective in controlling the coagulopathy.