Risk of hepatitis B reactivation and the role of novel agents and stem-cell transplantation in multiple myeloma patients with hepatitis B virus (HBV) infection.

BACKGROUND: The purpose of the study is to analyse the prevalence of hepatitis B virus (HBV) infection and its incidence of reactivation among multiple myeloma (MM) patients treated in the era of novel therapy in an endemic Asian setting. PATIENTS AND METHODS: From 2000 to 2008, 273 patients with newly diagnosed MM were screened for the presence of hepatitis B virus surface antigen and HBV core antibody. HBV-infected patients were prospectively followed for reactivation with serial monitoring of serum alanine transferase and HBV DNA load. The patterns of HBV reactivation in relation to treatment received, exposure to high-dose therapy with autologous stem-cell transplantation (HDT/ASCT) and novel agents were studied. RESULTS: The prevalence of HBV infection was 5.5%. Three cases of HBV reactivation despite lamivudine prophylaxis were reported. Two patients reactivated 3-5 months after HDT/ASCT while receiving thalidomide maintenance and one reactivated 3 years after HDT/ASCT and shortly after bortezomib salvage therapy. Emergence of a mutant HBV strain was documented in one patient. CONCLUSIONS: Use of prophylaxis may reduce but will not preclude HBV reactivation. Highest risk occurs during immune reconstitution phase of HDT/ASCT. The role of immunomodulatory agents in HBV reactivation needs to be further elucidated. Separate HBV prophylaxis and surveillance guidelines ought to be developed for patients with MM.

Impact of Microcystis aeruginosa on membrane fouling in a biologically treated effluent.

Microcystis aeruginosa was cultured in biologically treated municipal effluent to simulate blue-green algal bloom conditions in a treatment lagoon. The effect of algae in the early, mid and late phases of growth on membrane fouling, chemical coagulation (alum or aluminium chlorohydrate (ACH)) and hydraulic cleaning on the microfiltration of this effluent was investigated. The effect of M. aeruginosa in the early phase was negligible and gave a similar flux profile and permeate volume to that of effluent alone. The increase in M. aeruginosa concentration for the mid and late phases caused a significant reduction in permeate volume compared with the early phase. Full flux recovery was achieved with an alum dose of 1 mg Al3+ L(-1) (early phase) and 10 mg Al3+ L(-1) (mid phase), demonstrating that membrane fouling was hydraulically reversible. For the late phase, the highest flux recovery was 89%, which was achieved with an alum dose of 5 mg Al3+ L(-1). Higher alum dosages resulted in a reduction in flux recovery. The use of 1.5 pm pre-filtration after alum treatment showed little improvement in water quality but led to a drastic reduction in flux recovery, which was attributed to diminishing the protective layer on the membrane surface, thus enabling internal fouling. The performance of ACH was comparable to alum at low dissolved organic carbon (DOC) and cell concentration, but was not as effective as alum at high DOC and cell concentration due to the formation of more compact ACH flocs, which resulted in a higher cake layer specific resistance, leading to the deterioration of performance.

An abnormal nonhyperdiploid karyotype is a significant adverse prognostic factor for multiple myeloma in the bortezomib era.

Multiple myeloma is clinically heterogeneous and risk stratification is vital for prognostication and informing treatment decisions. As bortezomib is able to overcome several high-risk features of myeloma, the validity of conventional risk-stratification and prognostication systems needs to be reevaluated. We study the survival data of 261 previously untreated myeloma patients managed at our institution, where bortezomib became available from 2004 for the treatment of relapse disease. Patient and disease characteristics, and survival data were evaluated overall, and with respect to bortezomib exposure. Overall, the international staging system (ISS), metaphase karyotyping and interphase fluorescence in situ hybridization (FISH) were discerning of survival outcomes, where the median for the entire cohort was 5.2 years. However, when stratified by bortezomib exposure, only metaphase karyotyping was still discriminating of long-term prognosis. The presence of an abnormal nonhyperdiploid karyotype overrides all other clinical and laboratory parameters in predicting for a worse outcome on multivariate analysis (median survival 2.6 years, P = 0.001), suggesting that bortezomib used at relapse is better able to overcome adverse risk related to high tumor burden (as measured by the ISS) than adverse cytogenetics on conventional karyotyping. Metaphase karyotyping provides additional prognostic information on tumor kinetics where the presence of a normal diploid karyotype in the absence of any high-risk FISH markers correlated with superior survival and could act as a surrogate for lower plasma cell proliferation.

Reducing the effect of cyanobacteria in the microfiltration of secondary effluent.

Cyanobacterial blooms in the lagoons of sewage treatment plants can severely impact the performance of membrane plants treating the effluent. This paper investigates the impact of Microcystis aeruginosa in a secondary effluent on the microfiltration filterability and cleaning of the membrane. Alum coagulation and dissolved air flotation (DAF) were investigated to remove the algae and so enhance the volume of effluent processed, and their influence on reversible and irreversible fouling. Degree of fouling due to the algal components was found to be in decreasing order of algal cells, algal organic matter and extracellular organic matter. Alum coagulation with 5 mg L⁻¹ as Al³(+) led to a substantial increase in permeate volume, an increase in dissolved organic carbon removal, and a foulant layer which protected the membrane from internal fouling but which was hydraulically removable resulting in full flux recovery. Pre-treatment by DAF or 1.5 µm filtration following alum coagulation enhanced the flux rate and permeate volume but exposed the membrane to internal irreversible fouling.

Use of the cytomegalovirus pp65 antigenemia assay for preemptive therapy in allogeneic hematopoietic stem cell transplantation: a real-world review.

Despite advances in surveillance strategies and antivirals, cytomegalovirus (CMV) infection continues to pose problems to patients receiving hematopoietic stem cell transplants (HSCTs). The bone marrow transplant (BMT) unit at the Singapore General Hospital embraced the preemptive strategy in late 2003. Although several studies have demonstrated its usefulness, we conducted this review to document CMV-related events at our institution. Forty-six patients underwent CMV surveillance using the CMV pp65 antigenemia (CMV Ag) assay from January 2004 to December 2005. Twenty-seven patients had CMV infection, and 19 remained antigenemia-negative. No differences were found between the 2 groups for the following potential risk factors for CMV infection: age, total number of co-morbidities, duration of neutropenia after conditioning, baseline creatinine, type of conditioning regimen (conventional vs. reduced intensity), type of transplant (matched sibling vs. others), recipient CMV status, donor CMV status, and use of total body irradiation. Two patients received alemtuzumab; both developed CMV Ag. Twelve episodes of CMV infection occurred after the 100th post-HSCT day. Two patients developed CMV disease. One of them could be considered a failure of the preemptive strategy, as she had CMV gastritis diagnosed on the same day that she became pp65-positive. The other developed CMV disease despite prompt institution of ganciclovir, although she had multiple post-HSCT complications requiring enhanced immunosuppression, as well as relapsed disease. One-year disease-free survival was 55.5% in those with CMV infection and 52.3% in those without infection. Survival was not affected by CMV infection.

An exploration of the applicability of the refined disease risk index and its integration with other independent risk factors for individualized prognostication.

The refined disease risk index (DRI) is a powerful prognostic model based solely on the disease type and stage for predicting survival outcomes of various hematological malignancies after allogeneic transplant. Here, we analyzed our series of 690 patients transplanted over the past 15 years, and showed that besides overall survival (OS), the refined DRI is also able to segregate event-free survival and relapse mortality in our cohort of largely Southeast Asian patients with a long and complete follow-up. Stratification by refined DRI remains statistically significant even when broken down by specific diseases each with a smaller number of patients, as well as for a small subset of patients younger than 18 years old, providing a robust model for prognostication. Multivariable analysis shows that refined DRI, age, year of transplant and donor type are independent risk factors for OS. We further demonstrated here that prognostication for a given patient with a specific disease can be made more discriminating by integrating independent risk factors such as age and donor type with the refined DRI. The future development of prognostic system incorporating the refined DRI with patient- and transplant-related risk factors will provide a more precise estimate of transplant outcome.

Successful treatment of primary granulocytic sarcoma by non-myeloablative stem cell transplant.

Pre-leukemic granulocytic sarcoma (GS) may pose an initial diagnostic problem and its therapeutic approach has never been formally established. To our knowledge, non-myeloablative stem cell transplantation has been reported in cases of leukemic GS, but not in primary GS. We report a case of primary GS with extensive and aggressive presenting features and successfully treated with intensive chemotherapy followed by non-myeloablative allogeneic stem cell transplant. This resulted in complete remission with minimal complications. Our case demonstrates the potential of graft-vs.-tumour effect in the treatment of GS and suggests that non-myeloablative allogeneic stem cell transplant may be a feasible therapeutic approach for primary GS.

Early relapse post autologous transplant is a stronger predictor of survival compared with pretreatment patient factors in the novel agent era: analysis of the Singapore Multiple Myeloma Working Group.

The clinical outcome of multiple myeloma is heterogeneous. Both the depth of response to induction and transplant as well as early relapse within a year are correlated with survival, but it is unclear which factor is most relevant in Southeast Asian patients with multiple myeloma. We retrospectively analyzed outcomes of 215 patients who were treated with upfront autologous transplant in Singapore between 2000 and 2014. In patients who received novel agent (NA)-based induction, achieving only partial response (PR) post-induction was associated with poorer OS (HR 1.95, P=0.047) and PFS (HR 2.9, P<0.001), while achieving only PR post-transplant was strongly correlated with both OS (HR 3.3, P=0.001) and PFS (HR 7.6, P<0.001), compared with patients who achieved very good partial response (VGPR) or better. Early relapse was detected in 18% of all patients, although nearly half had initially achieved VGPR or better post-transplant. Early relapse after NA-based induction led to significantly shorter OS (median 22 months vs not reached, P<0.001), and was strongly associated with OS (HR 13.7, P<0.001). The impact of suboptimal post-transplant response and early relapse on survival may be more important than pretransplant factors, such as International Staging System or cytogenetics, and should be considered in risk stratification systems to rationalize therapy.

Therapeutic leukapheresis in hyperleukocytic leukaemias--the experience of a tertiary institution in Singapore.

INTRODUCTION: Hyperleukocytic leukaemias are associated with early mortality due to respiratory or neurological complications. They result from endothelial damage secondary to leukostasis. Leukapheresis, which aims to lower the white blood cell (WBC) count, has been used in certain patients to reduce the threat from leukostasis. However, there are very few published clinical investigations on the most appropriate use of leukapheresis in hyperleukocytosis. MATERIALS AND METHODS: We performed a retrospective analysis of 14 patients with hyperleukocytic leukaemia who presented to our institution and underwent therapeutic leukapheresis. We compare their clinical and biological characteristics and investigate the impact of leukapheresis on early mortality and long-term prognosis. RESULTS: The median presenting WBC count was 439 x 10(3)/mm(3). Although patients with acute myeloid leukaemia (AML) had the lowest median presenting WBC counts, they constituted the largest group of patients with symptomatic hyperleukocytosis. Leukapheresis was highly effective, with the mean absolute and percentage reduction in WBC after each cycle being 126 x 10(3)/mm(3) and 31.9% respectively. Four patients with AML died within 2 weeks of presentation despite prompt and effective leukapheresis. CONCLUSION: The interaction between the leukaemic cells and the vascular environment, a mechanism that none of the current therapies directly address, is probably more important in causing leukostasis than the absolute cell count itself.

Severe acute graft-versus-host disease occurring after syngeneic BMT for AML in a patient not given prior cyclosporin A therapy.

A syndrome akin to graft-versus-host disease in the recipient of syngeneic stem cells is hitherto described as being milder, self-limiting and confined to the skin. It is enhanced by prior cyclosporin A therapy. We describe here a recipient of a syngeneic marrow transplant who did not receive priming with cyclosporin A and yet developed severe and progressive graft-versus-host disease which necessitated and responded to high-dose immunosuppressive therapy. We believe that this is because the conditioning regimen in stem cell transplant acts to reset the immune system enabling it to recognise 'self' antigens. Bone Marrow Transplantation (2000) 25, 205-207.

Imatinib mesylate (STI-571) given concurrently with nonmyeloablative stem cell transplantation did not compromise engraftment and resulted in cytogenetic remission in a patient with chronic myeloid leukemia in blast crisis.

The main obstacles to successful hematopoietic stem cell transplantation for patients with chronic myeloid leukemia (CML) in blast crisis (BC) are increased post-transplant relapse and high treatment-related mortality. We report a patient with CML in BC who was treated initially with imatinib mesylate and was then concurrently treated with a nonmyeloablative stem cell transplant. Successful engraftment of donor cells followed by complete cytogenetic remission was achieved in the absence of severe therapy-related toxicities. This case demonstrates that imatinib mesylate given through nonmyeloablative transplant is a minimally toxic therapeutic approach, which does not compromise engraftment and may result in a favorable outcome in patients with CML in BC.

A randomized trial of amifostine as a cytoprotectant for patients receiving myeloablative therapy for allogeneic hematopoietic stem cell transplantation.

We initiated a randomized study of amifostine (the organic thiophosphate formerly known as WR-2721) given to patients during myeloablative conditioning therapy for allogeneic bone marrow transplantation. Amifostine was given at a dose of 1000 mg/day of conditioning and was well tolerated if attention was given to serum calcium levels, blood pressure and antiemetics. Since August 1998, 60 patients (30 on each arm) have completed the study. There was no significant difference in the days to neutrophil or platelet engraftment in either arm of the study. Significantly, the duration of grade I-IV mucositis was decreased in the group that received amifostine (P=0.02). Also grade III or IV infections (P=0.008), duration of antibiotic therapy (P=0.03) and duration of fever (P=0.04) were significantly reduced with amifostine. However, there were no differences in the incidence of grade III or IV mucositis, liver toxicity or renal toxicity. There were also no differences in early mortality, relapse and long-term survival. We conclude that amifostine, while reducing the duration of mucositis and infections (possibly through some preservation of gut mucosal integrity), has a modest effect in allogeneic bone marrow transplants given the multiplicity of factors influencing organ toxicity and survival in this setting.

Successful treatment of idiopathic hypereosinophilic syndrome with imatinib mesylate: a case report.

Patients with idiopathic hypereosinophilic syndrome (HES) show persistent hypereosinophilia of unknown etiology that is associated with end-organ damage. Different treatments, including the use of corticosteroids and cytotoxics, have been investigated for HES with modest success. We describe a patient with HES who had significant end-organ damage from hypereosinophilia and remained refractory to conventional therapy. Therapy with imatinib mesylate, a selective tyrosine kinase inhibitor that is highly effective in treating patients with BCR-ABL-positive chronic myeloid leukemia, was tried with the patient. The result was impressive, with hematologic remission achieved after 12 days of administration. Our finding concurs with recent reports that imatinib mesylate may be a promising agent in the treatment of some cases of HES.

Acute promyelocytic leukemia with a dicentric chromosome involving chromosomes 11, 17, and 18.

We report a case of acute promyelocytic leukemia with dicentric chromosome resulting from translocation of chromosomes 11, 17, and 18.

Relapse of leukemia and lymphoma after marrow transplant: a review of cases with extramedullary relapse.

We review our cases of leukemia and lymphoma relapse after allogeneic marrow transplant and describe here a series of 10 patients with extramedullary (EM) relapse. In the 13 relapses in acute myeloid leukemia, 5 cases had EM involvement. There were 3 EM involvement out of 13 acute lymphoblastic leukemia relapses, one EM disease in 11 chronic myeloid leukemia relapses and one case of lymphoma with EM relapse. A common observation is that in some of these cases, EM relapse occurred in the presence of continuous marrow remission, In those cases with both marrow and EM involvement marrow remission could often be achieved and maintained temporarily while EM disease progressed despite chemotherapy or immunotherapeutic measures such as immunosuppressant withdrawal and donor lymphocyte infusion. Survival in partial remission after relapse could be prolonged in some cases but eventual death from progressive disease was often the case.

Therapeutic plasmapheresis for the treatment of the thrombotic thrombocytopenic purpura-haemolytic uraemic syndromes.

INTRODUCTION: The thrombotic thrombocytopenic purpura-haemolytic uraemic syndromes (TTP-HUS) are uncommon disorders that are fatal if untreated. Therapeutic plasma exchange has resulted in excellent remission and survival rates in this patient population. METHODS: We reviewed our experience of therapeutic plasmapheresis for TTP-HUS syndromes for 11 patients who presented in the last five years. Parameters captured included haemoglobin and platelet counts at presentation as well as the number of plasmapheresis sessions and adjunctive treatment given. RESULTS: We found a response rate of 82 percent to plasma exchange, of whom 55 percent attained complete remission. Responses were excellent in the five patients who presented with primary or idiopathic TTP (100 percent response) among whom 80 percent had sustained long term responses. Responses were poor and often unsustained (only one out of six survived) in patients who presented with thrombotic microangiopathies secondary to underlying disorders such as bone marrow transplantation and metastatic carcinoma. CONCLUSION: Plasmapheresis is mandatory and extremely effective for primary TTP. However, it is at most an adjunct for patients who developed it secondary to an underlying disorder until and if the primary disorder can be successfully treated.

Granulocyte colony stimulating factor significantly influences neutrophil recovery and duration of hospitalisation in bone marrow transplantation.

Eighty-eight consecutive patients undergoing bone marrow transplantation (BMT) from July 1985 to June 1993 were retrospectively studied for their bone marrow engraftment characteristics with and without granulocyte colony stimulating factor (R-metHUG-CSF, Filgrastim). Seventy-seven patients (87.5%) achieved engraftment, 55 out of 65 patients (84.6%) without R-metHUG-CSF and 22 out of 23 patients (95.7%) with R-metHUG-CSF (P > 0.1). The mean duration of administration of R-metHUG-CSF was 15.1 days. The mean time to engraftment was significantly reduced by 7.1 days, from 20.5 days to 13.4 days (P < 0.0001). The mean duration of hospitalisation was also significantly reduced by 11.1 days, from 52.6 days to 41.5 days (P < 0.0001). There were no side effects directly attributable to R-metHUG-CSF encountered. We conclude that R-metHUG-CSF is very effective in shortening the duration of neutropenia in the immediate post-BMT period with lesser BMT morbidity, earlier discharge from hospital and lower cost of BMT. We recommend a routine 2-week course beginning on the day after marrow infusion.

Treatment of acute promyelocytic leukaemia using a combination of all-trans retinoic acid and chemotherapy.

INTRODUCTION: The combination of all-trans retinoic acid (ATRA) with chemotherapy has improved the outcome of acute promyelocytic leukaemia (APL). Effective induction as well as maintenance therapy for APL can be achieved using this combination of anti-leukaemic agents. MATERIALS AND METHODS: Twenty-four consecutive patients with newly-diagnosed APL were treated with ATRA daily together with either daunorubicin or idarubicin. Therapy with ATRA was continued until complete remission (CR) was achieved; thereafter, patients were treated with 2 cycles of an anthracycline-based consolidation chemotherapy (either daunorubicin or idarubicin). Maintenance therapy was achieved using 5 alternating cycles of low-dose methotrexate (MTX) plus 6-mercaptopurine (6MP) followed by ATRA alone. RESULTS: Twenty-three out of 24 patients (96%) completed induction therapy and achieved haematological CR (HCR) as well as molecular remission (MR); however, 1 patient (5%) died from retinoic acid syndrome. Twenty-one out of 23 evaluable patients (91%) completed consolidation chemotherapy, and 2 patients (10%) died, 1 from neutropenic sepsis and the other from relapse following non-compliance to therapy. All 21 surviving patients in the present study received maintenance chemotherapy and are still in HCR and MR at a median follow-up of 23 months. The estimated actuarial 2-year overall survival (OS) and event-free survival (EFS) rates were both 84% +/- 9%. CONCLUSION: The combination of ATRA with an anthracycline is an effective remission-induction therapy for newly-diagnosed APL. Maintenance therapy using alternating cycles of MTX plus 6MP followed by ATRA alone is effective in maintaining CR and MR as well as prolonging the survival of patients with APL.