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.

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.

High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses.

Preliminary evidence suggests that the multikinase inhibitor sorafenib has clinical activity in FLT3-ITD-positive (FLT3-ITD) acute myeloid leukemia (AML). However, the quality and sustainability of achievable remissions and clinical variables that influence the outcome of sorafenib monotherapy are largely undefined. To address these questions, we evaluated sorafenib monotherapy in 65 FLT3-ITD AML patients treated at 23 centers. All but two patients had relapsed or were chemotherapy-refractory after a median of three prior chemotherapy cycles. Twenty-nine patients (45%) had undergone prior allogeneic stem cell transplantation (allo-SCT). The documented best responses were: hematological remission in 24 patients (37%), bone marrow remission in 5 patients (8%), complete remission (with and without normalization of peripheral blood counts) in 15 patients (23%) and molecular remission with undetectable FLT3-ITD mRNA in 10 patients (15%), respectively. Seventeen of the patients without prior allo-SCT (47%) developed sorafenib resistance after a median treatment duration of 136 days (range, 56-270 days). In contrast, allo-SCT patients developed sorafenib resistance less frequently (38%) and significantly later (197 days, range 38-225 days; P=0.03). Sustained remissions were seen exclusively in the allo-SCT cohort. Thus, sorafenib monotherapy has significant activity in FLT3-ITD AML and may synergize with allogeneic immune effects to induce durable remissions.

The anti-tumour activity of allogeneic cytokine-induced killer cells in patients who relapse after allogeneic transplant for haematological malignancies.

We performed a Phase I/II clinical trial to study the feasibility, toxicity and efficacy of allogeneic cytokine-induced killer (CIK) cell expansion, and treatment for patients with haematological malignancies who relapsed after allogeneic haemopoietic SCT (allo-HSCT). Allogeneic CIK cells were successfully generated for a total of 24 patients, including those from patients' own leukapheresis products in 5 patients who had no access to further donor cells. The median CD3(+) T-cell expansion was 9.33 (1.3-38.97) fold, and CD3(+)CD56(+) natural killer (NK)-like T-cell expansion was 27.77 (2.59-438.93) fold. A total of 55 infusions were done for 16 patients who had either failed or progressed after initial response to various individualized chemotherapy regimens and donor lymphocyte infusion (DLI), at doses ranging from 10 to 200 million CD3(+) cells/kg. Response attributable to CIK cell infusion was observed in five patients. These included two with ALL, two with Hodgkin's disease (HD) and one with AML, and two of whom had a response sustained for more than 2 years. Acute GVHD occurred in three and was easily treatable. This study provides some evidence suggestive of the efficacy of allogeneic CIK cells even after failure of DLI in some cases.

Natural history of severe eosinophilia with uncertain aetiology and proposals on a practical approach to its management.

BACKGROUND: Eosinophilia is commonly encountered during clinical practice. Some can be attributed to well-defined causes while others cannot. Optimal management of hypereosinophilia with unknown aetiology is uncertain as the natural history is not well described. METHODS: We retrospectively studied patients with hypereosinophilia (>5 × 10(9)/L) and described the characteristics, natural history and treatment of those with eosinophilia of uncertain aetiology. RESULTS: There were 141 patients with hypereosinophilia: 87 with well-defined causes, 54 with uncertain aetiology. The latter was managed as hypereosinophilic syndrome (HES) (n = 5), idiopathic hypereosinophilia (IH) (n = 11), presumptive helminthic infection (n = 11) and reactive eosinophilia (n = 5), while 22 were insufficiently investigated and did not have definite working diagnoses. Their median age and peak eosinophil count were 64 (22 to 94) years and 10.0 (5.2-33.9) × 10(9)/L respectively. Forty-six per cent had symptoms attributable to eosinophilia, with the HES and insufficiently investigated groups having the highest (100%) and lowest (27%) percentages respectively. HES and IH patients were most extensively investigated. All 14 HES or IH patients who received steroids responded. All presumptive helminthic infection patients received mebendazole: nine responded, and two had unassessable responses. For the remaining patients, seven received steroids and all responded; one received mebendazole but defaulted; 19 were not treated: 11 resolved spontaneously. No non-HES patients developed eosinophilia-related organ dysfunction. No mortality was caused by hypereosinophilia. CONCLUSIONS: Patients with hypereosinophilia of uncertain aetiology can be empirically managed according to working diagnoses derived from history taking, examination and selective investigations. Most patients have benign short-term outcomes, but longer monitoring is required to assess long-term outcomes from untreated hypereosinophilia.

Single center retrospective analysis of BU-based conditioning regimens in allogeneic transplantation.

We performed a single institution retrospective analysis of 114 patients treated with BU-based pretransplant conditioning regimens. Oral BU was administered to 76 patients (total dose 16 mg/kg or 8 mg/kg) and i.v. BU to 38 others (total dose 12.8 mg/kg or 6.4 mg/kg). Either CY (n=74) or fludarabine (n=40) was given in combination with BU. Median age was 35 years in the oral BU group and 48.5 years with i.v. BU (P<0.001). OS and PFS rates at 3-years post HSCT were not different in patients who received either i.v. or oral BU (OS: 41.3 vs 44.0% (P=0.981); PFS: 52.7 vs 54.7% (P=0.526), respectively). The i.v. BU, however, was associated with a significantly shorter time to engraftment (13.5 days vs 16 days, respectively; P<0.001). There were no significant differences in survival or 100-day mortality for patients who received either CY or fludarabine, in combination with BU. After adjustment for confounders, multivariate analysis showed that age of transplant (P=0.002), donor type (sibling or unrelated; P=0.003), GVHD (P<0.05) and route of administration (P=0.023) were significant risk factors for OS. The i.v. BU used in an older age group yielded equivalent survival compared with oral BU used in a younger population.

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.

Treatment of severe neutropenic sepsis with granulocyte transfusion in the current era--experience from an adult haematology unit in Singapore.

OBJECTIVES: Granulocyte transfusion's (GT) efficacy among adult severe neutropenic sepsis (SNS) patients remains uncertain. We assessed GT's efficacy and its determinants among SNS patients in an adult haematology unit. The feasibility and safety of granulocyte donation (GD) and determinants of granulocyte yield were also evaluated. METHODS: Retrospective analysis of granulocyte donors and recipients from March 2008 to October 2009. RESULTS: Donors: Sixty GDs with a median WBC yield (WBCY) of 65·49 (31·30-131·72) × 10(9) were collected from 48 donors (9 repeat donors) using hydroxyethyl starch and intermittent flow centrifugation aphaeresis after receiving 8 mg dexamethasone and 300 mcg granulocyte colony-stimulating factor, with no serious adverse reactions (SAR). Six donations were urgently collected <3 h after pre-medication, the median WBCY of which was not significantly different from donations collected >12 h after pre-medication [59·18 (45·68-62·90) × 10(9) vs 67·45 (31·30-131·72) × 10(9) , P = 0·140]. Only pre-GD absolute neutrophil count (ANC) correlated with WBCY. PATIENTS: Fifteen patients (12 acute leukaemias, 1 severe AA, 1 myelodysplastic syndrome and 1 lymphoma) received median 3 (2-9) ABO/RhD-matched GTs over 2-24 (median 7) days at 3-61 (median 28) days from severe neutropenia (SN) onset without SAR. They received intensive chemotherapies (N = 9), allogeneic transplant (N = 3), autologous stem cell rescue (N = 1) or immunosuppressants (N = 2). Fourteen had bacterial (N = 1) infections, fungal (N = 3) infections or both (N = 10) and one had severe viral pneumonitis; 63·6 and 30·8% of bacterial and fungal infections responded, respectively. Median ANC increase (ANC(increase) ) was 1·26 (0-9·25) × 10(9) at 5-20 (median 11) h post-GT. On multivariate analysis, each patient's median ANC(increase) only significantly correlated positively with median WBC dose/kg (P = 0·013). Five (33·3%) patients survived to discharge; the rest had infection-related mortality (IRM). IRM was significantly associated with inotropic requirement (P = 0·004), ventilatory requirement (P = 0·017) and persistent SN (P = 0·007). CONCLUSION: GD is safe and feasible with good WBCY obtainable using our protocol. The effect of shortening pre-medication interval on WBCY which may prevent delay in initiating GT is worth evaluating. GT most likely benefits SNS patients with prospects of neutrophil recovery before haemodynamic deterioration. Large randomised trials investigating the role and timing of GT among such patients are required.

Attainment of at least a very good partial response after induction treatment is an important surrogate of longer survival for multiple myeloma.

The importance of achieving a very good partial response or better (≥VGPR) after induction treatment of myeloma has traditionally only been discussed in the context of high-dose therapy with auto-SCT (HDT/auto-SCT). Of late, the advent of novel agents for induction treatment has resulted in improved CR and VGPR rates, which are comparable with those observed with HDT/auto-SCT. We show that in an unselected group of 179 myeloma patients with diverse baseline characteristics, and treated with different modern induction regimens within a single institution, the attainment of ≥VGPR with or without HDT/auto-ASCT represents a major surrogate marker of better clinical outcomes. On the basis of a 1-year landmark survival analysis, patients achieving ≥VGPR enjoy a significantly longer PFS, which translated to a longer OS. Superseding the adverse effects of advanced age, high International Staging System (ISS) stage, adverse cytogenetics and independent of the transplant status, the attainment of ≥VGPR emerged as the single most significant predictor of long-term survival on multivariate analysis.

Effect of missing killer-immunoglobulin-like receptor ligand in recipients undergoing HLA full matched, non-T-depleted sibling donor transplantation: a single institution experience of 151 Asian patients.

This retrospective analysis studied the impact of natural killer (NK) alloreactivity based on the missing ligand model, for a cohort of recipients undergoing haemopoietic stem cell transplant without T-cell depletion from HLA full-matched sibling donors. All patients received a uniform myeloablative conditioning regimen and prophylaxis for GVHD. A total of 151 patients were studied, including 62 patients with AML or myelodysplastic syndrome, 42 patients with ALL and 47 patients with CML. We found that 81% of patients had at least one missing KIR-ligand (KIR-L), and HLA-C1 allogroup homozygosity is present in 70% of patients. From multivariate analysis, we observed that the only consistently significant factor that was associated with superior survival was disease stage. Missing KIR-L, whether considering HLA-Bw and HLA-C alleles, without or with HLA-A ligands or narrowing to only HLA-C alleles alone to classify the number of missing KIR-L, did not have any impact on OS or relapse-free survival. This negative finding implies that as the KIR-L composition of recipient is not important in this matched non-T-depleted setting, further immunotherapeutic measures involving adoptive NK cell infusions have to be explored to exploit the benefit of NK alloreactivity for such transplants.

Characterization of hemopoietic engraftment kinetics and development of secondary cytopenia in AML post auto-SCT and its correlation with survival outcome.

We performed a single center retrospective analysis of 84 autologous hemopoietic stem cell transplants done for AML to characterize the pattern of hemopoietic engraftment, post-transplant cytopenia and their impact on survival outcome. Following autologous transplant and engraftment, 30 patients (35.7%) had a transient secondary decline in their plt counts, which was not associated with graft rejection, relapse or infection. The median time to onset of thrombocytopenia was 59 days post transplant, with spontaneous recovery after a median period of 41 days. A secondary decline in ANC also occurred in eight patients. Patients with secondary plt decline had a significantly earlier primary plt engraftment (median 15 days) and a trend towards earlier neutrophil engraftment compared with patients who maintained steady plt counts (median 21 days). There was a trend towards a lower incidence of secondary plt decline in patients who received BM stem cells compared with those who received PBSC. No cause was evident for the occurrence of a secondary cytopenia, and it did not adversely affect survival. We conclude that secondary cytopenia is a common and harmless occurrence after autologous transplant especially from PBSC graft.

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.

Fludarabine in comparison to alkylator-based regimen as induction therapy for chronic lymphocytic leukemia: a systematic review and meta-analysis.

The superiority of Fludarabine over conventional therapy as primary induction therapy for patients with chronic lymphocytic leukemia (CLL) has been shown in several studies but no studies have yet reported a pooled estimate of the treatment effect. We performed a systematic review of evidence from 5 randomized controlled trials involving approximately 1300 patients with CLL, comparing Fludarabine with several alkylator-based combination regimens in the primary treatment of CLL. Complete response rate was significantly higher for Fludarabine compared to alkylator-based chemotherapy (RR 1.87, 95% CI 1.10-3.19, P=0.02), while overall response, though superior, did not reach statistical significance (RR 1.22, 95% CI=0.88-1.69, P=0.24). Overall survival was similar for Fludarabine and alkylator-based therapy (the pooled log hazard ratio of death, HR=-0.05, 95% CI=-0.36-0.26, P=0.75). Infection rate was significantly higher (RR 1.58, 95% CI=1.10-2.27, P=0.01), but there was no significant difference in the incidence of thrombocytopenia, neutropenia and anemia. Therefore, this meta-analysis supports the findings that Fludarabine as an induction agent for patients with CLL yields a better clinical response with acceptable toxicity when compared with alkylator-based combination therapy, but without a survival benefit by 5-6 years of follow up.

Long term follow-up of Asian patients with chronic myeloid leukemia (CML) receiving allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical sibling-evaluation of risks and benefits.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known curative therapy for patients with chronic myeloid leukemia (CML), but is associated with significant morbidity and mortality. The recent introduction of imatinib mesylate (STI-571) and reduced intensity transplant regimens has made the choice of primary treatment for patients with CML increasingly difficult. We have evaluated the outcome of 53 patients who have received allogeneic HSCT from human leukocyte antigen (HLA)-identical sibling donors between October 1985 and March 2002, determined the variables affecting the outcome, and tried to define indications for this aggressive approach. Successful engraftment occurred in 49 (98%) of evaluable patients. Acute graft-versus-host disease (GVHD) of grade II to IV severity was observed in 63% of the evaluable patients whereas the incidence of chronic GVHD was 57.5%. The Kaplan-Meier estimate of survival at 10 years was 54% [95% confidence interval (CI): 38-70%] and 31% (95% CI: 6-56%) for patients with first chronic phase and more advanced diseases, respectively. Multivariate analysis showed that younger age, absence of grade III-IV GVHD, the use of busulphan and cyclophosphamide (BuCy) as preparative regimen, and transplantation performed after January 1992 were factors associated with improved survival. Patients who were 30 years of age or younger who had transplantation done within 1 year after diagnosis during their first chronic phase of disease had a particularly good prognosis, with a probability of surviving 10 years of 72% (95% CI: 52-92%). We conclude that allogeneic HSCT remains a feasible option for Asian patients with CML. The most favorable outcome is observed in younger patients with early phase of the disease.

Cytokine-induced killer cells: NK-like T cells with cytotolytic specificity against leukemia.

Cytokine-induced killer (CIK) cells are a unique population of cytotoxic T lymphocytes (CTL) with the characteristic CD3+CD56+ phenotype. These cells have demonstrated higher proliferative and cytolytic activities in comparison to the reported CD3-CD56+ lymphokine activated killer (LAK) cells that are essentially activated natural killer (NK) cells. CIK cells are non-MHC-restricted in target cell recognition and killing. We have shown the feasibility of generating CIK cells from a series of marrow samples of patients with acute myeloid leukemia (AML) collected at diagnosis. At maturity, the CIK cells exhibit potent cytotoxicity against autologous AML targets as well as allogeneic myeloid leukemia cells, regardless of the HLA types of these targets. This observed cytotoxicity is not entirely due to NK cells as prior pre-absorption of the NK cells cytolytic activities does not abolish the subsequent cytotolytic activities against leukemic targets. It has also been reported by others that CIK cells are cytolytic against chronic myeloid leukemia (CML) cells, both in vitro and in the SCID mouse tumor model. In a mouse transplant model across MHC barrier, the CIK cells generated from the donor do not induce graft vs. host disease as observed for unfractionated donor splenocytes. In comparison to untreated control mice, the infusion of CIK cells results in the prolonged survival of murine leukemia-bearing mice. CIK cells also express CD94, part of the NK receptor comprising of CD94-NKG2 heterodimer. However, only low level of the killer immunoglobulin-like receptors are expressed by the CIK cells. In addition, as reported for the classical CTL, CIK cells could interact with dendritic cells (DC) to result in the enhancement of cytotolytic activities against tumor cells. The characteristic biological properties of the CIK cells would, therefore, enable them to be exploited for anti-leukemic therapy.

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.

Subdural hematoma in two hematopoietic stem cell transplant patients with post-dural puncture headache and initially normal CT brain scan.

Subdural hematoma (SDH) is a rare complication in patients after lumbar puncture. We report two patients receiving hematopoietic stem cell transplantation (HSCT) who developed post-dural puncture headache (PDPH) and SDH following intrathecal methotrexate (MTX). Both patients initially had normal computed tomography (CT) scan findings at the onset of headache. The diagnosis was established only when a repeat CT brain scan was performed for deteriorating neurological signs coinciding with improving platelet counts. These cases demonstrate the importance of continued vigilance for the early recognition of this salvageable entity. A normal initial CT finding and platelet count do not exclude the occurrence of SDH. A repeat CT scan, or even magnetic resonance imaging (MRI), are indicated if the clinical suspicion remains strong.