A Grigg

Austin Health, Melbourne, Victoria, Australia

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Publications (232)862.35 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The efficacy of a fixed-dose rituximab schedule was prospectively explored in primary/acute refractory, relapsed or chronic (platelet count >10 × 109/l and ≤50 × 109/l) idiopathic thrombocytopenic purpura (ITP). Patients received two doses of rituximab (1000 mg) on days 1 and 15 and were followed-up on weeks 1–8, 12, 26, 39 and 52. A total of 122 patients were included in the safety population; efficacy was analysed in 108 patients. Overall response rate (ORR) at week 8, defined as the proportion of patients achieving complete response (CR; platelet count >150 × 109/l) or partial response (PR; platelet count >50 × 109/l) was 44%. Therapeutic response, defined as achieving a response at week 8, with at least a minor response (MR; platelet count >30 × 109/l), sustained up to weeks 26 and 52 and accompanied by a reduction in ITP medications, was achieved in 44% (week 26) and 35% (week 52) of patients, respectively. Treatment was well tolerated with no safety concerns. While this study failed to meet its primary endpoint of an ORR of 50%, the efficacy of two fixed doses of rituximab appear to provide similar efficacy to the standard 375 mg/m2 four-dose schedule in relapsed/chronic ITP.
    British Journal of Haematology 07/2014; · 4.94 Impact Factor
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    ABSTRACT: In CML patients, a BCR-ABL1 value >10% at 3 months of therapy is statistically associated with poorer outcome, yet many of these patients still achieve satisfactory outcomes. We investigated 528 first-line imatinib-treated patients to determine whether patients with the poorest outcome can be better discriminated at 3 months. All outcomes were significantly superior for the 410 patients with BCR-ABL1 ≤10% at 3 months, P<.001. However, the poorest outcomes among the 95 evaluable patients with BCR-ABL1 >10% at 3 months were identified by the rate of BCR-ABL1 decline from baseline; assessed by estimating the number of days over which BCR-ABL1 halved. Patients with BCR-ABL1 halving time less than 76 days (n=74) had significantly superior outcomes compared to patients whose BCR-ABL1 values did not halve by 76 days (n=21); 4 year overall survival 95% versus 58%, P=.0002; progression-free survival 92% versus 63%, P=.008; failure-free survival 59% versus 6%, P<.0001; and MMR 54% versus 5%, P=.008. By multivariate analysis, the halving time was an independent predictor of outcome in this poor risk group. Our study has highlighted that the rate of BCR-ABL1 decline may be a critical prognostic discriminator of the patients with very poor outcome among those >10% at 3 months. The Iris trial was registered at http://www.clinicaltrials.gov as NCT00006343. The Tops trial was registered at http://www.clinicaltrials.gov as NCT00124748. The TIDEL I trial was registered at www.ANZCTR.org.au as ACTRN12607000614493. The TIDEL II trial was registered at www.ANZCTR.org.au as ACTRN12607000325404.
    Blood 05/2014; · 9.78 Impact Factor
  • Internal Medicine Journal 05/2014; 44(5). · 1.82 Impact Factor
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    ABSTRACT: To identify favored choice of transplantation in patients with acute promyelocytic leukemia in second complete remission. We studied 294 acute promyelocytic leukemia (APL) patients receiving allogeneic (n=232) or autologous (62) hematopoietic cell transplantation (HCT) in second complete remission (CR2) reported to the Center for International Blood and Marrow Transplantation Research (CIBMTR) from 1995 to 2006 including pre-HCT PML/RAR∝ status in 155 (49% of allogeneic and 66% of autologous). Patient characteristics and transplant characteristics including treatment related mortality, overall survival, and disease free survival were collected and analyzed for both univariate and multivariate outcomes. With median follow-up of 115 (allogeneic) and 72 months (autologous), 5-year disease-free survival (DFS) favored autologous 63% (49-75%) compared to allogeneic 50% (44-57%) (p=0.10) and overall survival (OS) 75% (63-85%) vs. 54% (48-61%) (p=.002) Multivariate analysis showed significantly worse DFS after allogeneic HCT (HR=1.88, 95% CI=1.16-3.06, p=0.011) and age >40 years (HR=2.30, 95% CI 1.44-3.67, p=0.0005). OS was significantly worse after allogeneic HCT (HR=2.66, 95%CI 1.52-4.65, p=0.0006; age >40 (HR=3.29, 95% CI 1.95-5.54, p<0.001) and CR1<12 months (HR=1.56 95% CI 1.07-2.26, p=0.021). Positive pre-HCT PML-RAR∝ status in 17/114 allogeneic and 6/41 autologous transplants did not influence relapse, treatment failure or survival in either group. The survival advantage for autografting was attributable to increased 3 years TRM: allogeneic 30%; autologous 2%, and GVHD. We conclude that autologous HCT yields superior overall survival for APL in CR2. Long term DFS in autologous recipients, even with MRD+ grafts remains an important subject for further study.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2014; · 3.15 Impact Factor
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    ABSTRACT: Therapeutic options are limited for elderly patients with acute myeloid leukemia (AML). A phase Ib/II study was undertaken to evaluate the maximum-tolerated dose (MTD) and preliminary efficacy of the pan-histone deacetylase inhibitor panobinostat (LBH589) in combination with azacitidine in patients with AML or high-risk myelodysplastic syndrome (MDS) naïve to intensive chemotherapy. Thirty-nine patients (AML=29, MDS=10) received azacitidine 75 mg/m(2) subcutaneously (days 1-5) and oral panobinostat (starting on day 5, thrice weekly for seven doses) in 28-day cycles until toxicity or disease progression. Dose-limiting toxicities during the phase Ib stage were observed in 0/4 patients receiving 10 mg panobinostat, in 1/7 patients (fatigue) receiving 20 mg, in 1/6 patients (fatigue) receiving 30 mg and in 4/5 patients (fatigue, syncope, hyponatremia and somnolence) receiving 40 mg. In phase II, an additional 17 patients received panobinostat at a MTD of 30 mg. The overall response rate (ORR=CR+CRi+PR) in patients with AML was 31% (9/29) and that in patients with MDS was 50% (5/10). After a median follow-up of 13 months, the median overall survival was 8 and 16 months in patients with AML and MDS, respectively. Increased histone H3 and H4 acetylation was a useful early biomarker of clinical response. Combining panobinostat with azacitidine was tolerable and clinically active in high-risk MDS/AML patients, warranting further exploration.
    Blood Cancer Journal 01/2014; 4:e170. · 1.40 Impact Factor
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    ABSTRACT: Increasing dose intensity (DI) of chemotherapy for patients with aggressive non-Hodgkin lymphoma (NHL) may improve outcomes at the cost of increased toxicity. This issue was addressed in a randomised trial aiming to double the DI of myelosuppressive drugs. Between 1994 and 1999, 250 patients with previously untreated aggressive NHL were randomised to treatment with 6 cycles of three weekly standard (s) or intensive (i) chemotherapy: s-CEOP – cyclophosphamide 750 mg/m2, epirubicin 75 mg/m2, vincristine 1.4 mg/m2 all on day 1 and prednisolone 100 mg days 1-5; i-CEOP – cyclophosphamide 1500 mg/m2, epirubicin 150 mg/m2, vincristine 1.4 mg/m2 all on day 1 and prednisolone 100 mg days 1-5. Primary endpoint was 5-year overall survival (OS). Relative to s-CEOP patients, i-CEOP patients achieved a 78% increase in the DI of cyclophosphamide and epirubicin. Despite this, there was no significant difference in any outcome: 5-year OS (56.7% i-CEOP; 55.1% s-CEOP; P=0.80); 5-year PFS (41% i-CEOP; 43% s-CEOP; P=0.73), 5-year TTP (44% i-CEOP; 47% s-CEOP; P=0.72) or CR + unconfirmed CR (CRu) rates (53% i-CEOP; 59% s-CEOP; P=0.64). Long-term follow up at 10 years also showed no significant differences in OS, PFS, or TTP. The i-CEOP arm had higher rates of febrile neutropenia (70% vs 26%), hospitalisations, blood product utilisation, haematological and gastrointestinal toxicities, and lower QOL scores during treatment, although without significant differences 6 months later. In the treatment of aggressive NHL in the pre-rituximab era, increasing DI did not result in improved outcomes while at the same time lead to increased toxicity.
    American Journal of Hematology 01/2014; · 4.00 Impact Factor
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    ABSTRACT: The effectiveness of ethanol locks for prevention of central venous catheter (CVC)-associated bloodstream infection (CLABSI) in adult haematology patients has not been thoroughly evaluated. This study aimed to compare prospectively heparinized saline with 70% ethanol locks using 2 h dwell time in patients with tunnelled CVCs. In saline (N = 43) and ethanol (N = 42) groups, CLABSI rates were 6.0 [95% confidence interval (CI): 3.4–9.8] and 4.1 (95% CI: 1.9–7.7) per 1000 CVC days, respectively (P = 0.42). In the ethanol group, two exit-site infections and one tunnel/pocket infection were observed. Reduction in device-associated infection was not achieved with prophylactic 70% ethanol locks in patients with haematological malignancy and tunnelled CVCs.
    Journal of Hospital Infection. 01/2014;
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    ABSTRACT: Patients with lymphoma who have experienced a first relapse or progression and have disease deemed sensitive to salvage chemotherapy nevertheless have a high likelihood of having a second relapse. To decrease the likelihood of a second relapse after high-dose therapy (HDT) and autologous stem cell transplantation (ASCT), interferon (IFN) α-2b was given in a prospective randomized international trial. In this trial, 221 patients with varying histologic diagnoses (8 small lymphocytic, 37 follicular, 9 mantle, 90 diffuse large B-cell, 20 peripheral T-cell, 3 high-grade B-cell non-Hodgkin lymphoma, and 54 Hodgkin lymphoma) were randomly assigned to receive no further treatment (arm A: 117 patients) or IFNα-2b, 3 MU three times weekly, for 18 months (arm B: 104 patients). In arm B, 21 patients (20%) did not receive IFNα-2b because of early progression or absence of hematologic recovery, 29 patients (28%) completed the 18 months of treatment, and 54 patients (52%) interrupted treatment because of progression (23%) or toxicity (29%). Event-free survival and overall survival were not different between the two arms on an intent-to-treat analysis and also if analysis was restricted to patients who were alive and had not experienced disease progression three months after transplantation. The study was not sufficiently powered to evaluate effects in histologic subtypes. In this trial, post-autograft IFNα-2b did not improve outcomes in a heterogeneous group of patients with lymphoma.
    The Oncologist 10/2013; · 4.10 Impact Factor
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    ABSTRACT: Central nervous system (CNS) multiple myeloma (MM) is exceedingly rare and portends a dismal prognosis. While immunomodulators have contributed to the improvement in survival in MM, they appear to have limited activity against CNS MM and, paradoxically, may contribute to the evolution of resistant MM clones capable of surviving within the CNS. We undertook a retrospective analysis to characterize the features of CNS MM and outcome in 17 patients from four institutions identified between 2000 and 2011. The median age was 58 years. Patients had received a median of three prior therapies and all had been exposed to at least one of the so-called novel anti-MM agents before the diagnosis of CNS MM. The median time to CNS disease from initial diagnosis was 36 months. Cerebrospinal fluid (CSF) light chain measurements produced discrepant results to serum light chain measurements in some patients. Treatments included systemic pharmacotherapy, intrathecal (IT) chemotherapy and/or radiotherapy (RT). The median overall survival (OS) from diagnosis of CNS MM was only 4 months. OS was significantly better in patients who received IT chemotherapy (20 months vs. 2 months, respectively; P < 0·02). We conclude that the systematic evaluation of IT therapy and diagnostic utility of CSF light chain measurements in CNS MM are warranted.
    British Journal of Haematology 05/2013; · 4.94 Impact Factor
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    ABSTRACT: Most patients with chronic myeloid leukemia (CML) treated with imatinib will relapse if treatment is withdrawn. We conducted a prospective clinical trial of imatinib withdrawal in 40 chronic phase CML patients who had sustained undetectable minimal residual disease (UMRD) by conventional Q-PCR on imatinib for at least 2 years. Patients stopped imatinib and were monitored frequently for molecular relapse. At 24 months the actuarial estimate of stable treatment-free remission was 47.1%. Most relapses occurred within 4 months of stopping imatinib, and no relapses beyond 27 months were seen. In the 21 patients treated with interferon before imatinib a shorter duration of interferon treatment before imatinib was significantly associated with relapse risk, as was slower achievement of UMRD after switching to imatinib. Highly sensitive patient-specific BCR-ABL DNA PCR showed persistence of the original CML clone in all patients with stable UMRD, even several years after imatinib withdrawal. No patients with molecular relapse after discontinuation have progressed or developed BCR-ABL mutations (median follow-up 42 months). All patients who relapsed remained sensitive to imatinib re-treatment. These results confirm the safety and efficacy of a trial of imatinib withdrawal in stable UMRD with frequent, sensitive molecular monitoring and early rescue of molecular relapse. (Trial registered: ACTRN 12606000118505, http://www.anzctr.org.au/).
    Blood 05/2013; · 9.78 Impact Factor
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    ABSTRACT: Background: The optimal treatment strategy in patients with aggressive B cell central nervous system lymphoma suitable to receive intensive therapy is unknown. The benefit of incorporating rituximab in systemic therapy remains unclear. We performed a retrospective study examining the impact of rituximab in the context of concomitant therapies, including methotrexate, cytarabine, and radiotherapy, in patients treated with curative intent at 4 university teaching hospitals during 1996-2011.MethodsA retrospective study of CNS lymphoma cases treated at the participating institutions was performed in accordance with institutional ethical guidelines. Patients were included if they received a diagnosis of primary diffuse large B cell lymphoma of the CNS, were HIV negative, and were treated with curative intent.ResultsOne hundred twenty patients aged 21-81 years were identified. Rituximab recipients and nonrecipients were similar, except for rituximab recipients being more likely to have received a diagnosis after 2004. The median follow-up of surviving patients was 30 months. The 5-year overall survival was 46%. Univariate analysis revealed age ≤60 years, ECOG performance status ≤1, normal lactate dehydrogenase, diagnosis after 2004, and treatment with cytarabine and rituximab as predictive of favorable overall survival. Multivariate analysis identified age to be an independent predictor of overall survival, with a trend toward improved survival from the other variables that were significant in univariate analyses.ConclusionsIn this retrospective analysis, the addition of rituximab to high-dose methotrexate-based chemotherapy in patients with aggressive B cell CNS lymphoma was associated with improved overall survival. Further studies are underway to prospectively validate these findings.
    Neuro-Oncology 03/2013; · 6.18 Impact Factor
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    ABSTRACT: BACKGROUND: Fluconazole, posaconazole and voriconazole are used prophylactically in patients with acute myeloid leukaemia (AML). This study evaluated the clinical and economic outcomes of these agents when used in AML patients undergoing consolidation chemotherapy. METHODS: A retrospective chart review (2003-10) of AML patients receiving consolidation chemotherapy was performed. Patients were followed through their first cycle of consolidation chemotherapy. Antifungal prescribing patterns, clinical outcomes and resource consumptions were recorded. A decision analytical model was developed to depict the downstream consequences of using each antifungal agent, with success defined as completion of the designated course of initial antifungal prophylaxis without developing invasive fungal disease (IFD). Cost-effectiveness and sensitivity analyses were performed. RESULTS: A total of 106 consecutive patients were analysed. Baseline characteristics and predisposing factors for IFD were comparable between groups. Three IFDs (one proven, one probable and one suspected) occurred, all in the posaconazole group. Patients receiving posaconazole had the highest rate of intolerance requiring drug cessation (13% versus 7% in each of the fluconazole and voriconazole groups). Fluconazole conferred overall savings per patient of 26% over posaconazole and 13% over voriconazole. Monte Carlo simulation demonstrated a mean cost saving with fluconazole of AU$8430 per patient (95% CI AU$5803-AU$11 054) versus posaconazole and AU$3681 per patient (95% CI AU$990-AU$6319) versus voriconazole. One-way sensitivity analyses confirmed the robustness of the model. CONCLUSIONS: This is the first study to show that, in the setting of consolidation therapy for AML, fluconazole is the most cost-effective approach to antifungal prophylaxis compared with posaconazole or voriconazole.
    Journal of Antimicrobial Chemotherapy 03/2013; · 5.34 Impact Factor
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    ABSTRACT: Chronic GVHD (cGVHD) is an important complication of allogeneic hematopoietic cell transplantation (HCT). As preemptive therapy might be efficacious if administered early post transplant, we set out to determine whether cGVHD can be predicted from the serum level of a biomarker on day 7 or 28. In a discovery cohort of 153 HCT recipients conditioned with BU, fludarabine and rabbit antithymocyte globulin (ATG), we determined serum levels of B-cell-activating factor, vascular endothelial growth factor, soluble TNF-α receptor 1, soluble IL2 receptor α, IL5, IL6, IL7, IL15, γ-glutamyl transpeptidase, cholinesterase, total protein, urea and ATG. Patients with low levels of IL15 (<30.6 ng/L) on day 7 had 2.7-fold higher likelihood of developing significant cGVHD (needing systemic immunosuppressive therapy) than patients with higher IL15 levels (P<0.001). This was validated in a validation cohort of 105 similarly-treated patients; those with low IL15 levels had 3.7-fold higher likelihood of developing significant cGVHD (P=0.001). Low IL15 was not associated with relapse; it trended to be associated with acute GVHD and was associated with low infection rates. In conclusion, low IL15 levels on day 7 are predictive of cGVHD, and thus could be useful in guiding preemptive therapy.Bone Marrow Transplantation advance online publication, 19 November 2012; doi:10.1038/bmt.2012.210.
    Bone marrow transplantation 11/2012; · 3.00 Impact Factor
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    ABSTRACT: PURPOSE OF REVIEW: Therapeutic drug monitoring (TDM) may be an important adjunct to optimizing the use of posaconazole. RECENT FINDINGS: Limited clinical studies suggest that an exposure-response relationship for posaconazole exists for the treatment of established invasive fungal diseases (IFDs), with emerging but less compelling data supporting its role in prophylaxis. The high prevalence of subtherapeutic levels has not translated to high prophylactic failure rates perhaps because of preferential uptake by effector cells important in the front-line defence against Aspergillus species. Nevertheless, TDM would appear prudent in patients deemed at highest risk for IFD with correction of patient modifiable factors and attention to drug administration important in optimizing drug exposure. TDM performed within a few days after commencing posaconazole may be predictive of steady-state levels, thus minimizing the delay in obtaining results in addition to identifying a subset of patients who may remain persistently subtherapeutic and also resistant to dose-escalation. Trough levels may be supplanted by untimed levels at steady state, thereby expanding the practicalities of TDM. We propose that TDM becomes one of the several measures in an integrated approach to IFD prevention combining screening of high-risk haematology patients for invasive aspergillosis at presentation, together with prospective surveillance for IFD, explicit criteria for switching to an alternative prophylactic agent and adherence to infection control practices. SUMMARY: Growing evidence supports the value of TDM for posaconazole to identify patients who may benefit from correction of modifiable factors impacting bioavailability, dosage adjustment or switch to an alternative agent.
    Current Opinion in Infectious Diseases 10/2012; · 4.87 Impact Factor
  • Leukemia & lymphoma 10/2012; · 2.61 Impact Factor
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    ABSTRACT: The treatment of acute promyelocytic leukemia has improved considerably after recognition of the effectiveness of all-trans-retinoic acid (ATRA), anthracycline-based chemotherapy, and arsenic trioxide (ATO). Here we report the use of all 3 agents in combination in an APML4 phase 2 protocol. For induction, ATO was superimposed on an ATRA and idarubicin backbone, with scheduling designed to exploit antileukemic synergy while minimizing cardiotoxicity and the severity of differentiation syndrome. Consolidation comprised 2 cycles of ATRA and ATO without chemotherapy, followed by 2 years of maintenance with ATRA, oral methotrexate, and 6-mercaptopurine. Of 124 evaluable patients, there were 4 (3.2%) early deaths, 118 (95%) hematologic complete remissions, and all 112 patients who commenced consolidation attained molecular complete remission. The 2-year rate for freedom from relapse is 97.5%, failure-free survival 88.1%, and overall survival 93.2%. These outcomes were not influenced by FLT3 mutation status, whereas failure-free survival was correlated with Sanz risk stratification (P[trend] = .03). Compared with our previously reported ATRA/idarubicin-based protocol (APML3), APML4 patients had statistically significantly improved freedom from relapse (P = .006) and failure-free survival (P = .01). In conclusion, the use of ATO in both induction and consolidation achieved excellent outcomes despite a substantial reduction in anthracycline exposure. This trial was registered at the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12605000070639.
    Blood 06/2012; 120(8):1570-80; quiz 1752. · 9.78 Impact Factor
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    ABSTRACT: Anti-thymocyte globulin (ATG) is polyclonal, containing Ab specificities capable of binding to various immune-cell subsets implicated in the pathogenesis of GVHD, including T cells, B cells, natural killer cells, monocytes/macrophages, neutrophils and DC. We wished to determine which ATG specificities are important for GVHD prevention. We measured day 7 serum levels of 23 ATG specificities in 120 hematopoietic cell transplant recipients whose myeloablative conditioning included 4.5 mg/kg ATG (thymoglobulin). High levels of ATG specificities capable of binding to T- and B-cell subsets were associated with a low likelihood of acute GVHD (aGVHD). High levels of these ATG specificities were associated with increased rates of viral but not bacterial or fungal infections. They were not associated with an increased risk of malignancy relapse; on the contrary, high levels of ATG specificities capable of binding to regulatory T cells and invariant NKT cells were associated with a low risk of relapse. In conclusion, high levels of ATG antibodies to Ag(s) expressed on T and B cells are associated with a low risk of aGVHD and a high risk of viral but not bacterial or fungal infections. These antibodies have neutral or beneficial effects on relapse.Bone Marrow Transplantation advance online publication, 4 June 2012; doi:10.1038/bmt.2012.99.
    Bone marrow transplantation 06/2012; · 3.00 Impact Factor
  • Prahlad Ho, Peter Sherman, Andrew Grigg
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    ABSTRACT: Granulocyte Colony-Stimulating Factor (G-CSF) is commonly used to maintain dose intensity in patients receiving ABVD chemotherapy (doxorubicin, bleomycin, vinblastine and dacarbazine) for Hodgkin lymphoma. However, the need for growth factor support is unclear, with studies suggesting that dose intensity can be maintained without G-CSF. Moreover, G-CSF is expensive (pegfilgrastim: EUR 1540/cycle; 300 μg filgrastim for 7 days: EUR 700/cycle) and is associated with side effects including bone pain and increased risk of bleomycin lung toxicity. Intermittent G-CSF may be an effective compromise, given that the effect of G-CSF on granulocyte precursors in vitro persists for 4-5 days after administration. After promising results of a pilot study, this schedule has been used subsequently in the majority of our patients receiving G-CSF as secondary prophylaxis for ABVD complicated by neutropenia. Retrospective analysis of the incidence of febrile neutropenia and treatment delay in a variety of different G-CSF schedules used as secondary prophylaxis in patients receiving ABVD. 848 cycles in 85 consecutive patients were evaluated. Most patients (86%) received G-CSF, generally commenced prophylactically for neutropenia when cycle 1B was due. Intermittent G-CSF (typically given on days 4, 8 and 12) was used in 413 cycles compared with daily or pegylated G-CSF in 99 cycles. In patients receiving intermittent G-CSF, the median neutrophil count, across all cycles, was 7.3 × 10(9) /L (range: 1.4-47.1) when the next scheduled chemotherapy was due. There were two cases of febrile neutropenia (0.45%) and no treatment delays. One patient developed possible bleomycin toxicity. Intermittent G-CSF is effective in maintaining dose intensity in patients receiving ABVD.
    European Journal Of Haematology 02/2012; 88(5):416-21. · 2.55 Impact Factor
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    ABSTRACT: Initial therapy for patients with acute promyelocytic leukemia most often involves the combination of all-trans-retinoic acid with anthracycline-based chemotherapy. The role of non-anthracycline drugs in induction and consolidation is less well-established and varies widely between different cooperative group protocols. In an attempt to minimize relapse and maximize survival for patients with newly diagnosed acute promyelocytic leukemia, the Australasian Leukaemia and Lymphoma Group utilized all-trans-retinoic acid and idarubicin as anti-leukemic therapy for both induction and consolidation. The protocol (known as APML3) was subsequently amended to incorporate maintenance with all-trans-retinoic acid, methotrexate and 6-mercaptopurine. Eight (8%) of 101 patients died within 30 days, and 91 (90%) achieved complete remission. With a median estimated potential follow-up of 4.6 years, 4-year overall survival was 84%, and 71% of the patients remained in remission at 4 years. The cumulative incidence of all relapses was 28.1%, with 15 of the 25 relapses initially identified as an isolated molecular relapse. Both FLT3 mutations (internal tandem duplications and codon 835/836 kinase domain mutations) and increased white cell count at diagnosis were associated with inferior overall survival, but in multivariate analyses only FLT3 mutations remained significant (hazard ratio 6.647, P=0.005). Maintenance therapy was significantly associated with improved remission duration (hazard ratio 0.281, P<0.001) and disease-free survival (hazard ratio 0.290, P<0.001). The combination of all-trans-retinoic acid and just two cycles of idarubicin followed by triple maintenance produced durable remissions in most patients, but patients with high-risk disease, especially those with FLT3 mutations, require additional agents or alternative treatment approaches. The significant reduction in relapse seen after the addition of maintenance to the protocol supports a role for maintenance in the context of relatively low chemotherapy exposure during consolidation. (actr.org.au identifier: ACTRN12607000410459).
    Haematologica 02/2012; 97(2):227-34. · 5.94 Impact Factor
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    ABSTRACT: Adult immune thrombocytopenia (ITP) is a heterogeneous disease and its immunobiology is incompletely understood. Establishing associations between candidate genes and ITP susceptibility may provide insight into pathogenesis. Previous studies have associated overrepresentation of FCGR3a-V158 allele with pediatric ITP. We prospectively accrued DNA from 102 adult patients with persistent/chronic or relapsed primary ITP identified by defined criteria. The distribution of KIR2 genes and polymorphisms of FCGR3a, both associated with autoimmunity, were compared with 105 healthy white individuals. Results were stratified by ethnicity. Carriers of the KIR2DS2/KIR2DL2 genotype [KIR2DS2/KIR2DL2 versus KIR2DS2/KIR2DL2 and KIR2DS2/KIR2DL2; odds ratio (OR) 2.51, P = 0.002] were overrepresented. In addition, frequency of the high-binding affinity FCGR3a-V/V158 genotype (VV versus VF/FF; OR = 3.05, P = 0.007) was increased, whereas that of the FCGR3a-F158 allele was reduced (OR = 2.58, P = 0.00.002). In a regression model to adjust for age, sex and the effects of the other gene, the KIR2 genotype independently conferred increased susceptibility from the FCGR3a-158 polymorphisms. In a comparison of healthy controls and a tightly defined cohort of adult ITP patients, the KIR2DS2/KIR2DL2 genotype was found to be associated with ITP independently of FCGR3a-158 polymorphisms. Further studies are required to establish the mechanistic basis for these observations and their potential impact on immune-based therapies.
    Blood coagulation & fibrinolysis: an international journal in haemostasis and thrombosis 01/2012; 23(1):45-50. · 1.25 Impact Factor

Publication Stats

5k Citations
862.35 Total Impact Points

Institutions

  • 2004–2014
    • Austin Health
      Melbourne, Victoria, Australia
  • 1993–2014
    • Royal Melbourne Hospital
      • Department of Nephrology
      Melbourne, Victoria, Australia
    • Alfred Hospital
      Melbourne, Victoria, Australia
  • 2011
    • University of Adelaide
      • Discipline of Medicine
      Adelaide, South Australia, Australia
    • Monash University (Australia)
      • Faculty of Pharmacy and Pharmaceutical Sciences
      Melbourne, Victoria, Australia
  • 2010
    • Australasian Leukaemia and Lymphoma Group
      East Melbourne, Victoria, Australia
  • 2007–2010
    • Peter MacCallum Cancer Centre
      • Division of Haematology and Medical Oncology
      Melbourne, Victoria, Australia
  • 2002–2008
    • IMVS Pathology
      • • Genetics and Molecular Pathology Division
      • • Haematology Division
      Adelaide, South Australia, Australia
  • 2006
    • University of Melbourne
      • Department of Medicine
      Melbourne, Victoria, Australia
    • Westmead Hospital
      • Department of Haematology
      Sydney, New South Wales, Australia
  • 1997–2006
    • Walter And Eliza Hall Institute For Medical Research
      Melbourne, Victoria, Australia
  • 2005
    • Malaghan Institute
      Wellington, Wellington, New Zealand
  • 2003
    • Hanson Institute
      Tarndarnya, South Australia, Australia
  • 1992–1996
    • Vancouver General Hospital
      • Department of Pathology and Laboratory Medicine (UBC)
      Vancouver, British Columbia, Canada
    • University of British Columbia - Vancouver
      • Department of Radiology
      Vancouver, British Columbia, Canada