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Susan Branford,
David T Yeung,
David M Ross,
Jodi A Prime,
Chani R Field,
Haley K Altamura,
Alexandra L Yeoman,
Jasmina Georgievski,
Bronte A Jamison,
Stuart Phillis,
Brad Sullivan,
Nancy E Briggs, Mark Hertzberg,
John F Seymour,
John Reynolds,
Timothy P Hughes
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ABSTRACT: Key points Independent predictors of stable undetectable BCR-ABL1 on first-line imatinib therapy were female sex and the BCR-ABL1 value at 3 monthsThe time to achieve an MMR influenced time to stable undetectable BCR-ABL1, suggesting slower dynamics of BCR-ABL1 decline with delayed MMR.
Blood 03/2013; · 9.90 Impact Factor
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Harry J Iland,
Ken Bradstock,
Shane G Supple,
Alberto Catalano,
Marnie Collins, Mark Hertzberg,
Peter Browett,
Andrew Grigg,
Frank Firkin,
Amanda Hugman, [......],
Juliana Di Iulio,
Campbell Tiley,
Kerry Taylor,
Robin Filshie,
Michael Seldon,
John Taper,
Jeff Szer,
John Moore,
John Bashford,
John F Seymour
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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. · 9.90 Impact Factor
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ABSTRACT: Background: HLA haploidentical bone marrow transplantation is a treatment option in patients with hematological malignancies who have no available HLA matched donor, but is limited by conditioning regimen toxicity, graft failure, relapse and graft versus host disease. Aims: To demonstrate safety and efficacy of haploidentical bone marrow transplantation with nonmyeloablative conditioning and high-dose post-transplant cyclophosphamide in adult patients with leukaemia or lymphoma. Methods: 12 patients, median age of 51 years, underwent transplantation with T cell replete bone marrow from a haplotype matched relative. The conditioning regimen consisted of cyclophosphamide, fludarabine, and low-dose TBI. Post-transplant immunosuppression consisted of a single dose of cyclophosphamide 50 mg/kg on day 3, followed by oral tacrolimus and mycophenolatemofetil. Outcomes reported are overall survival, engraftment and chimerism, toxicity, and clinical outcome. Results: All patients had neutrophil recovery (median 14.5 days), and 11 of 12 had platelet engraftment (median 17 days). Two patients had autologous reconstitution. Seven of 9 assessable patients had complete donor chimerism. Four patients had grade II-III GvHD, and none had grade IV GvHD. Four patientsdeveloped limited stage chronic GvHD. Five patients with AML relapsed. Two patients died of non-relapse causes, both from other malignancies, and 5 patients remain alive and relapse free. Median overall survival was324 days (range 88-1163). Conclusion: This regimen is feasible and well-tolerated in older patients with high risk leukemia or lymphoma, with minimal short-term toxicity, and low rates of GVHD. The proportion of disease-free survivors indicates a graft versus malignancy effect is present in survivors. © 2012 The Authors. Internal Medicine Journal © 2012 Royal Australasian College of Physicians.
Internal Medicine Journal 05/2012; · 1.54 Impact Factor
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Harry Iland,
Ken Bradstock,
John Seymour, Mark Hertzberg,
Andrew Grigg,
Kerry Taylor,
John Catalano,
Paul Cannell,
Noemi Horvath,
Sandra Deveridge,
Peter Browett,
Tim Brighton,
Li Chong,
Francisca Springall,
Juliet Ayling,
Alberto Catalano,
Shane Supple,
Marnie Collins,
Juliana Di Iulio,
John Reynolds
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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. · 6.42 Impact Factor
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ABSTRACT: Laboratory identification of lupus anticoagulants (LA), an important component of the clinical diagnosis of the autoimmune disorder antiphospholipid syndrome (APS), is challenged by the heterogeneity of tests available, the diagnostic and laboratory approach undertaken, and the heterogeneity of the autoantibodies present.
: To assess the laboratory approach for investigation of LA, as well as the utility of various tests and test approaches, given a difficult clinical scenario in which LA might or might not be present.
Ninety-three participants in the Royal College of Pathologists of Australasia (RCPA) Haematology Quality Assurance Program (QAP) were sent 4 mL of a complex but strongly positive LA sample blinded to the nature of the abnormality.
Seventy-three (79%) participants returned results and in most cases diagnostic interpretations. The laboratory approach to LA investigation of this sample was quite varied: 34.7% of participants concluded the sample was LA negative, with 91.7% of these performing dilute Russell viper venom time (dRVVT) testing without mixing, whereas 43.5% of participants identified a strong LA, with 96.7% of these having performed mixing studies. Most laboratories reporting negative LA instead identified the false presence of specific factor inhibitors against a variety of factors, including II, V and VIII.
For this difficult challenge, performance of non-mixing dRVVT was associated with a high false negative LA rate.
Pathology 12/2011; 44(3):240-7. · 2.38 Impact Factor
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ABSTRACT: There are limited data on the impact of H1N109 infection in patients undergoing hematopoietic stem cell transplantation (HSCT). We reviewed individual medical records of patients who underwent HSCT or were on follow-up post-HSCT between May and September 2009. Thirteen patients with H1N109 infection were identified: 2 <100 days post-HSCT, 7 >100 days post-HSCT, and 4 just prior to HSCT. Five (38.7%) had lower respiratory tract involvement (LRTI), whereas the remainder had upper respiratory tract involvement (URTI). LRTI occurred in patients who were profoundly neutropenic post-HSCT or on potent immunosuppression for chronic graft-versus-host disease (cGVHD). At 100 days post-H1N109 infection, only 1 patient with LRTI survived, whereas all with URTI are alive. Four patients successfully treated for H1N109 infection prior to HSCT underwent the procedure after 4 to 6 weeks without any complications. Another 6 patients received oseltamivir prophylaxis during conditioning and none developed H1N109 infection. In conclusion, H1N109 infection was associated with LRTI in HSCT recipients who were profoundly neutropenic or immunosuppressed. Prior H1N109 infection did not affect the successful outcome of HSCT and oseltamivir prophylaxis in a small group of recipients resulted in no infection. Further studies are required.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2011; 17(1):147-53. · 3.15 Impact Factor
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Mark A Dawson,
Stephen S Opat,
Yamna Taouk,
Mark Donovan,
Michele Zammit,
Katherine Monaghan,
Noemi Horvath,
Andrew W Roberts,
H Miles Prince, Mark Hertzberg,
Catriona A McLean,
Andrew Spencer
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ABSTRACT: Multiple myeloma is an incurable disease with heterogeneous clinical behavior. Bortezomib has offered some patients with relapsed and refractory disease an opportunity for prolonged survival. However, there remains a paucity of data in patients treated with bortezomib that accurately delineates and identifies such patients. This information is crucial to guide management.
In this study, we aimed to identify the patients most likely to respond to bortezomib salvage therapy. We analyzed the baseline clinical variables and profiled the baseline expression of a broad range of immunohistochemical markers of cell cycle activity, apoptosis, and angiogenesis in a large cohort of multiply relapsed myeloma patients recruited to one of two prospective multicentre trials assessing the efficacy of bortezomib salvage therapy.
Using the European Group for Bone Marrow Transplantation criteria, response (complete or partial) to bortezomib salvage therapy was associated with a previous history of complete response to alternative antimyeloma treatment. Patients who expressed cyclin D1 were more likely to achieve a response. In contrast, patients who expressed p16(INK4A), cytoplasmic p53, and the highest intensity of Bcl-2 staining had a poor response. Patients who achieved a response to bortezomib and those patients who expressed cyclin D1 at baseline showed a significant survival advantage. Patients who expressed FGFR3, a poor prognostic marker, responded equally well and had similar outcomes with bortezomib compared with FGFR3-negative patients.
Baseline clinical variables and selective immunohistochemical markers expressed by patients may be used effectively to identify patients that are most likely to achieve a meaningful clinical response to bortezomib salvage therapy.
Clinical Cancer Research 02/2009; 15(2):714-22. · 7.74 Impact Factor
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ABSTRACT: Unrelated umbilical cord blood has emerged as an alternative stem cell source for allogeneic transplantation for patients with haematological malignancies, but in adults is limited by the low number of stem cells present in banked cord blood units. We report our experience with double cord blood transplants for adult patients. The aim of the study was to compare the outcomes of double unrelated cord blood transplants in adults with poor prognosis haematological diseases with single cord blood transplants.
Eleven patients, median age 27 years and median weight 69 kg, received transplants of two partially matched unrelated cord blood units after myeloablative conditioning therapy.
Neutrophil recovery to 0.5 x 10(9)/L was seen by median day 32 (18-53), and platelet recovery to 50 x 10(9)/L by day 91 (56-381). These results were not significantly different from those reported in patients receiving single cord blood transplants. Acute graft-versus-host disease of grades II-IV was seen in four patients, but no chronic graft-versus-host disease occurred. Transplant-related complications were responsible for the deaths of five patients in the first 3 months post-transplant, whereas two patients died of relapse of their haematological malignancy. Four patients survive, disease free, 17-33 months post-transplant.
Transplantation using two partially matched unrelated cord blood units did not appear to result in improvements either in engraftment or survival, as compared with a previous cohort of patients receiving single cord blood units. Further strategies appear to be needed to reduce the duration of severe neutropenia and reduce the high transplant-related mortality in these patients.
Internal Medicine Journal 12/2008; 39(11):744-51. · 1.54 Impact Factor
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Timothy P Hughes,
Susan Branford,
Deborah L White,
John Reynolds,
Rachel Koelmeyer,
John F Seymour,
Kerry Taylor,
Chris Arthur,
Anthony Schwarer,
James Morton, [......],
Robin Filshie,
Anthony K Mills,
Keith Fay,
Simon Durrant,
Henry Januszewicz,
David Joske,
Craig Underhill,
Scott Dunkley,
Kevin Lynch,
Andrew Grigg
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ABSTRACT: We conducted a trial in 103 patients with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML) using imatinib 600 mg/day, with dose escalation to 800 mg/day for suboptimal response. The estimated cumulative incidences of complete cytogenetic response (CCR) by 12 and 24 months were 88% and 90%, and major molecular responses (MMRs) were 47% and 73%. In patients who maintained a daily average of 600 mg of imatinib for the first 6 months (n = 60), MMR rates by 12 and 24 months were 55% and 77% compared with 32% and 53% in patients averaging less than 600 mg (P = .037 and .016, respectively). Dose escalation was indicated for 17 patients before 12 months for failure to achieve, or maintain, major cytogenetic response at 6 months or CCR at 9 months but was only possible in 8 patients (47%). Dose escalation was indicated for 73 patients after 12 months because their BCR-ABL level remained more than 0.01% (international scale) and was possible in 45 of 73 (62%). Superior responses achieved in patients able to tolerate imatinib at 600 mg suggests that early dose intensity may be critical to optimize response in CP-CML. The trial was registered at www.ANZCTR.org.au as #ACTRN12607000614493.
Blood 09/2008; 112(10):3965-73. · 9.90 Impact Factor
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ABSTRACT: Liposomal daunorubicin (DaunoXome) was substituted for doxorubicin in the CHOP regimen, aiming to reduce toxicity and maintain or improve efficacy in elderly patients. Eligibility criteria included: age >or=60 years; previously untreated aggressive non-Hodgkin Lymphoma (NHL) and performance status (PS) 0-2. Treatment was cyclophosphamide 750 mg/m(2), vincristine 1.4 mg/m(2) (maximum 2 mg), and DaunoXome 100 mg/m(2) i.v. on day 1, prednisolone 100 mg po on days 1-5 and G-CSF 5 microg/kg/day sc, for 6-8 cycles. For the 51 patients, median age was 70 years (range 60-88), 94% had diffuse large B-cell lymphoma (DLBCL) and 55% were high-intermediate or high-risk according to the age-adjusted international prognostic index. A mean of 6 cycles was delivered, with dose reductions of DaunoXome in 8.3% of cycles. The combined CR and CRu rate was 65.2%, survival was 566 days and 5-year survival 35%. Three deaths occurred during treatment and may have been related to COP-X. Only 4 (7.8%) of the remaining patients had >or=10% reduction in LVEF. However, 35% of patients were hospitalised during treatment, mostly for febrile neutropenia. The response rate to COP-X was similar to that expected with CHOP, with low cardiac toxicity. The high rate of infectious complications suggests that the DaunoXome dose used may be too high for this patient group. These results support further investigation of this regimen in patients with aggressive NHL.
Leukemia & lymphoma 05/2008; 49(5):924-31. · 2.40 Impact Factor
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Blood 04/2007; 109(5):2263; author reply 2263-4. · 9.90 Impact Factor
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ABSTRACT: Regular multilaboratory surveys of laboratories derived primarily from Australia, New Zealand, and Southeast Asia have been conducted during the last 8 years to evaluate testing proficiency in the diagnosis of von Willebrand disease (vWD). We summarize and update the findings of these surveys with a particular emphasis on diagnostic errors and error rates associated with particular tests or test panel limitations. A total of 43 plasma samples have been dispatched to survey participants. These have included 13 normal samples, five type 1 vWD samples, eight type 2 vWD samples (three 2A, three 2B, one 2M, and one 2N), and four type 3 vWD samples. In addition to numerical test results, participant laboratories (currently, n = 49) were asked to provide diagnostic interpretations regarding results, and whether or not vWD was suggested, and if so, a probable subtype. Although laboratories usually provided correct interpretative responses, diagnostic errors occurred in a substantial number of cases. On average, type 1 vWD plasma was misidentified as type 2 vWD in 13.3% of cases, and laboratories performing von Willebrand factor (vWF):ristocetin cofactor activity (RCo) without vWF:collagen-binding activity (CB) were seven times more likely to make such an error compared with those performing vWF:CB. Similarly, type 2 vWD plasma was misidentified as type 1 or type 3 vWD in an average of 20.1% of cases, and laboratories performing vWF:RCo without vWF:CB were three times more likely to make such an error compared with those performing vWF:CB. Finally, normal plasma was misidentified as vWD in an average of 6.7% of cases, and laboratories performing vWF:RCo without vWF:CB were four times more likely to make such an error compared with those performing vWF:CB. We conclude that although laboratories are generally proficient in tests for vWD, diagnostic errors do occur and error rates are substantially reduced when test panels are more comprehensive and include the vWF:CB.
Seminars in Thrombosis and Hemostasis 08/2006; 32(5):505-13. · 4.52 Impact Factor
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ABSTRACT: Because of the potential implications of results of genetic analyses of thrombophilic mutations, laboratories must undertake stringent internal quality control measures and participate in external quality assurance (QA) programs. A small number of external QA surveys of thrombophilic defects have been conducted across a large number of molecular laboratories and generally have indicated favorable levels of correct responses. The Royal College of Pathologists of Australasia QA program has conducted external QA testing of factor V Leiden G1691 A, prothrombin G20210A, and MTHFR C677T gene mutations for the past 5 years, including 133 DNA samples in 10 multilaboratory surveys. Of 3,799 responses, the overall success rate was 98.63%; the poorest individual sample result was 15% incorrect for a homozygous factor V Leiden sample. Success rates in identifying specific mutations were 98.13% for factor V Leiden, 98.84% for prothrombin G20210A, and 99.3% for the MTHFR C677T mutation. Among responding laboratories, 51% (20/39) made at least 1 error; 3 of 39 laboratories were responsible for 46% of all errors (24/52). Although encouraging, these data underscore the need for ongoing participation of molecular diagnostic laboratories in external QA programs to ensure the provision of quality genetic testing services.
American Journal of Clinical Pathology 03/2005; 123(2):189-93. · 2.60 Impact Factor
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ABSTRACT: Regular multilaboratory surveys of laboratories primarily in Australia, New Zealand, and Southeast Asia have been conducted over the past 8 years to evaluate testing proficiency in the diagnosis of von Willebrand disorder (VWD). We have reassessed the findings of these surveys with a particular emphasis on the diagnostic errors and error rates associated with particular tests or test panel limitations. The 37 plasma samples dispatched to survey participants include 9 normal samples, 4 type 1 VWD samples, 8 type 2 VWD samples (2A x 3, 2B x 3, 2M x 1, and 2N x 1), and 4 type 3 VWD samples. In addition to providing numerical test results, participant laboratories (average, n = 35) were asked to provide diagnostic interpretations of their test results regarding whether VWD was evident and, if so, the probable subtype. Although laboratories usually provided correct interpretative responses, diagnostic errors occurred in a substantial number of cases. On average, type 1 VWD plasma was misidentified as type 2 VWD plasma in 11% of cases, and laboratories that performed the ristocetin cofactor assay for von Willebrand factor (VWF:RCo) without performing the collagen-binding activity assay for VWF (VWF:CB) were 6 times more likely to make such an error than those that did perform the VWF:CB. Similarly, type 2 VWD plasma samples were misidentified as type 1 or type 3 VWD in an average of 20% of cases, and laboratories that performed the VWF:RCo without the VWF:CB were 3 times more likely to make such an error than those that performed the VWF:CB. Finally, normal plasma was misidentified as VWD plasma in an average of 5% of cases, and laboratories that performed the VWF:RCo without the VWF:CB were 10 times more likely to make such an error than those that performed the VWF:CB. We conclude that laboratories are generally proficient in their testing for VWD and that diagnostic error rates are substantially reduced when test panels are more comprehensive and include the VWF:CB.
Laboratory Hematology 02/2005; 11(2):91-7.
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ABSTRACT: A survey of 44 laboratories was conducted to evaluate current testing proficiency in the diagnosis of von Willebrand disorder (vWD) and to assess recent changes in test practices. Laboratories performed their usual panel of tests for vWD and interpreted results for the likelihood of vWD and potential subtype. Samples were as follows: normal plasma; borderline normal or abnormal levels of von Willebrand factor (vWF) and factor VIII; type 3 vWD; type 2A vWD; and 2 samples from a healthy person, processed after handling at 22 degrees C and 4 degrees C, respectively. Interassay and within-method coefficients of variation were similar for all assays (approximately 15%-25%). Most laboratories reported test values consistent with expected findings and made correct interpretations, although discrepant results for 5% to 10% of responses are of concern. For the sample stored at 4 degrees C, all laboratories detected low or borderline levels of vWF and factor VIII coagulant, and no laboratory identified this sample as from a healthy person. In contrast, for the sample stored at 22 degrees C, most laboratories reported normal results. Compared with previous results, performance of some assays has declined while that of others has increased. Laboratories generally are proficient in tests for vWD, and transport of samples at 4 degrees C before processing may lead to false identification of vWD, suggesting that NCCLS guidelines should be reviewed.
American Journal of Clinical Pathology 07/2003; 119(6):882-93. · 2.60 Impact Factor
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ABSTRACT: We report on a cross-laboratory study of type 2N von Willebrand disease (vWD). We tested 101 selected plasma samples for factor VIII and factor VIII binding activity of von Willebrand factor (vWF). Of these plasma samples, 31 were cotested by 2 specialist centers using different detection procedures for vWF-factor VIII binding: there was good agreement between results obtained by chromogenic assay and enzyme-linked immunosorbent assay. In total, 8 patients with type 2N vWD were identified. The 2-stage factor VIII assay detected a deficiency of factor VIII relative to vWF antigen in all 8 patients; the 1-stage factor VIII assay detected a relative deficiency in only 3 patients. Four patients were homozygous for the most common type 2N mutation (R854Q), 3 patients were presumed to be compound heterozygotes, and in 1 patient no type 2N mutations were identified. In this study of patients from 5 specialist centers in Australia, type 2N vWD was found in 5 families. The 2-stage factor VIII assay was more useful as a screening test than the 1-stage assay, and both vWF-factor VIII binding assays were equally effective.
American Journal of Clinical Pathology 09/2002; 118(2):269-76. · 2.60 Impact Factor
