[Show abstract][Hide abstract] ABSTRACT: Objectives:
The primary objectives were to investigate the prescribing practices of primary antifungal prophylaxis (PAP) and incidence of invasive fungal disease (IFD) in adult patients with ALL receiving induction-consolidation chemotherapy. Secondary objectives were to determine risk factors for IFD and resource utilization associated with IFD.
A retrospective chart review of adult patients with ALL from commencement of induction until completion of consolidation chemotherapy was undertaken from January 2008 to June 2013 in four hospitals in Melbourne, Australia. IFD was classified according to the revised European Organisation for Research and Treatment of Cancer criteria. Cost analysis was performed from an Australian public hospital perspective.
Ninety-eight patients were included in the audit; 83 (85%) received PAP. Most patients (49/83, 59%) switched between two different antifungal agents, predominantly between liposomal amphotericin B and an azole. Five proven/probable and six possible IFD cases were identified. Proven/probable IFD was most common in patients receiving the BFM95 chemotherapy protocol. The incidence of proven/probable IFD was significantly lower in patients receiving PAP compared with those who did not (2/78, 2.6% versus 3/14, 21.4%; P = 0.024). For every five patients receiving PAP, one proven/probable IFD case would be prevented. Proven/probable IFD was associated with an additional median cost of 121 520 Australian dollars (95% CI: 90 781-180 141 Australian dollars; P < 0.001) compared with patients without IFD.
This is the first multicentre study evaluating PAP use in patients with ALL. With the caveats of interpretation of retrospective, non-randomized data, PAP was associated with a reduced IFD risk.
Journal of Antimicrobial Chemotherapy 10/2015; DOI:10.1093/jac/dkv343 · 5.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vanishing bile duct syndrome (VBDS) in association with Hodgkin lymphoma (HL) is well described but not well understood. We report an unusual case of a 75-year-old patient presenting with biopsy-proven VBDS and immunodeficiency, without identifiable cause, which showed a waxing and waning course, culminating in the development of HL 18 months later. To our knowledge, this is the first adult case in which VBDS preceded the diagnosis of HL by such a long period.
Internal Medicine Journal 12/2014; 44(12a). DOI:10.1111/imj.12609 · 1.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The myelodysplastic syndromes (MDS) are a group of disorders characterized by ineffective haematopoiesis, bone marrow dysplasia and cytopenias. Failure of red cell production often results in transfusion dependency with subsequent iron loading requiring iron chelation in lower risk patients. Consistent with previous reports, we have observed haematopoietic improvement in a cohort of patients treated with the oral iron chelator deferasirox (DFX). It has been postulated that MDS patients have a pro-inflammatory bone marrow environment with increased numbers of activated T cells producing elevated levels of tumour necrosis factor (TNF), which is detrimental to normal haematopoiesis. We demonstrate that DFX inhibits nuclear factor (NF)-κB dependent transcription without affecting its proximal activation, resulting in reduced TNF production from T cells stimulated in vitro. These results suggest that the haematopoietic improvement observed in DFX-treated patients may reflect an anti-inflammatory effect, mediated through inhibition of the transcription factor NF-κB and support the therapeutic targeting of this pathway, which is aberrantly activated in a large proportion of haematological malignancies.
British Journal of Haematology 10/2014; 168(4). DOI:10.1111/bjh.13151 · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report long-term results in 40 patients with Philadlephia chromosome-positive (Ph +) acute leukemia who received an imatinib monotherapy window to evaluate in vivo effects on BCR-ABL signaling prior to induction chemotherapy. The first 25 patients (cohort 1) received the LALA-94 protocol without further imatinib (newly diagnosed Ph + acute lymphoblastic leukemia [ALL]) or induction chemotherapy followed by single-agent imatinib. Subsequent patients (cohort 2) continued imatinib concurrently with either LALA-94 (newly diagnosed Ph + ALL) or other intensive chemotherapy regimens. Cohort 2 had a complete response (CR) rate of 93% and 5-year survival of 69%. For newly diagnosed Ph + ALL, survival was superior in cohort 2 compared with cohort 1. Toxicity was similar to that expected for chemotherapy alone. Among 10 evaluable patients, rapid loss of phospho-CRKL occurred during the imatinib window in seven patients (all achieved CR) and incomplete inhibition in three patients (none with CR). In summary, a pharmacodynamic window design permitted biomarker assessment of BCR-ABL targeting without compromising clinical outcomes.
Leukemia and Lymphoma 09/2014; 56(3):1-9. DOI:10.3109/10428194.2014.925547 · 2.89 Impact Factor
[Show abstract][Hide abstract] 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.
[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; 167(2). DOI:10.1111/bjh.13029 · 4.71 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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 05/2014; 89(5). DOI:10.1002/ajh.23684 · 3.80 Impact Factor
[Show abstract][Hide abstract] 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; 20(7). DOI:10.1016/j.bbmt.2014.03.025 · 3.40 Impact Factor
[Show abstract][Hide abstract] 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; 18(11). DOI:10.1634/theoncologist.2013-0223 · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract Cyclical thrombocytosis, acquired von Willebrand syndrome, aggressive non-melanoma skin cancers and other hydroxyurea complications have been reported in Philadelphia-negative myeloproliferative neoplasms (MPN) but their incidence and clinical consequences have not been defined in a large cohort of patients. We conducted a retrospective analysis of 188 consecutive patients with MPN specifically addressing the incidence of these complications. Cyclical thrombocytosis was documented in 29 patients (15%), the majority of whom were receiving hydroxyurea. Acquired von Willebrand syndrome was identified in 17 of the 84 screened patients (20%), but was not associated with any major bleeding complications. Non-melanoma skin cancers were reported in 51 patients (27%). Hydroxyurea-related fever occurred in 9 of 149 patients (6%) who received hydroxyurea. Seventy-three patients (39%) experienced a total of 98 major thrombotic events with the majority of these occurring prior-to or within three months of the diagnosis. Cyclical thrombocytosis, acquired von Willebrand syndrome, aggressive non-melanoma skin cancers and other hydroxyurea-related complications are not infrequent in MPN and have important clinical consequences for management.
[Show abstract][Hide abstract] ABSTRACT: As a group of more than 100 experts in chronic myeloid leukemia (CML), we draw attention to the high prices of cancer drugs, with the particular focus on the prices of approved tyrosine kinase inhibitors for the treatment of CML. This editorial addresses the multiple factors involved in cancer drug pricing and their impact on individual patients and health care policies, and argues for the need to (1) lower the prices of cancer drugs to allow more patients to afford them and (2) maintain sound long-term health care policies.
[Show abstract][Hide abstract] 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; 162(3). DOI:10.1111/bjh.12404 · 4.71 Impact Factor