Retrospective pharmaceutical financial benefits and cost avoidance analysis of clinical trial participation in the Australian haematology setting.

BACKGROUND: Clinical trial participants receiving investigational new drugs, which subsequently become approved by a medicines regulatory authority for its trialled indication, effectively gain free early access to efficacious treatment. Participants may also benefit from receiving approved, but unsubsidised medicines. These financial benefits of clinical trial participation have not previously been defined or quantified. Additionally, there are limited Australian pharmaceutical cost avoidance studies quantifying government savings through sponsored clinical trials. AIMS: To calculate pharmaceutical financial benefits and cost avoidance of clinical trial participation at a single Clinical Research Unit. METHODS: Recruiting clinical trials between 1 January 2006 and 31 December 2017 conducted at the Haematology Clinical Research Unit, Concord Repatriation General Hospital, Sydney were reviewed. Dispensing records were used to quantitate the pharmaceuticals dispensed to every participant. Financial calculations were based on Pharmaceutical Benefits Scheme (PBS) pricing, or from UpToDate for non-PBS listed agents. RESULTS: Thirty-six eligible clinical trials involving 245 participants accrued AU$3 971 357 in financial benefit from early access to subsequently approved investigational new drugs, AU$12 209 538 in financial benefit from accessing approved medications not PBS listed, and AU$6 728 576 in government cost avoidance. These findings totalled AU$22 909 471, 89% of which was derived in the past 5 years. CONCLUSION: Pharmaceutical financial benefit is a previously unquantified aspect of clinical trial participation, its assigned value reflecting a measure of the quality and quantity of life delivered to patients. These data, albeit from a single discipline and institution, suggest that financial benefit represents a greater value than cost avoidance, and that its inclusion in cost-analyses may better reflect the monetary benefits of accessing efficacious pharmaceutical agents through clinical trials.

TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets.

The Therapeutic Intensification in De Novo Leukaemia (TIDEL)-II study enrolled 210 patients with chronic phase chronic myeloid leukemia (CML) in two equal, sequential cohorts. All started treatment with imatinib 600 mg/day. Imatinib plasma trough level was performed at day 22 and if <1000 ng/mL, imatinib 800 mg/day was given. Patients were then assessed against molecular targets: BCR-ABL1 ≤10%, ≤1%, and ≤0.1% at 3, 6, and 12 months, respectively. Cohort 1 patients failing any target escalated to imatinib 800 mg/day, and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later. Cohort 2 patients failing any target switched to nilotinib directly, as did patients with intolerance or loss of response in either cohort. At 2 years, 55% of patients remained on imatinib, and 30% on nilotinib. Only 12% were >10% BCR-ABL1 at 3 months. Confirmed major molecular response was achieved in 64% at 12 months and 73% at 24 months. MR4.5 (BCR-ABL1 ≤0.0032%) at 24 months was 34%. Overall survival was 96% and transformation-free survival was 95% at 3 years. This trial supports the feasibility and efficacy of an imatinib-based approach with selective, early switching to nilotinib. This trial was registered at www.anzctr.org.au as #12607000325404.

Formalising multidisciplinary peer review: developing a haematological malignancy-specific electronic proforma and standard operating procedure to facilitate procedural efficiency and evidence-based clinical practice.

BACKGROUND: Multidisciplinary team (MDT) meetings aimed at facilitating peer review have become standard practice in oncology. However, there is scant literature on the optimal structure and conduct of such meetings. AIMS: To develop a process for formal peer review of patients with haematological malignancies and to audit any resulting changes made to the management recommendations of the treating physician. METHODS: A standard operating procedure (SOP) for MDT meetings was developed essentially to integrate clinical peer review with weekly pathology and radiology meetings. The centrepiece is the electronic submission of a patient-specific proforma (Microsoft InfoPath) prior to the meeting. It serves as the template for presentation, discussion and recording of recommendations and conclusions. The final verified document is stored in the electronic patient record, and a copy is sent to the general practitioner. The proposed management plans were compared to the consensus recommendations of the meeting for the first 4 years since inception. RESULTS: Both SOP and proforma underwent continual improvements. These provided the framework for the conduct of a robust weekly MDT meeting for peer review of the management of patients with haematological malignancies. On 20% of occasions, patient management plans were altered to optimise patient care as a direct consequence on peer review at the MDT. CONCLUSION: Our streamlined process, in its ultimate format, has provided a mature and efficient forum for formal peer review in a genuine multidisciplinary environment. Both initial data and informal feedback support its ongoing activity as an integral component of delivering quality patient care.

Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study.

This randomized, noninferiority (NI), global, phase 3 study evaluated the efficacy and safety of bendamustine plus rituximab (BR) vs a standard rituximab-chemotherapy regimen (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or rituximab plus cyclophosphamide, vincristine, and prednisone [R-CVP]) for treatment-naive patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Investigators preassigned the standard treatment regimen they considered most appropriate for each patient; patients were randomized to receive BR (n = 224) or standard therapy (R-CHOP/R-CVP, n = 223) for 6 cycles; 2 additional cycles were permitted at investigator discretion. Response was assessed by a blinded independent review committee. BR was noninferior to R-CHOP/R-CVP, as assessed by the primary end point of complete response rate (31% vs 25%, respectively; P = .0225 for NI [0.88 margin]). The overall response rates for BR and R-CHOP/R-CVP were 97% and 91%, respectively (P = .0102). Incidences of vomiting and drug-hypersensitivity reactions were significantly higher in patients treated with BR (P < .05), and incidences of peripheral neuropathy/paresthesia and alopecia were significantly higher in patients treated with standard-therapy regimens (P < .05). These data indicate BR is noninferior to standard therapy with regard to clinical response with an acceptable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT00877006.

High melphalan exposure is associated with improved overall survival in myeloma patients receiving high dose melphalan and autologous transplantation.

AIM: High dose melphalan (HDM) and autologous stem cell transplantation (ASCT) retains a central role in the treatment of myeloma. The aim of this study was to determine whether HDM exposure (area under the concentration vs. time curve, AUC), is significantly associated with transplant outcomes. METHODS: Melphalan concentrations were measured in six to 11 plasma samples collected after HDM (median 192 mg m(-) (2) ) to determine melphalan AUC for a total of 114 patients. Binary logistic regression was used to assess whether melphalan AUC was associated with severe (≥ grade 3) oral mucositis. Multivariate Cox regression was used to assess whether melphalan AUC was significantly associated with time to progression, progression-free survival and overall survival (OS). RESULTS: Melphalan AUC ranged from 4.9 to 24.6 mg l(-1)  h, median 12.84 mg l(-1) h. Melphalan AUC above the median was a risk factor for severe mucositis (HR 1.21, 95% CI 1.06, 1.38, P = 0.004) but was also associated with significantly improved overall survival (OS) (HR 0.40, 95% CI 0.20, 0.81, P = 0.001), with an estimated median survival of 8.50 years vs. 5.38 years for high vs. low AUC groups. Multivariate analysis did not identify melphalan AUC as being significantly associated with time to progression or progression-free survival. CONCLUSIONS: This large scale pharmacodynamic analysis of HDM demonstrates that high melphalan exposure is associated with improved survival, with an acceptable increase in transplant toxicity. These results suggest studies targeting a higher AUC are warranted in patients undergoing HDM and ASCT for myeloma.

Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy.

AIMS: To i) investigate the pharmacokinetics of total and unbound plasma melphalan using a population approach, ii) identify clinical factors that affect melphalan disposition and iii) evaluate the role of melphalan exposure in melphalan-related toxicity and disease response. METHODS: Population pharmacokinetic modelling (using NONMEM) was performed with total and unbound concentration-time data from 100 patients (36-73 years) who had received a median 192 mg m(-2) melphalan dose. Model derived estimates of total and unbound melphalan exposure (AUC) in patients with serious melphalan toxicity and those who had a good disease response (>or=90% decrease in paraprotein concentrations) were compared using the Mann-Whitney test. RESULTS: A two compartment model generated population mean estimates for total and unbound melphalan clearance (CL) of 27.8 and 128 l h(-1), respectively. Estimated creatinine clearance, fat free mass and haematocrit were important determinants of total and unbound CL, reducing the inter-individual variability in total CL from 34% to 27% and in unbound CL from 42% to 30%. Total AUC (range 4.9-24.4 mg l(-1) h) and unbound AUC (range 1.0-6.5 mg l(-1) h) were significantly higher in patients who had oral mucositis (>or=grade 3) and long hospital admissions (P < 0.01). Patients who responded well had significantly higher unbound AUC (median 3.2 vs. 2.8 mg l(-1) h, P < 0.05) when assessed from diagnosis to post-melphalan and higher total AUC (median 21.3 vs. 13.4 mg l(-1) h, P= 0.06), when assessed from pre- to post-melphalan. CONCLUSIONS: Creatinine clearance, fat free mass and haematocrit influence total and unbound melphalan plasma clearance. Melphalan exposure is related to melphalan toxicity while the association with efficacy shows promising trends that will be studied further.

Epstein Barr virus-positive mucocutaneous ulcer of the colon associated Hodgkin lymphoma in Crohn's disease.

Epstein Barr virus (EBV) positive mucocutaneous ulcers (EBVMCU) form part of a spectrum of EBV-associated lymphoproliferative disease. They have been reported in the setting of immunosenescence and iatrogenic immunosuppression, affecting the oropharyngeal mucosa, skin and gastrointestinal tract (GIT). Case reports and series to date suggest a benign natural history responding to conservative management, particularly in the GIT. We report an unusual case of EBVMCU in the colon, arising in the setting of immunosuppression in the treatment of Crohn's disease, with progression to Hodgkin lymphoma 18 mo after cessation of infliximab. The patient presented with multiple areas of segmental colonic ulceration, histologically showing a polymorphous infiltrate with EBV positive Reed-Sternberg-like cells. A diagnosis of EBVMCU was made. The ulcers failed to regress upon cessation of infliximab and methotrexate for 18 mo. Following commencement of prednisolone for her Crohn's disease, the patient developed widespread Hodgkin lymphoma which ultimately presented as a life-threatening lower GIT bleed requiring emergency colectomy. This is the first report of progression of EBVMCU to Hodgkin lymphoma, in the setting of ongoing iatrogenic immunosuppression and inflammatory bowel disease.

T cell stimulation and expansion using anti-CD3/CD28 beads.

Following appropriate stimulation, T lymphocytes will proliferate extensively in vitro. Traditionally, mitogenic lectins such as phytohemagglutinin (PHA) and concanavalin A (Con A) have been used for polyclonal T cell stimulation. A more physiologically relevant approach uses beads coated with anti-CD3 and anti-CD28 to stimulate T cells in a manner that partially mimics stimulation by antigen-presenting cells. This protocol describes the steps involved in T cell stimulation and their subsequent in vitro expansion using anti-CD3/CD28 beads.

Ex vivo expansion of functional T lymphocytes from HIV-infected individuals.

This study was designed to define the conditions for expansion of functional T lymphocytes from human immunodeficiency virus (HIV)-infected subjects, with the ultimate goal of using these cells for immunotherapy. The most appropriate culture conditions for good T cell proliferation included stimulation with anti-CD3 and anti-CD28 coated microspheres, and propagation in Aim V serum-free media with 20 U/ml interleukin-2 (IL-2), supplemented with decreasing concentrations of serum for the initial 8 days. Under these conditions, a 14-day culture period yielded approximately a 10,000-fold expansion of T lymphocytes from HIV-infected donors. The cultured cells comprised approximately 15% CD4+ cells and 70% CD8+ cells. These cells retained functional capacity as assessed by cytotoxicity towards HIV proteins, and production of IL-2 and interferon-gamma (IFN-gamma). Viral replication within the culture system was controlled, but not eliminated, without the requirement for antiviral agents. These culture conditions were demonstrated to be suitable for larger scale expansion of cells in hollow fibre bioreactors. This methodology provides a suitable means of producing large quantities of functional T cells for use in autologous immunotherapy protocols.

Flexible low-intensity combination chemotherapy for elderly patients with acute myeloid leukemia.

Twenty-five patients aged 57 to 88 years (median, 70 years) with acute myeloid leukemia were treated with a flexible low-intensity treatment regimen comprising mitozantrone (mitoxantrone) 6 mg/m2 administered by intravenous infusion x3 days, cytarabine 10 mg/m2 subcutaneously every 12 hours x7 to 14 days, and etoposide 100 mg orally x7 to 14 days. Seventeen of these patients had a preexisting myelodysplastic syndrome. The clinical response was correlated to the results of cytogenetic studies (23 patients) and of viability studies of leukemic blasts (7 patients). Eleven of the 25 patients achieved complete remission (CR), 8 achieved partial remission (PR), and 4 showed no response. There was 1 toxic death, and 1 patient died soon (1 week) after presentation. Treatment was well tolerated. Although myelotoxicity occurred regularly, the recovery time was < or = 3 weeks for most of the responding patients. Duration of survival for patients who had CR has ranged from 4+ to 43+ months and for patients who had PR, 3 to 16 months. Irrespective of the remission status (CR or PR), responding patients with favorable (n = 1) or intermediate (n = 10) cytogenetic findings had a significantly better survival time (median, 14 months) than did those with unfavorable (n = 7) cytogenetic findings (median, 5 months). In vitro studies showed a progressive reduction in the number of circulating blasts. The number of viable blasts 3 days after initiation of therapy appeared to give an early indication of clinical response. Treatment with a flexible low-intensity protocol seems to achieve results comparable with those reported for intensive antileukemia therapy and has much less toxicity.