Campbell Tiley

All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4)

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.

Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial

BACKGROUND Initial treatment of acute promyelocytic leukaemia traditionally involves tretinoin (all-trans retinoic acid) combined with anthracycline-based risk-adapted chemotherapy, with arsenic trioxide being the treatment of choice at relapse. To try to reduce the relapse rate, we combined arsenic trioxide with tretinoin and idarubicin in induction therapy, and used arsenic trioxide with tretinoin as consolidation therapy. METHODS Patients with previously untreated genetically confirmed acute promyelocytic leukaemia were eligible for this study. Eligibilty also required Eastern Cooperative Oncology Group performance status 0-3, age older than 1 year, normal left ventricular ejection fraction, Q-Tc interval less than 500 ms, absence of serious comorbidity, and written informed consent. Patients with genetic variants of acute promyelocytic leukaemia (fusion of genes other than PML with RARA) were ineligible. Induction comprised 45 mg/m(2) oral tretinoin in four divided doses daily on days 1-36, 6-12 mg/m(2) intravenous idarubicin on days 2, 4, 6, and 8, adjusted for age, and 0·15 mg/kg intravenous arsenic trioxide once daily on days 9-36. Supportive therapy included blood products for protocol-specified haemostatic targets, and 1 mg/kg prednisone daily as prophylaxis against differentiation syndrome. Two consolidation cycles with tretinoin and arsenic trioxide were followed by maintenance therapy with oral tretinoin, 6-mercaptopurine, and methotrexate for 2 years. The primary endpoints of the study were freedom from relapse and early death (within 36 days of treatment start) and we assessed improvement compared with the 2 year interim results. To assess durability of remission we compared the primary endpoints and disease-free and overall survival at 5 years in APML4 with the 2 year interim APML4 data and the APML3 treatment protocol that excluded arsenic trioxide. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12605000070639. FINDINGS 124 patients were enrolled between Nov 10, 2004, and Sept 23, 2009, with data cutoff of March 15, 2012. Four (3%) patients died early. After a median follow-up of 4·2 years (IQR, 3·2-5·2), the 5 year freedom from relapse was 95% (95% CI 89-98), disease-free survival was 95% (89-98), event-free survival was 90% (83-94), and overall survival was 94% (89-97). The comparison with APML3 data showed that hazard ratios were 0·23 (95% CI 0·08-0·64, p=0·002) for freedom from relapse, 0·21 (0·07-0·59, p=0·001) for disease-free survival, 0·34 (0·16-0·69, p=0·002) for event-free survival, and 0·35 (0·14-0·91, p=0·02) for overall survival. INTERPRETATION Incorporation of arsenic trioxide in initial therapy induction and consolidation for acute promyelocytic leukaemia reduced the risk of relapse when compared with historical controls. This improvement, together with a non-significant reduction in early deaths and absence of deaths in remission, translated into better event-free and overall survival. FUNDING Phebra.

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.

A phase II study of risk-adapted intravenous melphalan in patients with AL amyloidosis.

Thomas Prébet Steven D. Gore Sylvain Thépot Benjamin Esterni Bruno Quesnel Odile Beyne Rauzy François Dreyfus Claude Gardin Pierre Fenaux Norbert Vey Department of Hematologic malignancies, Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA, Departement d’Hematologie, Institut Paoli Calmettes, Marseille, Groupe Francophone des Myelodysplasies, Bobigny, E-mail: veyn@marseille.fnclcc.fr

Consensus guidelines for 'rainy day' autologous stem cell harvests in New South Wales.

Autologous stem cell transplantation (ASCT) has a well‐established role in the treatment of haematological malignancies. Stem cells are commonly collected following salvage chemotherapy although there may be advantages in collecting earlier in the disease course. A ’rainy day’ harvest (RDH) refers to the collection of autologous haemopoietic stem cells for long‐term storage. Although there are few data to support RDH, there is increasing evidence that such harvests are being carried out, creating storage pressures in stem cell laboratories across New South Wales. The Bone Marrow Transplant Network New South Wales conducted a three‐staged exercise to develop consensus‐based RDH guidelines. Using available evidence, guidelines were developed supporting RDH for specific patients with acute and chronic myeloid leukaemias, follicular and other lymphomas, and multiple myeloma. Physician agreement with these disease‐specific guidelines ranged between 58 and 100%. These consensus guidelines will improve equity of access to appropriate RDH and assist the planning of future storage requirements in New South Wales.

Enrolment of patients to clinical trials in haematological cancer in New South Wales: current status, perceived barriers and opportunities for improvement

Background: Enrolment of cancer patients in clinical trials is associated with significant positive outcomes. There are, however, limited Australian data on enrolment of patients with haematological malignancies to clinical trials.

‘Real-world’ Australian experience of pomalidomide for relapsed and refractory myeloma

Ashleigh Scott , Nicholas Weber, Campbell Tiley, Kerry Taylor, John Taper, Simon Harrison, Kah-Lok Chan, Richard Stark, Cindy Lee, Kirk Morris, P. Joy Ho, Anthony Dodds, Sundra Ramanathan, Raj Ramakrishna, Anne-Marie Watson, Bradley Auguston, Fiona Kwok, Hang Quach, Pauline Warburton, Philip Rowlings and Peter Mollee Princess Alexandra Hospital, Woollongabba, Brisbane, Australia; University of Queensland, St Lucia, Brisbane, Australia; Royal Brisbane and Women’s Hospital, Herston, Brisbane, Australia; Gosford Hospital, Gosford, New South Wales, Australia; Icon Cancer Care, South Brisbane, Australia; Nepean Hospital, Nepean, Sydney, Australia; Peter MacCallum Cancer Centre, Melbourne, Australia; Port Macquarie Base Hospital, Port Macquarie, New South Wales, Australia; Royal Adelaide Hospital, Queen Elizabeth Hospital, Adelaide, Australia; Royal Prince Alfred Hospital, Sydney, Australia; St Vincent’s Hospital, Sydney, Australia; St George Hospital, Kogarah, Sydney, Australia; Southern Sydney Haematology, Kogarah, Sydney, Australia; Liverpool Hospital, Liverpool, Sydney, Australia; Sir Charles Gairdner Hospital, Perth, Australia; Westmead Hospital, Sydney, Australia; St Vincent’s Hospital, Melbourne, Australia; Wollongong Hospital, Wollongong, New South Wales, Australia; Calvary Mater Hospital, Newcastle, New South Wales, Australia

Idarubicin Dose Escalation During Consolidation Therapy for Adult Acute Myeloid Leukemia

Purpose Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and Methods Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m2 daily for 5 days, etoposide 75 mg/m2 daily for 5 days, and idarubicin 9 mg/m2 daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Results Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3-internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation ( P < .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm ( P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3-internal tandem duplication and NPM1 gene mutation subgroups. Conclusion An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.

Lymphoma cell-of–origin assignment by gene expression profiling is clinically meaningful across broad laboratory contexts

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