Throughout the decade, ALLG built further links with other national cancer trials’ groups to establish research infrastructure funding, developed stronger links with international trials’ groups, developed a mechanism for consumer representation on ALLG, improved the publication record of ALLG, ensured a sustained Tissue Bank and cemented the relationship with the Leukaemia Foundation and Lymphoma Australia. Some of the impacts from ALLG trials included:
ALLG’s highly successful APML4 trial improves treatments in acute promyelocytic leukaemia
The APML4 trial for patients with previously untreated acute promyelocytic leukaemia (a subtype of acute myeloid leukemia), represented the most successful and high impact trial conducted by the ALLG membership. Incorporation of arsenic trioxide in initial therapy induction and consolidation for acute promyelocytic leukaemia reduced the risk of relapse and increased patients’ survival. The 5 year freedom from relapse was 95%, disease-free survival was 95%, event-free survival was 90%, and overall survival was 94%. Results were published in 2012.
ALLG APML4 treatment was then recommended [in 2018] by the US National Comprehensive Cancer Network and by a panel of Canadian Acute Promyelocytic Leukemia (APL) experts for the treatment of high risk APL.
Following the successful outcomes that were achieved with the APML4 trial, arsenic trioxide (ATO) was registered in Australia by the Therapeutic Goods Administration for the initial treatment of APL.
The ATO [in 2018] was listed also on the Pharmaceutical Benefits Scheme for the initial treatment of APL, another major achievement of the APML4 study, as it ensures that all Australian patients can access this powerful three-drug combination.
ALLG advancements in acute promyelocytic leukemia (APL)
The ALLG APML3 and ALLG APML4 trials led by ALLG Member Harry Iland have revolutionised APL therapy and dictated how most patients in Australia are managed today through introduction of ATRA and arsenic, respectively. These trials also provided supporting care guidelines, which is an important aim for ALLG trials to support patients living better lives. The established treatment of APML4 is recognised standard of care world-wide, and has led to the development of oral (tablet form) arsenic being trialled in the APML5 trial.
Major ALLG contributions in chronic myeloid leukaemia (CML) and myeloproliferative neoplasms (MPN)
The ALLG and its members have contributed widely to understanding the science of chronic leukaemias such as chronic myeloid leukaemia (CML) and the related condition of myeloproliferative neoplasms (MPN). Our first CML trial activity was led by Chris Arthur who made substantial contributions to CML therapy.
In chronic myeloid leukaemia (CML) the theme of dose intensity and the degree of kinase inhibition achieved being critical for initial molecular response and for long-term outcomes has been a common thread developed in numerous correlative studies linked to the ALLG clinical trial program including four seminal papers from ALLG Member Deb White (Blood, 2006 and 2007; JCO 2007; JCO 2010).
ALLG Member, Sue Branford’s laboratory for molecular monitoring of CML enabled ALLG to conduct ambitious and complex trials that are based around the precision and sensitivity of the PCR technology (CML6,8,9,11). Sue has published many high profile papers that have relied on critical data from the ALLG studies as well as international CML trials. Key publications derived from ALLG trial data include Blood papers in 2003, 2004, 2008, 2009, 2012 and 2013, as well as Leukaemia in 2006, and Clinical Cancer Research in 2007.
The other major contribution in CML from the ALLG group was in the area of treatment cessation. ALLG CML08 established the complete molecular response in CML. David Ross and colleagues had a major publication in Leukaemia in 2010, followed by the clinical analysis in the publication of Blood in 2013.
CML08 trial, led by ALLG members David Ross and Tim Hughes, researched the safety and efficacy of stopping treatment (imatinib cessation) with stable undetectable minimal residual disease (MRD) results. Published in Blood 2013. The CML08/9 trial, with ALLG member Sue Branford, looked at Early molecular response and gender predict stable BCR-ABL1 and the criteria for imatinib discontinuation in CML. Published in Blood in 2013.
The ALLG’s CML program introduced molecular monitoring in Australia in 2017, well ahead of its time, with three publications in leading peer-reviewed journals on various aspects of imatinib as well as establishing a method of next-generation sequencing to detect leukaemic mutations. These data were supportive in enabling Pharmaceutical Benefits Advisory Committee to allow excellent access for Australian patients to the latest in treatment, TKI.
ALLG advancements in Acute myeloid leukaemia (AML)
The ALLG’s AML trial portfolio was strengthened in 2011 with the publication of ALLG AMLM7, which identified risk factors for early death after high-dose cytosine arabinoside (HiDAC) based chemotherapy for adult AML. This work by ALLG members John Seymour, Ken Bradstock and Andrew Wei would form the basis of numerous trials on AML therapies.
FLT3 mutations were established as a key target for AML therapy in 2012 through the work of ALLG leader Andrew Wei on ALLG AML16. This work has been key to determining the role of FLT3 inhibitors for treating patients with FLT3-ITD AML.
ALLG launched the AMLM22 trial in 2019, its first adaptive platform trial investigating targeted therapies for those with AML. Novel drugs are assessed in parallel, expediting results and truncating trial setup times.
ALLG trials for better treatments in multiple myeloma (MM)
In 2014, ALLG MM15, led by members Andrew Spencer and Hang Quach closes recruitment and enters follow-up phase. Initial results showed benefit of tandem transplant and consolidation in young myeloma patients.
In 2015, ALLG MM11 demonstrated that addition of steroid to lenalidomide maintenance did not improve outcomes in myeloma, an important trial which defined future treatment. It proved the pivotal role of ASCT in upfront management in young patients. This Australian arm of a European Myeloma Network (EMN) trial led by Andrew Spencer produced numerous game-changing results, including that treatment intensification with ASCT and lenalidomide maintenance improves survival in patients with newly diagnosed multiple myeloma in 2018. Outcomes from MM11 are still being published today (eg. Zaccaria et al EHA June 2020).
ALLG MM16 led by members Joy Ho and Douglas Joshua showed safety of carfilzomib in renal impairment and enabled a change to the EVIQ guidelines. Prof Ho was awarded the Presidential Lecture for her MM16 work at the BLOOD conference in Perth in October 2019.
ALLG improving outcomes in myelodysplastic syndrome (MDS)
ALLG members Melita Kenealy and John Seymour led ALLG MDS03, which demonstrated in 2016 a successful combination of thalidomide and azacitidine in clinically-advanced MDS, CMML and low blast count AML. The MDS04 trial followed on exploring the role of azacytidine and lenalidomide, this was published in 2019. Both trials enabled important correlative research including a quality of life and transfusion substudy. The ALLG has continued its focus on MDS.
ALLG Hodgkin Disease trial improving treatment and lives
The ALLG HD03 trial, led by ALLG Life Member Max Wolf, was published in 2011 after accruing 150 patients from 28 centres. The study provided local benchmark results for a combination of limited chemotherapy and involved field radiotherapy in early-stage disease and resulted in significantly improved outcomes with 83% CR/CRu. This followed an early international collaboration with the National Canadian Cancer Trials Group (NCIC) in 1987 and was the first local HD trial in collaboration with Trans Tasman Radiation Oncology Group (TROG Cancer Research).
In 2013, initial results from the ALLG HD08 RATHL trial, led by ALLG member (and current Chair of ALLG Scientific Advisory Committee) Judith Trotman, and Leanne Berkahn, presented at the International Conference on Malignant Lymphoma in Lugano in June 2013. These data showed safe withdrawal of bleomycin in interim PET negative Hodgkin lymphoma, which is now standard practice.
Advancing treatment options in Myeloma & Related Diseases
The ALLG and its Members have a significant track record in developing the science of and treatments for multiple myeloma.
Led by ALLG member Andrew Spencer, the ALLG MM06 trial, already with two publications in 2009, underpinned post-transplant thalidomide maintenance in ANZ for many years to come.
ALLG MM08, led by member Peter Mollee, was published in 2012 and was one of the first Australian trials looking at risk-adapted intravenous melphalan in patients with AL amyloidosis. This would pave the way for MM13 in later years, a game-changing trial showing the effectiveness of bortezomib, which is now standard therapy.
ALLG Tissue Bank to accelerate research
The ALLG Tissue Bank, an innovation of ALLG’s first Laboratory Science Committee, was established by member Paula Marlton. It remains pivotal to ALLG’s clinical trial program (as part of today’s National Blood Cancer Registry and Biobank) and provides an abundant source of samples and data; a platform to translational research.
Tissue Bank, Safety and data monitoring, and consumer input to trials
In 2002, ALLG establishes a National Leukaemia and Lymphoma Bank, and a dedicated Safety and Data Monitoring Committee, and involves consumer representatives.
Improving treatment for AML
The AMLM12 study, led by Ken Bradstock, was the largest randomized study ever conducted by the group, recruiting 442 patients between 2003 and 2010 to investigate the primary question of whether an extra dose of idarubicin in each of two consolidation cycles would improve AML outcomes.
The ALLG AML studies have also benefited from advances in supportive care. These led to substantial reductions in induction deaths and have been critical for delivering the improvements in clinical outcome observed with chemotherapy.
Board and Scientific Advisory
In 2010, ALLG established an independent Board of non-executive directors and a Scientific Advisory Committee.
Dedicated Trial Centre
In 2013, the ALLG Trial Centre is established.