Filling the gaps to empower regional centres to manage myelodysplastic syndrome and acute myeloid leukaemia leading to wider cancer healthcare delivery and access to clinical trials

Abstract

Background

The management of patients with haematological malignancies in rural and regional Australia is different to that in metropolitan centres due to many factors. Lower‐intensity and easier‐to‐access treatments that are now available for acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) have improved the deliverability of treatment options for these disorders. Despite the challenges, urgent work is required to allow the care and outcomes of these patients to mirror those living in metropolitan centres.

Aims

To highlight the challenges in management of AML and MDS in regional Victoria.

Methods

Four clinical cases describing the difficulties faced in the management of AML/MDS patients in regional Victoria.

Results

We describe limitations in inpatient services, supportive care, blood product access and both specialised diagnostics and specialist workforce. Access to clinical trials is limited but vital to allow the availability of all therapeutic options.

Conclusions

Limitations in management of AML/MDS patients exist in regional centres. We utilised focused clinical fellows in a partnership between Latrobe Regional Health and Alfred Health in Victoria to improve treatment options for these patients. Moreover, we demonstrate future areas of focus, which will further enable rural and regional healthcare providers to bridge the gap in the care of patients with haematological malignancies.

Introduction

Acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDSs) are aggressive haematological malignancies, the treatment for which requires urgent attention in rural and regional Australia. There are approximately 1100 cases of AML diagnosed in Australia each year, ¹ with a median age of 69.1 years at diagnosis, ¹ and it has been shown that patients with cancer living outside of metropolitan areas ² and in lower socioeconomic ³ areas have lower survival. Treatment pathways for AML are based on patient age and fitness, intensive chemotherapy for young and fit patients (generally under 70 years) and non‐intensive therapy for older or frail patients. The addition of venetoclax (VEN) to the Pharmaceutical Benefit Scheme (PBS), when used in combination with the hypomethylating agent azacitidine (AZA), representing a new standard of care (SOC) has expanded access to more efficacious treatment for unfit adults, with response rates approaching 70% compared to 28% for the historical SOC, single‐agent AZA. ⁴ MDS sits on the same disease spectrum as AML but has a wide range of severity, defined by either the MDS international prognostic scoring system (IPSS) or the revised IPSS (R‐IPSS). Hypomethylating agents are the mainstay of treatment for MDS, with AZA the only available drug for IPSS intermediate‐2 or higher MDS (including low blast count AML) on the PBS, until the recent approval of INQOVI (decitabine‐cedazuridine 35–100 mg oral tablet). This enables delivery of treatment to patients without requiring the resources to deliver subcutaneous injections. Access to clinical trials for this population is essential but scarcely available to regional and rural patients, with only 10% of Victorian clinical trials being accessible at rural sites. ⁵ Importantly, the management of these patients with either SOC or clinical trial therapies, particularly for induction treatment, is resource heavy, with frequent infectious complications, significant blood product dependence and the requirement for sophisticated laboratory testing. Due to these factors, metropolitan or tertiary‐level care is often required, and while induction treatment is burdensome, ongoing consolidation cycles can be delivered as an outpatient in almost all settings. Treatment of patients from regional centres pose further challenges in addition to the those described. For patients and their carers from regional and remote communities, access to metropolitan services is associated with substantial indirect costs associated with long travel distances and length of treatment. People in remote and regional areas are less likely to accept care in a metropolitan centre and are more likely to delay seeking any care compared to individuals living in major cities. ⁶

Methods

Alfred Health (AH) in Melbourne, Victoria, and Latrobe Regional Health (LRH) in Gippsland, Victoria, have an established partnership for managing haematology patients. From 2022, haematology fellows with a clinical trial focus have attended LRH weekly to expand access to both SOC and clinical trial therapies. The initiation of the haematology fellow programme was supported by TrialHub, ⁷ a nationally funded programme designed to increase regional and remote patients’ access to clinical trials and foster autonomous growth in this area. Fellows with active clinical trial experience bring up‐to‐date trial access and subspecialty interest to drive growth in treatments for disease crafts. Increased staffing and support are designed to bring regional centres in line with metropolitan hospitals in terms of access to treatment including clinical trials. We highlight the challenges of regional management of AML/MDS in Victoria and illustrate areas of need via the four case reports. Patients and/or next of kin provided written informed consent for inclusion in this publication.

By identifying the clinical service needs required to improve regional patient access to therapy for myeloid malignancies, we similarly recognise the opportunities for the broader delivery of improved cancer services as well as access to clinical trials.

Results

Case 1

An 80‐year‐old man presented to LRH with several weeks of fatigue, anorexia, weight loss and the recent onset of haematuria. Medical history included rectosigmoid cancer treated 7 years earlier with surgery and adjuvant fluorouracil attaining complete remission (CR), cerebellar stroke 12 months earlier, hypertension and type 2 diabetes mellitus managed with oral hypoglycaemics. Full blood count demonstrated haemoglobin 99 g/L, white blood cell count 33 × 10⁹/L and platelet count 61 × 10⁹/L. There was evidence of disseminated intravascular coagulation (DIC) with INR 1.4, activated partial thromboplastin time 40.2 s, fibrinogen 1.4 g/L and D‐dimer 20.4 μg/mL (upper limit of normal (ULN) 0.49) acute kidney injury (creatinine 151 μmol/L, estimated glomerular filtration rate 37 mL/min/1.73 m²), elevated LDH 3261 U/L (ULN 250), reduced calcium 2.07 mmol/L but preserved potassium and phosphate. He was stabilised with blood products for DIC and transferred to AH, where bone marrow biopsy demonstrated 39% blasts with deletion 3p and myeloid next‐generation sequencing (NGS) revealing mutations in NRAS, TET2 and KRAS, fulfilling the diagnosis of myeloid neoplasm post cytotoxic therapy (MN‐pCT). Treatment with AZA 75 mg/m² days 1–7 and VEN dose adjusted with posaconazole to a 400 mg daily equivalent day 1–28 after a 3‐day dose escalation was initiated. Admission lasted 27 days and was uncomplicated. He was discharged on day 15 of treatment for further management closer to home. Repeat bone marrow biopsy demonstrated CR. Further treatment cycles were delivered via our regional centre, which incorporates a haematology unit consisting of haematologists and specialist nurse consultants who are able to monitor weekly blood tests and arrange transfusions and symptom or urgent care assessments. Patient has required no blood transfusions, no admissions to hospital, no requirements for travel or significant complications and remains in remission up to currently cycle 6.

Case 2

A 76‐year‐old woman was diagnosed with secondary AML with pre‐existing MDS, demonstrating 20% blasts, trisomy of chromosome 19 and 13 with mutations of FLT3‐ITD, NRAS, TET2, SRSF2, ASXL1, RUNX1 and STAG2 on targeted NGS. Treatment with VEN (100 mg day 1–28 after dose escalation, with posaconazole) and AZA (75 mg/m² day 1–7) was commenced with an inpatient stay that was largely uncomplicated with acute suppurative otitis media the only infectious complication. Significant transfusion support was required, with second daily red cells and platelet requirements. This was complicated by platelet refractoriness and the identification of HLA antibodies requiring HLA matched platelet transfusions. VEN was ceased at day 25 due to ongoing pancytopenia, with bone marrow biopsy at day 28 and again at day 40 showing marrow aplasia with no increased blasts. She did not regain blood count recovery, remained heavily transfusion dependent and eventually opted for inpatient palliative care.

Case 3

A 68‐year‐old man presented with pancytopenia with haemoglobin 86 g/L, neutrophils 0.3 × 10⁹/L and platelets 20 × 10⁹/L. Bone marrow biopsy demonstrated 10% blasts and a complex karyotype. Molecular studies were not performed. The diagnosis of myelodysplasia with increased blasts 2 ⁸ or MDS/AML with myelodysplasia‐related cytogenetic abnormalities ⁹ was made. He was transferred to AH for assessment and treatment discussion. Due to patient wishes to be managed locally for induction and minimise hospital involvement, treatment with INQOVI (decitabine‐cedazuridine 35–100 mg oral tablet) was initiated with a standard schedule of 5 out of 28 days. There were three bags of red cells and one bag of platelets transfused. He was discharged 5 days after initiation of INQOVI to be managed at our regional centre. The remainder of induction cycles were uncomplicated, with no blood transfusions required and no infectious complications. Bone marrow biopsy after two cycles of treatment demonstrated CR with 4% blasts and near normalisation of blood counts. The patient has received six cycles of therapy with no admissions, no further blood transfusions and no infectious complications to date.

Case 4

A 76‐year‐old man is being managed at our regional centre for MDS. His disease harbours two TET2 mutations and is characterised by profound cytopenias with haemoglobin 73 g/L, neutrophils 0.5 × 10⁹/L and platelets 21 × 10⁹/L, so IPSS intermediate‐1 or R‐IPSS intermediate disease. He requires fortnightly red cell transfusion and intermittent platelet transfusions despite the use of prophylactic tranexamic acid to reduce bleeding. In this context he has experienced several episodes of minor bleeding requiring increased platelet transfusion and hospitalisation. We have initiated discussions for enrolment in a recently opened clinical trial for low and intermediate risk MDS, otherwise inaccessible via the PBS.

Discussion

These cases highlight several important points related to regional management of MDS/AML. Firstly, low‐intensity regimens such as VEN and AZA are well tolerated and easily deliverable for many patients, although sufficient inpatient and outpatient resources and expertise are still required, with suitably trained junior medical and specialist nursing staff vital for the management of these patients. On the other hand, case 2 demonstrates a difficult management situation with the same chemotherapy regimen requiring regular blood product support, particularly platelets, which can be difficult in a regional transfusion centre. This is exemplified by ambulatory blood product support in our regional setting being capped to weekly visits due to a combination of the constraints of activity‐based funding, blood product supply logistics and availability and capacity of ambulatory treatment centres. The addition of HLA matched platelet requirements adds increased complexity and planning; moreover, the patient remained aplastic more than 50 days after initiating treatment. Fear of travelling or unwillingness to travel to metropolitan centres is a major barrier for many rural patients. This patient had staunch opposition to travel back to AH for increased transfusion support, and given this, further consideration of treatment prior to commencement should have been made.

Recent studies have shown that the duration of VEN therapy in this population can be shortened from the standard dosing of 28 days VEN without compromising disease outcomes, ¹⁰ , ¹¹ , ¹² and this is an approach we have adopted for many of our patients. Case 3 had adverse cytogenetics, portending median survival generally less than 10–12 months. ¹³ , ¹⁴ Patient wishes were taken into consideration when selecting treatment, with a low‐intensity treatment option the only acceptable choice in this situation. In addition, the outcome with intensive chemotherapy is likely to be similar, ¹⁵ with far more toxicity and hospital inpatient time. The addition of INQOVI to the PBS has further enabled where patients request and desire more autonomy, fewer hospital visits and less burden of care, by avoiding subcutaneous injections. Thus far with an excellent outcome, this patient has already exceeded the median survival at diagnosis and could have been managed entirely regionally with the right forethought and resources. Finally, for MDS, there is no access to treatment for patients with IPSS intermediate‐1 or less disease on the PBS. This includes a large proportion of patients with symptomatic disease either requiring frequent blood or platelet transfusions or at risk of infection from neutropenia. In this context, access to clinical trials would be a potential alternative for disease modification and improving quality of life. Since 2019, LRH has developed its clinical trial programme from formative to high performing, including a mix of sponsor types, independent site and teletrials. ⁷ The AH‐LRH haematology fellow partnership provides the regional site with direct access to a leading clinical trial site with associated local, national and international academic partnerships. As a consequence, the fellow partnership has improved access and stimulus for increased clinical trial activity. Specifically related to AML and MDS, this has led to opening an independent clinical trial examining combination therapies with hypomethylating agents not available through the PBS.

This case series demonstrates; some of the clinical complexities of managing regional AML/MDS patients. Collaboration with a metropolitan service such as AH certainly mitigates some of the challenges in providing support in areas of need however, there remain several barriers to the delivery of better care to regional AML/MDS patients. We comment on the following five healthcare delivery components required to build a successful myeloid malignancy programme: access to specialist inpatient services; blood product access in regional and remote areas in Victoria; supportive care; molecular diagnostics and specialist health workforce in regional settings. Addressing each healthcare delivery component adds to the ability to deliver greater clinical trial access and equity to our regional community.

Access to specialist inpatient services

Victoria has six regional health services, only one of which, Barwon Health, has an established independent haematology inpatient service. All other regional health services including LRH operate under a shared oncology‐haematology bed card. LRH provides a comprehensive inpatient haematology consultation service including access to metropolitan expertise. However, this is not equivalent to a dedicated haematology service supporting the delivery of high‐intensity inpatient care. Contemporary medical oncology training provides minimal exposure to the delivery of intensive treatments for haematological malignancies and optimal inpatient care for haematology patients also requires access to experienced allied health, nursing and non‐haematology specialist consultation services as well as health services capacity to support and train the junior medical workforce in this specialist area. These requirements for optimal inpatient care of individuals with a haematological malignancy directly impact regional centres to develop these programmes. LRH is in a period of establishment of a more robust haematology service. This is a long process, the initial priorities include being able to first manage dedicated haematology patients and then to expand to deliver therapies such as low‐intensity chemotherapy regimens requiring inpatient monitoring (e.g. VEN/AZA). This would be an enormous benefit to local patients and reduce several burdens on regional patients and families.

Translation to clinical trial access

Developing an inpatient unit will allow access to clinical trials that mandate inpatient monitoring, for example, tumour lysis syndrome monitoring, more intensive pharmacokinetic testing and frequent clinical reviews.

Blood product access to regional and remote areas

The complexity of optimal blood product inventory is increased in regional and remote areas. For example, the private pathology provider for LRH holds an inventory of one bag of pooled platelets to service a wide geographical area. The National Blood Authority provides recommended blood and blood product transfer processes to mitigate these access risk for regional and remote areas. ¹⁶ However, in many Victorian regional centres, this is limited by multiple public and private pathology providers across the region and by the fact that Victoria lacks the more integrated local health network structures available in Queensland, South Australia and New South Wales, which facilitate more collaborative transfer and hub and spoke arrangements. Further, to ensure optimal inventory management in the region, there are often significant restrictions in place such as one pool of platelets held on site at LRH for access across most of the region. Developing a service to optimally manage myeloid malignancies at LRH requires attention to both the optimal provision of blood products as well as the adoption of a consistent evidence‐based safe restrictive transfusion policy across the service.

Translation to clinical trial access

Clinical trials related to myeloid malignancies rely on strong systems of blood product support for patient safety during trial participation.

Supportive care

Expert haematology nursing

LRH has developed an ambulatory specialist haematology nurse programme providing dedicated symptom and urgent review, complex haematology care coordination and specialist haematology supportive care. In line with the development of an inpatient unit, this specialist haematology supportive care service must be incorporated into a 24/7 access to experienced ambulatory and inpatient nursing care and advice.

Access in the ambulatory setting

Activity‐based funding (ABS) in the ambulatory chemotherapy day unit limits the provision of a range of supportive care services critical to patients receiving treatment for AML/MDS, for example, a patient that attends for a blood test and review without transfusion or chemotherapy – a situation that frequently provides a safety net at metropolitan centres – is not funded. Addressing fiscally responsible approaches to ABS to deliver the range of supportive care services that myeloid malignancy treatments require will have additional flow‐on impacts for cancer supportive care more broadly (Table 1).

Table 1.

Description of problems in management of rural myeloid malignancy patients and potential solutions

Problem	Possible solution
Access to specialist inpatient services	Development of a specialist inpatient unit with metropolitan support
Blood product access	Evidence‐based transfusion practice Eventual expansion of delivery of blood products based on treatment activity
Supportive care	Specialist haematology nursing staff Fiscally responsible approach to outpatient activity‐based funding Expansion of ambulatory care resources
Molecular diagnostics	Metropolitan partnerships to support advanced molecular diagnostics and clinical implications
Specialist workforce	Recruitment of visiting metropolitan fellows Subspecialty clinical leads to progress treatments and clinical trials Utilisation of metropolitan multidisciplinary meetings

Translation to clinical trial access

Clinical haematology programmes are built around excellence in supportive care due to the intensive nature of treatments for blood cancers. AML represents a subset of disease with a heavy ambulatory care requirement. Building a supportive care network in regional settings based on AML requirements sets up a strong framework for successful ambulatory and inpatient management of resource‐heavy disorders such as these, critical to the safety and efficacy of any clinical trial activity, as well as developing supportive care resources as an academic and clinical trial pursuit.

Molecular diagnostics

There is limited diagnostic availability in LRH through private pathology; however, updated MBS rebate criteria will help with providing these services for haematological malignancies. Previously regional patients relied on metropolitan funding for molecular testing, for example, myeloid NGS to inform risk. Larger centre support is still required for expert and multidisciplinary analysis and other tests such as measurable residual disease.

Translation to clinical trial access

Several research access programmes and clinical trials are focused on the integration of molecular diagnostics. Regional health services need to drive coordinated approaches to their unique settings to ensure that all available molecular diagnostic opportunities are harnessed for their communities and a sustainable access programme is built. Maturation of diagnostic services will eventually lead to tissue banks to enable more accurate study of regional patients prospectively.

Specialist workforce

Regional management can be isolating for physicians as well as patients. With reduced specialist staff, there is limited ability to have leukaemia‐specific multidisciplinary meetings to help guide management for AML patients, and clinicians often must make decisions without a community of haematology input. We have utilised the AH AML MDM for these discussions on management decisions and are building up the internal expertise. The integration of the AH haematology fellow programme has been instrumental in focusing dedicated expertise on underserviced populations, such as older individuals with AML/MDS, as well as developing skills in the rewarding aspect of regional healthcare delivery. In the next phase of development of the haematology fellowship programme, several clinical lead positions in subspecialty haematology at LRH have been established. Involvement of other medical specialties, including intensive care, radiology, infectious diseases and vascular surgery, are also vital to expand treatment delivery. Building subspecialist programmes within a general regional haematology service offers unique opportunities for medical and nursing specialists, with metro‐regional partnership appointments driving improvements in regional health outcomes.

Translation to clinical trial access

Building academic and research outcomes into regional specialist workforce roles and responsibilities directly results in opening more clinical trials and therefore greater access for the community. LRH has demonstrated their capability in building a clinical programme with a diverse portfolio of sponsor funding types and models of clinical trial delivery, including independent and teletrial site capability.

Conclusion

These cases demonstrate AML/MDS management can be complex due to resource‐, geography‐ and patient‐related factors. Regional centres require support to develop formal avenues to expand and bridge the care of regional patients. Each advance in service delivery adds to the ability of our health service to deliver more care to local communities, including expanding access to clinical trials, critical to achieving improve health outcomes.

While related to building a specialist complex haematology service informed from our case series, addressing critical foundational components of care will be applicable to many areas of specialist medicine.