Management of adult patients with haematological malignancies in critical care

There are a diverse range of haematological malignancies with varying clinical presentations and prognoses. Patients with haematological malignancy may require admission to critical care at the time of diagnosis or due to treatment related effects and complications. Although the prognosis for such patients requiring critical care has improved, there remain uncertainties in optimal clinical management. Identification of patients who will benefit from critical care admission is challenging and selective involvement of palliative care may help to reduce unnecessary and non‐beneficial treatments. While patients with haematological malignancy can present a challenge to critical care physicians, good outcomes can be achieved. In this narrative review, we provide a brief overview of relevant haematological malignancies for the critical care physician and a summary of recent treatment advances. Subsequently, we focus on critical care management for the patient with haematological malignancy including sepsis; acute respiratory failure; prevention and treatment of tumour lysis syndrome; thrombocytopaenia; and venous thromboembolism. We also discuss immunotherapeutic‐specific related complications and their management, including cytokine release syndrome and immune effector cell associated neurotoxicity syndrome associated with chimeric antigen receptor T‐cell therapy. While the management of haematological malignancies is highly specialised and increasingly centralised, acutely unwell patients often present to their local hospital with complications requiring critical care expertise. The aim of this review is to provide a contemporary overview of disease and management principles for non‐specialist critical care teams.


Summary
There are a diverse range of haematological malignancies with varying clinical presentations and prognoses. Patients with haematological malignancy may require admission to critical care at the time of diagnosis or due to treatment related effects and complications. Although the prognosis for such patients requiring critical care has improved, there remain uncertainties in optimal clinical management. Identification of patients who will benefit from critical care admission is challenging and selective involvement of palliative care may help to reduce unnecessary and non-beneficial treatments. While patients with haematological malignancy can present a challenge to critical care physicians, good outcomes can be achieved. In this narrative review, we provide a brief overview of relevant haematological malignancies for the critical care physician and a summary of recent treatment advances. Subsequently, we focus on critical care management for the patient with haematological malignancy including sepsis; acute respiratory failure; prevention and treatment of tumour lysis syndrome; thrombocytopaenia; and venous thromboembolism. We also discuss immunotherapeutic-specific related complications and their management, including cytokine release syndrome and immune effector cell associated neurotoxicity syndrome associated with chimeric antigen receptor T-cell therapy. While the management of haematological malignancies is highly specialised and increasingly centralised, acutely unwell patients often present to their local hospital with complications requiring critical care expertise. The aim of this review is to provide a contemporary overview of disease and management principles for non-specialist critical care teams.

Introduction
The critical care clinician will encounter patients with haematological malignancies at the time of diagnosis due to complications of treatment, or less commonly when the underlying condition has progressed despite treatment.
is highly specialised and increasingly centralised, acutely unwell patients still frequently present to their local hospital requiring that management principles are widely appreciated.
Historically, mortality for patients with haematological malignancies in critical care has been very high (up to 90%) but more recent reports have demonstrated improved outcomes [1]. A recent population-based cohort study of almost 90,000 patients with a new diagnosis of haematological malignancies demonstrated that need for an intensive care unit (ICU) admission in the first year after diagnosis is common (13.9% overall) and varies according to type: 7.3% for patients with indolent lymphoma to 22.5% in patients with acute myeloid leukaemia [1].
The aim of this review is to provide a summary of recent evidence underpinning current clinical management of patients admitted to critical care with complications of haematological malignancy. This is framed towards general intensive care clinicians working in non-specialist centres.  [4]. There are substantial differences between the subtypes of haematological malignancies and Table 1 illustrates this by comparing incidence rates and survival rates of various subtypes [4,5].

Methods
Little is known about risk factors for haematological malignancies. Associations with viruses and exposure to environmental causes such as exposure to ionising radiation and smoking have been reported. For example, there is an increased risk of non-Hodgkin's lymphoma in those with acquired or inherited immunodeficiency, and certain infections such as Epstein-Barr virus are linked with haematological malignancy [6]. There also appears to be an element of genetic predisposition, for example in myeloma, with an increased risk for first degree relatives of patients with myeloma.

Management of sepsis
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host immune response to infection [13] and is a common reason for patients with haematological malignancies to be admitted to the critical care unit [1]. Immunosuppression, either related to the underlying condition or to its treatments, increases the risk and severity of sepsis, caused by primary bacterial, viral, opportunistic or reactivation of latent infection.
The source of sepsis for patients with haematological malignancy is often unclear with non-specific clinical features, frequently leading to delays in diagnosis.
Additionally, multiple pathogens from multiple sites are also more common. Neutropenic sepsis is one of the most serious complications of systemic anti-cancer treatment and is more common in patients with haematological malignancy [14] compared with solid organ tumours. There are UK national guidelines on the management of neutropenic sepsis [15]. Emergency treatment includes taking blood cultures from any indwelling lines, and early administration of empiric broad spectrum antibiotics [15].
Of note, the National Institute for Health and Care Excellence does not recommend routine administration of granulocyte colony stimulating factor (G-CSF) in patients on chemotherapy with neutropenic sepsis [15]. The risk of neutropenic sepsis occurrence can be estimated using various scoring systems [16] that incorporate information about the patient, the malignancy and the treatment. The National Institute for Health and Care Excellence recommends using risk stratification scores for low-risk febrile neutropenic patients to facilitate implementation as outpatient therapy [15]. Perhaps counterintuitively, sepsis in patients with haematological malignancy in the absence of neutropenia is no less serious than in patients with haematological malignancy and neutropenia [17].
The surviving sepsis guidelines [13] are broadly applicable to this patient population, but with specific emphases (see Box 1). A large observational cohort study 876 from Spain demonstrated that patients infected with SARS-CoV-2 and haematological malignancy present with similar symptoms to patients without immunocompromise.
Consistent with expectations, these patients also had an elevated risk of in-hospital death (38.8% vs. 19.3%) [18].

Management of acute respiratory failure
Acute respiratory failure is a common complication in hospitalised haematological malignancy patients.
Historically, there has been reluctance to use invasive mechanical ventilation due to perceived poor outcomes, although this is contentious [20]. Aetiologically, the most  [21].

Diagnostic approach
Failure to identify specific causes of acute respiratory failure has been associated with worse outcomes [21]. To identify the specific putative pathogens responsible for the pneumonia, there are non-invasive tests suggested by some national guidelines [22], or invasive fibreoptic bronchoscopy to obtain bronchoalveolar lavage samples. • Sepsis relating to indwelling venous access lines is common [19] and source control needs to be timely. If no alternative focus of infection is identified, then removal of indwelling lines is advised. • The likelihood of opportunistic infections is greater, requiring more detailed microbiological investigation.
• Newer diagnostics, such as molecular multiplex PCR, may provide earlier and more accurate specific identification of putative organisms.
• The need for continued empirical therapy in the absence of confirmed diagnosis may include multiple antimicrobial and antiviral medicationsthis increases the risk of drug toxicities and also fluid accumulation (from the diluents) that can be hazardous, particularly when there is concurrent acute kidney injury.
• Daily scrutiny and involvement of a microbiologist or infectious disease expert is recommended.
• Multidrug resistance in Gram-negative bacteria (such as ESLB-producing or AmpC cephalosporinase hyperproducing Enterobacteriaceae) are growing in incidence in this population.
878 mechanical ventilation (52% mortality). Of those patients not intubated on admission, 39% received invasive mechanical ventilation subsequently. Use of initial high-flow nasal cannulae was associated with fewer patients progressing to invasive mechanical ventilation but had no effect on subsequent mortality.
A potential advantage of a more invasive approach is the possibility of improved access to the lower airways for secretion clearance and to obtain samples for microbiological analysis. The absence of evidence of optimal initial ventilatory management of haematological malignancy patients with acute respiratory failure is reflected in wide variation in practice with intubation rates varying considerably among ICUs, even after adjustment on individual characteristics [25]. Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is increasingly used as a rescue therapy for other causes of refractory hypoxaemia.
Recent data, however, supports the common practice of withholding VV-ECMO from haematological malignancy patients with acute respiratory failure, due to the absence of survival advantage [26].

Critical care management for patients receiving CAR-T cell therapy
The use of CAR-T cell therapy is an innovative immuneoncologic treatment strategy that has emerged over the past decade, with high response rates and long-lasting remissions in many refractory haematological conditions, particularly in B-cell malignancies [27]. While this treatment option is very promising, some serious and potentially fatal adverse effects are caused by the inflammatory response due to excessive cytokine release from activated CAR-T cells. Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome are reversible toxicities but are associated with significant morbidity, with up to 47% of patients requiring admission to critical care [28]. However, with prompt and appropriate management, the outcomes of CAR-T cell recipients who are admitted to critical care are good. Cytokine release syndrome affects between 54% and 91% of CAR-T cell recipients, presenting as a range of clinical symptoms including fever, hypoxia or hypotension, progressing to circulatory shock and multi-organ failure in some patients [29]. Treatment with interleukin-6 inhibitors such as tocilizumab form the mainstay of management of CRS, aimed at reducing the inflammatory response [30].  [32]. Tumour lysis syndrome is prevalent in adult and paediatric patients who require chemotherapy, typically in the first few days after its initiation. It is particularly likely to occur during induction chemotherapy where there is a high tumour burden [33].
In addition to high tumour burden, there are additional risk factors for the development of TLS: pre-existing renal impairment; increased age; and the concomitant use of drugs that increase uric acid levels [33]. While the prevalence is relatively rareaffecting 3-6% of patients with high-grade tumoursthe clinical consequences are substantial with an overall mortality rate of 15% reported [35]. Therefore, patients at increased risk of TLS should receive prophylactic treatment, with allopurinol and/or rasburicase.
Allopurinol is an oral xanthine oxidase inhibitor that reduces the rate of conversion of hypoxanthine to xanthine and xanthine to uric acid, reducing the formation of uric acid crystals in renal tubules [36]. The recommended dosing schedule for allopurinol prophylaxis in adults is 200-400 mg.m À2 per day in divided doses, up to 800 mg daily.
Rasburicase is a potent uricolytic drug that catalyses enzymatic oxidation of uric acid into allantoin, which is water soluble and easily excreted by the kidneys. Rasburicase prophylaxis is recommended for patients at very high risk of TLS at a dose of 0.2 mg.kg À1 for 5-7 days [37]. The British Haematology Society recommends testing for G6PD deficiency before starting rasburicase due to contraindication in patients with G6PD deficiency [33].
There is little evidence comparing the efficacy of allopurinol against rasburicase in TLS prophylaxis. Thrombocytopenia, particularly platelets of < 10 9 10 9 .l À1 is associated with increased bleeding risk.
The trial by Stanworth et al. randomly allocated patients to prophylactic vs. non prophylactic platelets. Prophylactic platelets reduced the risk of grade 2-4 bleeding events and reduced the number of days of bleeding [42]. Guidelines recommend administration of prophylactic platelet transfusion to patients with a platelet count of < 10 9 10 9 .l À1 with higher threshold set in those with higher bleeding risk [43]. unwanted life-sustaining therapies [47]. Unfortunately, palliative care is often initiated late, despite recommendations from major organisations (including the American Society of Clinical Oncology [48]) that palliative care input is received alongside standard oncology care ensuring that unmet needs are identified proactively. There are increasing data to suggest the use of referral criteria or triggers´to identify patients on admission to ICU who may benefit from early palliative care input [49].

Conclusions
Critical care physicians should expect to see patients with haematological malignancy referred to them for advanced organ support. Challenging decisions regarding management of these patients must be a collaborative effort with haemato-oncologists and care should be provided with a multidisciplinary approach, occasionally including palliative care, and always including the patient.
Although it is difficult to reliably prognosticate, it is clear that however, initially patients should be treated empirically as they are more at risk from a wider range of pathogens and multi-drug resistant bacteria.