An middle aged woman presented with a blast crisis following acute transformation of preexisting chronic myelomonocytic leukaemia. She failed to respond to several cycles of chemotherapy and underwent allogeneic bone marrow transplant. She subsequently developed neutropaenic septic shock and was found to have fungal pulmonary abscesses. Her sepsis was aggressively managed on ICU and she made steady progress and eventually recovered, and was discharged from hospital 5 weeks after her ICU admission.

What is the current evidence related to the mortality and morbidity associated with admission to intensive care for patients with haematological malignancy?

Sam Clark

 

Historically, patients in multi-organ dysfunction requiring admission to ICU have had such poor outcomes that they were often considered inappropriate for admission to intensive care (1). Data from the European Cancer Registry from 1995 suggested that patients, who required support of four organs had a 100% mortality (2,3).

The last fifteen years has seen significant advances in the management of acute haematological malignancies with the advent of multiple new agents including the monoclonal antibody drugs that target specific receptors (4,5). At the same time there has been improvements in survival for patients admitted to ICUs for the management of sepsis (5). Mortality figures have improved despite an increased burden of illness (2).

Hampshire and colleagues undertook a secondary analysis of ICNARC data to examine admission factors associated with mortality for patients with haematological malignancy. During a 12 year period (’95 – ’07) there were 7,689 admissions with an ICU mortality of 43.1% and hospital mortality was 59.2%. The study demonstrated that mortality was associated with a number of patient and disease factors including; number of organs requiring support on admission, length of stay in hospital prior to ICU admission, recent Bone marrow transplant. The study’s conclusion suggested that these patients would benefit from early admission to ICU for aggressive management.

Whilst Hampshire et al examined patients admitted to general ICUs, two studies reported data from specialist tertiary centers (2,7) . McGrath and colleagues published data from Guy’s and St Thomas’ hospitals, containing both retrospective and prospective data, examining 185 patients, with 259 admissions between 2004 and 2008 (2). The study divided patients into 2 groups: haematological malignancy and solid organ tumour group. The ICU mortalities were 30.4% and 27.1% respectively. Again there was significant longer-term mortality, with six-month mortalities reported as 73% for the haematological malignancies and 78.6% for solid organ tumours. There were no significant differences in the proportions of patients with sepsis, neutropaenia or chronic renal failure in either group when comparing survivors with non-survivors. Similar discriminating factors between survivors and non-survivors, including numbers of failed organ systems on admission, need for mechanical ventilation and a requirement for renal replacement therapy were present. Data published from the Royal Marsden over a 5 year period included 199 patients in a prospective cohort study They reported their ICU, in-hospital and 6-month mortalities as 33.7%, 45.7% and 59.2% respectively. All three of these figures improved through the time-course of the study by approximately 10% (though none were statistically significant), supporting the trend that there may be an ongoing improvement in survival. Both of these studies accepted that they were single center studies with high potential for bias, however the results do appear to suggest that early admission intervening before multi organ failure emerges has improved results and that the early involvement of senior Haematology input is also beneficial.

In the largest prospective cohort study to date, Azoulay et al examined 1,011 haematological malignancy patients admitted to critical care in France and Belgium from 17 tertiary centers between 2010-2011 in an 18-month period (8). Each center had a senior intensivist and a senior haematologist available 24 hours per day to make joint admission decisions. Exclsuion criteria included age under 18 and those that had remained disease free for over 5 years. Twenty one patients declined to be included and 131 patients were lost to follow up. The study used multivariate analysis to assess the risk factors for increased mortality. Identified risk factors included allogenic Haemopoietic stem cell transplant, high organ dysfunction scores and poor performance status. Acute respiratory or cardiovascular failure were the two commonest reasons for admission to ICU (62.5% & 42.3% respectively). Seventy two percent received life-supporting treatments, therefore 27.5 % were admitted for monitoring only. It is also worth noting that 23% of patients were currently in remission at the time of admission. Mortalities for hospital, 90-day and 1-year were 39.3%, 47.5% and 56.7% respectively, which was better than the previous studies discussed. They did find that hospital mortality was significantly increased if mechanical ventilation (60.5%), vasoactive drugs (57.5%) or renal replacement (59.2%) were required. However, for those, who survived to day 90, 80% had no change in physical and mental health compared to the overall cancer population, and 80% of survivors at 6-months were in remission. The results of this study were better than the other studies discussed and this may be due to the tertiary nature of the centers involved, but also it is likely in part to be related to lower APACHE II scores in the patient populations.

Finally, a prospective study from seven centers in Spain followed survivors following ICU discharge with haematological malignancy and outcomes in longer-term follow-up. (9) Patients were followed for up to 54 months. Of 161 patients, 62 were discharged from hospital alive, giving an in-hospital mortality of 61%. Multivariate analysis showed that there were three significant risk factors post discharge that predicted earlier mortality including an Eastern Cooperative Oncology group score of greater than 2 at ICU discharge (hazard ratio 9.7, CI 3.8 to 24), discontinuation of planned therapy (and that was a grade affect depending on the level of any disruption; hazard ratio 4.3, 1.2 to 14) and relapse of haematological disease (hazard ratio 9.7; CI 3.8 to 24). Again, the study suggested the small group of survivors that did not have these risk factors had significantly better outcomes with the inference that both ICU care and post ICU management has an impact on the long—term outcome of this cohort.

Overall, the literature suggests there has been a significant improvement in both short and long term mortality for patients with haematological malignancies that require critical care admission. However, this cohort still exhibit higher relative mortaility rates when compaored with the general ICU population within the UK. There are a number of issues that need to be incorporated in the evaluation of the data presented: all of the studies were observational or cohort studies and prone to bias and all grouped patients together with clinically different underlying malignancies, including patients, who have received a diagnosis of such a malignancy and those in remission. This may skew the results towards a more positive outcome. However, despite these reservations the aforementioned consistency in both multi-centered and specialist center trials demonstrate this similar trend of improving mortalities.

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Conclusions:

There is a consensus amongst the literature that survival rates have been improving over the last ten years. Risk factors for poor outcome included mechanical ventilation, renal replacement therapy, and number of organs requiring support and Allogenic stem cell grafts. The evidence suggests that patients should be reviewed early and potentially admitted prior to developing multi-organ failure. There is also suggestion that early senior Haematology input benefits patient outcomes. There are, however, limitations to the current research with all patients being included as homogenous. Perhaps further research could focus on the groups of patients from who admission is in the balance: patients with specific conditions or specific age groups in whom recovery to hospital discharge may be impaired to help guide joint decision making by both specialties.

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References:

(1)Schneiderman L., Jecker N. & Jonsen A.. Medical Futility: its meaning and ethical implications. Ann Intern Med 1990; 112:949-54
(2) McGrath S., Chatterjee F., Whiteley C., & Ostermann M. ICU and 6-month outcome of oncology patients in the intensive care unit. (2010) Q J Med 2010; 103 397-403.
(3)European Cancer Registry. http://www.europeancancerleagues.org/cancer-in-europe/resources-on-cancer-in-europe/221-european-network-of-cancer-registries-encr.html
(4) Smith M, Barnett M, Bassan R. et al. Adult acute myeloid leukaemia. Crit Rev Oncol Hematol. 2004; 50:197-222.
(5) Collins F. & Varmus H. A new initiative on precision medicine. NEJM 372;9: 793-795.
(6) Angus D., van der Poll T., Severe Sepsis and Septic Shock. N Engl J Med 2013; 369:840-851
(7) Bird T., Farquhar-Smith P., Wigmore T. et al Outcomes and prognostic factors in patients with haematological malignancy admitted to a specialist cancer intensive care unit: a 5 yr study. Br. J. Anaesth. (2012) 108 (3): 452-459.
(8) Azoulay E., Mokart D., Pene F., et al Outcomes of Critically Ill Patients With Hematologic Malignancies: Prospective Multicenter Data From France and Belgium—A Groupe de Recherche Respiratoire en Re ́animation Onco-He ́matologique Study. (2013) J Clin Onco 31;22:2810-2818.
(9) Bernal T., Pardavila E., Bonastre J., et al Survival of hematological patients after discharge from the intensive care unit: a prospective observational study. Crit Care (2013) 17:R302.