Outcomes of Patients with Hematological Malignancies Admitted to the Intensive Care Unit at a Tertiary Care Center in Saudi Arabia.

INTRODUCTION

Globally, over the past two decades, the incidence of leukemia and non-Hodgkin lymphoma (NHL) has increased by 26% and 45%, respectively.[ 1 ] Both conditions, although heterogeneous, have high mortality rates.[ 2 ] In 2020, worldwide, the estimated incidence rate of hematological malignancies (HM) was 1.3 million, with mortality peaking at 700,000 deaths.[ 1 ]

Patients with HM admitted non-electively to hospitals are at a higher risk of fatal disease outcomes due to several factors. The underlying pathogenic mechanisms and the chemotherapeutic regimens being administered to the patients influence the risk of clinical complications that can lead to more severe or fatal disease outcomes.[ 3 ] The most common complications that can lead to intensive care unit (ICU) admission, clinical deterioration, and/or death include chemotherapy-related organ-specific toxicities, infections, and the sequelae of malignancy itself, including bleeding, leukostasis, and tumor lysis syndrome.[ 3 , 4 ] Community-acquired and nosocomial infections are common causes of morbidity and mortality among the patients with HM.[ 5 ]

The prognostic indicators for overall ICU survival are typically unique to the underlying disease and its severity. These factors frequently influence the necessity for ICU admission, the anticipated course of the admission, and the interventions offered. Multiorgan failure at admission is the strongest risk factor, with correlation between the number of failing organ systems and a progressive rise in mortality rates.[ 6 ] Patients with lower long-term survival rates are less likely to benefit from ICU treatment and risk stratification. However, some malignancy groups, such as acute myeloid leukemia (AML) subtypes and diffuse large B-cell lymphoma, can show optimal long-term prognosis following ICU survival.[ 6 , 7 , 8 ] The course of the disease, such as relapse or newly diagnosed, can also influence the ICU survival rates.[ 6 ] The well-established prognostic markers, including cytogenetic markers and disease-specific risk scores, are not known to predict the survival rates in ICU-admitted patients with HM.[ 4 ]

The bone marrow reserves of the granulocytes significantly decrease in chemotherapy-induced neutropenia. Exogenous granulocyte colony-stimulating factor (GCSF) can assist in accelerating the proliferation and differentiation of progenitor cells, thereby rapidly compensating for the neutrophil replenishment and reducing the length of neutropenia phase.[ 9 ] However, the impact of exogenous GCSF on survival has not been well-established in the Saudi population. Furthermore, the literature on the outcomes of patients with HM admitted to the ICU is scarce from this region. These gaps necessitate the exploration of the disease outcomes for these patients and determining factors that increase the risk of mortality. This study aimed to evaluate the outcomes in HM patients admitted to the ICU of a tertiary care center in Saudi Arabia and identify the relationship between neutropenia, GCSF use, and overall survival.

METHODS

Study design, setting, and participants

This retrospective study included patients with HM who were initially admitted to the hematology unit and then shifted to the ICU of King Saud University Medical City (KSUMC) between January 2018 and December 2022. KSUMC is a major tertiary care hospital in Riyadh, Saudi Arabia. The patients admitted to the ICU with HM and transferred to a different setting during the treatment were excluded from this study.

The Institutional Review Board and Ethical Committee at King Saud University, Riyadh, approved the study. The collected data were stored with assigned codes that blinded any link to the patients.

Data collection

The data were retrieved from the electronic medical records and recorded in a confidential database. The selected variables were obtained directly from the electronic medical records or calculated using standardized tools. Any observed discrepancies were resolved by repeated record verification.

Demographic information, hematological diagnosis, admission characteristics before the ICU admission (performance status, neutropenia, and comorbidities), and outcomes were collected. The time course of ICU admission, the reason for the ICU admission, treatment prior to ICU admission, and the ICU intervention (intubation and/or use of vasopressors) were also recorded.

Statistical analysis

Descriptive statistics were computed for continuous variables, including means, standard deviations (SD), minimum and maximum values, and 95% confidence interval (CI), where appropriate, and frequencies for categorical variables. Cross-tabulation was done for categorical variables, and Fisher’s exact test was used, as the data set was small. Student’s t -test was used for continuous variables to determine significant differences in the mean values. Kaplan–Meier survival curves were used to illustrate the overall survival rate (defined as the time from treatment to death, regardless of disease recurrence) and survival analysis or time-to-event analysis (defined as analyzing the length of time until a well-defined endpoint of interest). A univariate log-rank (Mantel–Cox) test was used to compare the survival distribution of patients based on age (<50 years and ≥50 years) and gender. STATA software package (version 17) was used for the analysis. A statistical significance threshold of P = 0.05 was adopted. No attempt at imputation was made for missing data.

RESULTS

The study included 44 patients with HM. The mean age at admission was 50.2 ± 21.1 (range: 15.0–90.6) years. The age distribution is shown in Figure 1 . The average time from hospital admission to ICU transfer was 22.8 ± 31.0 (range: 0–135) days. Data regarding the ICU stay was available for 35 patients, with the mean length of ICU stay being 12.3 ± 14.7 (range: 0–62) days. Regarding gender distribution, there was a slight male predominance, with 25 males (56.8%) and 19 females (43.2%). In terms of mortality, 27 patients (61.4%) died during the hospital stay. Prior to ICU admission, neutropenia was present in 17 patients (38.6%) and GCSF was administered in 25 patients (56.8%).

The most common diagnoses were non-Hodgkin’s lymphoma ( n = 21; 48.8%) and Hodgkin lymphoma ( n = 11; 25.6%), collectively accounting for 74.4% of the cases. The remaining cases included acute leukemias (acute lymphoid leukemia [ALL], AML, and acute promyelocytic leukemia [APL]; 16.3%), chronic leukemias (chronic lymphocytic leukemia [CLL] and chronic myeloid leukemia [CML]; 4.7%), and plasma cell disorders (multiple myeloma [MM] and plasma-plastic lymphoma/myeloma; 4.7%). One patient’s diagnosis was not recorded in the provided data [ Table 1 ].

Sepsis and shock-related complications were the predominant indications (29.5%), followed by respiratory complications (18.2%) and hemodynamic issues (15.9%) [ Table 2 ]. Analysis of critical care interventions revealed that most patients required advanced organ support. Combined vasopressor support and mechanical ventilation were the most common interventions (31.8%), followed by isolated vasopressor/inotropic support (15.9%) and antimicrobial therapy and other supportive care measures without advanced organ support (15.9%). Special interventions were required in 4 (9.1%) patients, including one case each of ECMO support and cardiopulmonary resuscitation with central line placement. Five patients (11.4%) were admitted for monitoring and required no major interventions. Overall, 26 (59.1%) patients required some form of circulatory support (vasopressors/inotropes), while 21 (47.7%) patients needed either invasive or non-invasive ventilatory support [ Table 3 ].

ICU mortality was 61.4% ( n = 27), while early mortality, defined as death within 30 days of ICU admission, was 54.5% ( n = 24). The 90-day mortality rate was 61.4% ( n = 27), identical to the ICU mortality rate, and thus there were no deaths between ICU discharge and the following 90 days. This pattern suggests that the critical illness period during ICU stay represents the highest risk period for mortality in these patients. However, the ICU stay was not significantly related to ICU mortality using the Student’s t -test ( P = 0.67) or the Fisher information test using ICU stays less than or greater than 30 days as binary variables ( P = 0.198).

The Fisher’s exact test showed no significant association between age and survival status ( P = 0.205). The survival rate was 38.6%. Kaplan–Meier estimates for survival according to the patient’s age and gender are provided in Figure 2 , with survival time given in days. The graph shows that patients aged ≥50 years had lower survival rates than those aged <50 years. However, the log-rank test for equality of survivor functions for the two age groups showed no significant difference ( P = 0.59). The survival graph for gender did not indicate a gender-based difference in survival. The log-rank test for equality of survivor functions for the two gender groups showed no significant difference ( P = 0.7).

The distribution of diagnosis is illustrated in Figure 3 , which shows that the most frequent diagnosis were NHL (48.8%) and Hodgkin lymphoma (HL) (25.6%). The remaining diagnoses were ALL in 3 (7.0%), AML and APL in 2 (4.6%), and CLL, CML, and MM in 1 (2.3%) each. Among all diagnoses, HL and NHL comprised 32 (75%) patients.

The Fisher’s exact test between neutropenia before ICU admission and survival status (dead or alive) showed no significant association ( P = 0.566). Similarly, GCSF use prior to ICU admission did not improve survival status ( P = 0.882) [ Table 4 ]. There is a statistically significant association between the category of ICU intervention and survival ( P = 0.007). Patients requiring advanced organ support had the highest survival rate (62.96%), while those not requiring any significant intervention had the lowest (0%) [ Table 5 ].

DISCUSSION

HM patients are at an increased risk of short-term deterioration and poor outcomes following ICU admission. The overall disease outcomes can vary depending on the underlying disease condition, the type of malignancy, and the chemotherapeutic regimes.[ 10 ] Identifying these prognostic determinants can help in the risk stratification of HM patients. This can, in turn, assist in reducing the overall mortality rates caused by the short-term deterioration in these patients.[ 11 ] This study aimed to evaluate the disease outcomes in a cohort of HM patients admitted to the ICU and determine the prognostic value of the patient characteristics. Forty-four patients with HM were admitted to the ICU during the study period, of which only 38.6% survived. No statistically significant association was noted between neutropenia or the use of GCSF prior to ICU admission and survival; however, these findings could also have been owing to the small sample size of the study.

The average length of hospital stay varies in the previous studies on HM patients admitted to the ICU. Rawson et al .[ 4 ] reported an average stay of 4.4 days for these patients, while Yerzhan et al .[ 5 ] reported an average length of 14.9 days, which is similar to our study findings of 12.3 days. Discrepancies in length of stay can be attributed to the admission of intermediate-care patients with relatively reduced need for intensive care. The survival rate of our cohort was significantly lower compared with the survival rates reported by Rawson et al .[ 4 ] but similar to that reported by Yerzhan et al .[ 5 ] These findings suggest that the underlying cause for ICU admission can be an important factor in determining the overall mortality risk among patients. Hospital-acquired infections can increase the risk of more severe disease outcomes and mortality among patients suffering from malignancies. Unfortunately, even patients with HM who are discharged from the ICU continue to suffer high mortality in the short term.[ 12 ]

Neutropenia is a common complication of the chemotherapeutic agents used to treat HM[ 13 ] and can be a life-threatening complication for patients suffering from malignancies. However, we did not find any statistically significant correlation between neutropenia and outcomes in ICU-admitted patients. GCSF can reduce the overall duration of neutropenia during the hospital stay and can help in chemotherapy administration at closer intervals.[ 14 ] This study did not find a significant correlation between GCSF and the overall survival rates among ICU-admitted patients. Data regarding outcomes of ICU-admitted Saudi patients with HM are scarce in the literature.[ 12 , 15 ] The duration and severity of neutropenia are also important factors in hematological malignancy. Bahammam et al .[ 15 ] reported the outcome of a similar number of HM patients admitted to the ICU over a 12-year period, and found that mortality rates were very similar to our cohort, indicating little improvement in the survival of these patients. Al-Dorzi et al .[ 12 ] studied the outcome of HM patients who required mechanical ventilation in the ICU and reported a mortality rate of 71.5%, while most of the deaths occurred in the ICU.

The present study shows that patients with HM admitted to ICU continue to have high mortality. This study also explored the association of the key risk factors and found patients requiring advanced organ support had the highest survival rate (62.96%), while those who did not require any significant intervention had the lowest (0%); however, it was not found to be statistically significant and could be attributed to a relatively small sample size. Therefore, there is a need for further studies with larger sample sizes to identify and devise mitigation and management plans for key risk factors in patients suffering from HM.

The incidence of leukemia is higher than Hodgkin lymphoma and NHL in Saudi Arabia.[ 16 ] However, in this study cohort, the percentage of leukemia patients was much lower than lymphoma. Therefore, future studies must be designed with a sampling ratio representative of the actual prevalence rates of the HM in the country.

Limitations

Although this study investigates an important aspect of the outcomes of patients with HM admitted to the intensive care unit, it does not come without its limitations; such as, the small sample size, and the fact that it is a single-center study, which makes it difficult to generalize the results to the whole population of patients with HM admitted to the intensive care unit. It is also worth noting that the retrospective nature of this study could lead to certain biases that might lead to inaccurate results. However, this serves as an initial step for further studies that can build upon the findings presented in this study.

CONCLUSION

The mortality rate in patients with hematological malignancies admitted to an ICU in Saudi Arabia was 61.4%; there was no additional mortality within 90 days after discharge, suggesting that the critical illness period during ICU stay represents the highest risk period for mortality in these patients. No significant association was found between survival and neutropenia or the use of GCSF prior to ICU admission. There was a significant association between the category of ICU intervention and survival. However, the small sample size limits generalizability, and large-scale studies are needed to validate these findings.

Ethical considerations

The study was approved by the Institutional Review Board of King Saud University, Riyadh, Saudi Arabia (approval no.: E-22-7384; date: December 05, 2022). Requirement for patient consent was waived owing to the study design. The study adhered to the principles of the Declaration of Helsinki, 2013.

Peer review

This article was peer-reviewed by two independent and anonymous reviewers.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author contributions

Conceptualization: G.S.A., Y.A.; Methodology: G.S.A., Y.A., F.A., A.A.; Data analysis: G.S.A., Y.A., F.A., A.A.; Writing–original draft preparation: G.S.A., Y.A., F.A., A.A., M.A., M.A., B.A., F.A., S.S., F.A., K.A., A.J., A.A.; Writing – review and editing: G.S.A., Y.A., F.A., A.A., M.A., M.A., B.A., F.A., S.S., F.A., K.A., A.J., A.A.; Supervision: G.S.A.

All authors have read and agreed to the published version of the manuscript.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.

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Associated Data

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.