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ORIGINAL ARTICLE  
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Therapeutic leukapheresis as adjunctive therapy in hyperleukocytosis: Experience from a Tertiary Care Hemato-oncology center in South India


1 Department of Transfusion Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham University, Kochi, Kerala, India
2 Department of Clinical Haematology, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham University, Kochi, Kerala, India
3 Department of Biostatistics, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham University, Kochi, Kerala, India

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Date of Submission02-Apr-2022
Date of Acceptance03-Jul-2022
Date of Web Publication12-Dec-2022
 

   Abstract 

BACKGROUND: The usefulness of therapeutic leukapheresis procedure in patients with hyperleukocytosis (HL) is often debated. This retrospective study was done to determine the effect of therapeutic leukapheresis on hematological parameters in hyperleukocytic patients and to determine the factors affecting the collection efficiency (CE) of the procedure.
METHODS: Leukapheresis procedure was performed when the leukocyte counts were >100 × 109/L in the presence of symptoms of leukostasis and/or tumor lysis syndrome. The Cairo and Bishop classification was used to document the presence of tumor lysis syndrome. Apheresis procedural variables were retrieved for patients between August 2017 and March 2021. The CE for the leukocyte depletion procedure was determined. Wilcoxon signed-rank test was used to determine the significance of changes in hematology variables. Pearson's correlation coefficient was computed to test the linear relationship between apheresis procedure-related factors and CE.
RESULTS: Sixteen consecutive patients who underwent a total of 22 leukapheresises were included in the study. Leukapheresis yielded a significant reduction in white blood cell (WBC) (51%) and platelet count (24%) with clinical improvement in 75% of patients. No serious adverse events were observed. The volume of WBC removed and preprocedure hematocrit had a positive intermediate correlation with CE. The procedure flow rate negatively affected the CE (r = −0.43). The 30-day mortality was 50% with the median survival time of the entire cohort being 26 (5.8–46) days.
CONCLUSION: Leukapheresis was effective in reducing the leukemic cell burden to half in HL patients providing short-term benefits. The CE of apheresis was approximately 20% with only a few variables influencing the efficiency of the procedure.

Keywords: Therapeutic leukapheresis, collection efficiency, tumor lysis, leukostasis


How to cite this URL:
John L, Shenoy V, Ganapathi R, Kartha N, Unni M, Sidharthan N. Therapeutic leukapheresis as adjunctive therapy in hyperleukocytosis: Experience from a Tertiary Care Hemato-oncology center in South India. Asian J Transfus Sci [Epub ahead of print] [cited 2023 Jan 28]. Available from: https://www.ajts.org/preprintarticle.asp?id=363230



   Introduction Top


Hyperleukocytosis (HL), defined as the increase in leukocyte count >1 lakh/μl in the peripheral blood, causes blockage of capillaries by leukemic blast cells and subsequent multiorgan dysfunction such as cerebral infarction, respiratory failure, acute myocardial infarction, and acute renal failure.[1] Metabolic derangements caused by tumor lysis and disseminated intravascular coagulation due to excessive tissue factor release are also common in these patients. Around 5%–20% of patients with acute myeloid leukemia (AML), especially monocytic variants, present with this condition.[2] Emergent leukapheresis can act as an effective bridge along with other cytoreductive therapy such as hydroxyurea till the chemotherapeutic agents start acting and can help in reducing the WBC count by 10%–70%.[3] Leukapheresis provides the benefit of reducing the risk of spontaneous and postchemotherapy tumor lysis syndrome. Given the conflicting reports about the efficacy of this procedure, we aimed to determine, in retrospective design, the effect of therapeutic leukapheresis on hematological parameters in hyperleukocytic patients and to determine the factors affecting the collection efficiency (CE) of the leukapheresis procedure.


   Methods Top


This was a retrospective cohort study that included all the consecutive leukapheresis procedures performed in the department of transfusion medicine at a tertiary care hospital in Kerala, South India, between August 2017 and March 2021. Leukapheresis was considered when the leukocyte counts were >100×109/L in the presence of symptoms of leukostasis and/or tumor lysis syndrome. Patients with acute promyelocytic leukemia, coagulation disturbances, and hemodynamically unstable patients on life-supporting measures were excluded from performing the procedure. Therapy was initiated with hydration, antibiotics, steroids, and antimetabolites such as hydroxyurea. Leukapheresis was initiated as early as possible within 12–24 h of admission followed by induction chemotherapy. Patients were assessed for features suggestive of tumor lysis syndrome and leukostasis. Complete blood count was performed before the procedure and 12–24 h after the procedure. All the procedures were performed after obtaining written informed consent from the patient and/or the patient's relatives. The procedures were performed with COBE Spectra and Spectra Optia apheresis system (Terumo BCT, Lakewood, USA) using central venous access. The apheresis procedures were performed using acid citrate dextrose (ACD-A) anticoagulant at a ratio of 1:12. Continuous calcium infusion (four ampoules of 10% calcium gluconate added to 400 ml saline) was given prophylactically to prevent citrate toxicity. Procedures were performed until clinical improvement and/or the WBC count decreased to below 1 lakh/μL.[2]

The Cairo and Bishop classification of clinical and laboratory tumor lysis syndrome was used to document the presence of tumor lysis syndrome [Table 1].[4] Laboratory tumor lysis syndrome along with raised serum creatinine, seizures, cardiac dysrhythmia, or death constituted clinical tumor lysis syndrome.[4]
Table 1: Cairo and Bishop classification of clinical and laboratory tumor lysis syndrome

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As central venous catheters were placed for apheresis, platelet transfusions were given when platelet counts were <20,000/μl.[5] Preprocedure blood transfusions were avoided as far as possible and transfusion triggers in postapheresis period were hemoglobin ≤7 g/dL and platelet count ≤20,000/μL.

Apheresis procedural variables such as product volume, duration of procedures, blood flow rate, ACD volume, and blood volume processed were recorded. Patients' blood counts were recorded before and after the procedure. The CE for leukocyte depletion was calculated using the following formula:



The overall survival (OS) of patients was estimated from the day of the leukapheresis procedure to either death or till the last follow-up.

Statistical analysis

Statistical analysis was performed using IBM SPSS version 20.0 software (Chicago,USA). Categorical variables were expressed using frequency and percentage. Numerical variables were represented using mean (standard deviation) and median (Q1, Q3). To test the statistical significance of the changes in the mean of hematological parameters between pre- and postfindings in hyperleukocytic patients, a Wilcoxon signed-rank test for skewed data was applied. To test the linear relationship between apheresis procedure-related factors and CE, Pearson's correlation coefficient was computed. To compute the survival probability, Kaplan–Meier analysis was applied. A P < 0.05 was considered to be statistically significant.


   Results Top


Sixteen consecutive patients who underwent a total of 22 leukocyte depletion procedures were included in the study. Ten (62%) patients received one apheresis and six patients required two apheresis procedures. Fifty percent of patients were diagnosed with AML and among them, AML-M5 was the most common subtype. Patient characteristics are given in [Table 2].
Table 2: Patient characteristics undergoing therapeutic leukapheresis (n=16)

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The leukapheresis procedure yielded a significant decrease in WBC and platelet count [Table 3]. A median 51% reduction was achieved (P < 0.001) in the WBC count. There was a nonsignificant decrease in hemoglobin and hematocrit postprocedure. Indication for leukapheresis was leukostasis in 11 (69%) patients, tumor lysis in four (25%), and both in one (6%) patient. Five (31%) patients fulfilled the criteria for laboratory tumor lysis syndrome [Table 4]. Out of this, four patients had renal dysfunction which is a characteristic feature of clinical tumor lysis.
Table 3: Changes in hematological parameters after therapeutic leukapheresis (n=22 procedures)

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Table 4: Biochemical and clinical features of patients with tumor lysis syndrome

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Twelve patients with leukocytosis (75%) presented with varied symptoms such as headache, dizziness, diplopia, altered sensorium, and respiratory signs such as tachypnea, dyspnea, cough, and hemoptysis. Out of this, two patients had myocardial infarction during the procedure which is attributed to leukostasis in the cardiovascular system and one of them succumbed to it. Clinical improvement after leukapheresis was noted in 12 (75%) patients.

Preprocedural platelet transfusion was required in four patients. Five patients received packed red blood cells and seven patients received platelet transfusion after the procedure. Cytoreductive therapy was initiated with hydroxyurea in 11 patients and cyclophosphamide in five patients followed by appropriate induction chemotherapy. Tumor lysis was managed with intravenous fluids, diuretics, and febuxostat or rasburicase.

[Table 5] discusses the procedural parameters of apheresis.The median duration of the procedure was 191 (153– 225) min and blood volume processed was 8329 (5488 –9400) ml. The product volume harvested was 1059 (928–1533) ml. Fluid balance was maintained using saline replacement. Blood priming of the apheresis kit was performed on one pediatric patient. None of the patients had hypocalcemic symptoms or vasovagal reactions during apheresis. Procedure-related adverse effects such as hypotension and nausea were observed in two patients and bleeding associated with catheter placement occurred in one patient. All patients were clinically assessed and were better after the apheresis. There was no significant difference in the CE of the Spectra Optia and COBE Spectra apheresis system [Table 5]. Out of all the variables analyzed, there was a positive intermediate correlation of “volume of WBC removed” with the CE (P = 0.05, r = 0.4) and an intermediate negative correlation with flow rate (P = 0.04, r = −0.43). Furthermore, preprocedure hematocrit showed a moderate positive correlation with the CE of the procedure (P = 0.03, r = 0.5).
Table 5: Apheresis procedural parameters

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Four patients (29%) had an early death, within the 1st week of diagnosis. Ten patients (71%) survived beyond the 1st week with the median survival time of the entire cohort being 26 (95% confidence interval [CI]: 5.8–46) days. Two patients were referred to another center and could not be followed up. The 30-day mortality was 50%. Out of all patients, the OS rate was 25% (4 out of 16) at 6 months follow-up. The six deaths that occurred later than 7 days were due to sepsis (n = 1), progression of disease (n = 4), and graft versus host disease (n = 1). There was no significant difference in terms of WBC count, lactate dehydrogenase, and the presence of leukostasis between the patients who are alive and dead. However, one patient with B-ALL underwent a hematopoietic stem cell transplant and had a survival of 330 days from diagnosis and survived for 78 days posttransplant.


   Discussion Top


Hyperleukocytosis is reported predominantly in myelomonocytic (FAB-M4) and monocytic (FAB-M5) types of AML. Acute lymphoblastic leukemia (ALL) and blast crisis of chronic myeloid leukemia also present with high white cell counts. Leukapheresis, as adjunctive therapy, relieves the hyperviscosity symptoms and bridges the time taken by the chemotherapeutic drugs to act. It also benefits by increasing the efficiency of cytoreductive agents by shifting the cells to the synthetic S phase. Initiation of leukapheresis is guided by the patient's clinical condition rather than a specific WBC cutoff.[6] The American Society for Apheresis (ASFA) guidelines 2019 recommends leukapheresis to be considered in patients with symptomatic HL as second-line therapy (category II recommendation).[7] The role of leukapheresis in asymptomatic HL is not well-established (Category III). Among the hyperleukocytic patients, significantly higher leukostasis features are reported in the AML group compared to ALL.[8] This is attributed to the large and nondeformable myeloblasts. Leukostasis may occur at lower counts in AML (100 × 109/L), whereas it may not occur even at counts as high as 500 × 109/L in chronic lymphocytic leukemia.[9] This may be the reason for the overrepresentation of AML in a majority of cohorts including ours.

The median age in our study was 42 years along the lines of Porcu et al.[10] In our study, there was a mean 51% reduction in WBC and a 24% reduction in platelet count as observed by Jin et al.[11] Total leukocyte count reduction ranging from 31% to 77% is reported. This significant reduction in leukocyte counts is referred to as “leukapheresis efficiency.”[11] Mobilization of sequestered blast cells from marrow or spleen may reduce the effect of debulking achieved through leukapheresis. A significant reduction in platelets and minimal red cell loss occurs during the procedure. Aggravation of preexisting anemia and thrombocytopenia was noted in our study as described in the literature.[12] RBC priming of the apheresis kit was performed in a pediatric patient as the red cell mass in the extracorporeal circuit of apheresis was calculated to exceed 15% of the total red cell mass of the child.

The CE for leukocyte depletion is dependent on preprocedure leukocyte count and hematocrit.[11] Jin et al[11]. reported a negative correlation of preapheresis leukocyte counts with CE. Preprocedural hematocrit had a positive correlation with CE similar to our study.

About 1.5–2 blood volume was processed in our patient group to achieve leukoreduction as recommended in the ASFA guidelines. As hypocalcemia was the most common reported procedure-related risk, continuous calcium infusions were maintained throughout the procedure.[8] No serious procedure-related adverse effects occurred in our cohort in line with the published literature.[1],[13]

Even though Bug et al. reported a significantly low risk of early death in the leukapheresis group (16% vs. 32%, respectively; P = 0.015) when compared to the nonapheresis group, most authors reported high early mortality rates; ranging from 23% to 57%.[10],[14],[15],[16] Bewersdorf et al. observed that the patients who were selected for leukapheresis had bad prognostic factors such as leukostasis and hence the poor outcome.[17] Although long-term benefits are sparse, leukapheresis provides symptomatic relief to patients, avoids organ dysfunction, and facilitates the initiation of chemotherapy. Symptomatic improvement was recorded in 3/4th of our patients. Leukostasis was relieved in the 10 patients (71%) who survived beyond the 1st week and leukostasis was not the cause of death in those who expired after 7 days.

Limitations of the study

This study has a small sample size which involves a heterogeneous group of patients. A larger cohort may be required to determine the efficacy of the leukapheresis procedure. A control group with HL treated with chemotherapy alone and not with leukapheresis was not included in the study. The independent effect of therapeutic leukapheresis could not be assessed due to the concomitant use of hydroxyurea and chemotherapy.


   Conclusion Top


Leukapheresis is effective in reducing the leukemic cells in patients with hyperleukocytosis. The short-term clinical benefits outweigh the procedure-related adverse effects. CE of the apheresis equipment depends on the WBC volume removed and the preprocedural hematocrit. At 6-month follow-up, only 25% survived who underwent leukapheresis in our study. Leukapheresis probably does not provide a major impact on long-term prognosis in hyperleukocytic patients. Logistic hurdles in performing leukapheresis urgently can be counterproductive if it unduly delays the initiation of chemotherapy. As the feasibility of randomized clinical trials is meager in this hematological emergency, clinicians have to resort to the existing evidence from observational studies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Berber I, Kuku I, Erkurt MA, Kaya E, Bag HG, Nizam I, et al. Leukapheresis in acute myeloid leukemia patients with hyperleukocytosis: A single center experience. Transfus Apher Sci 2015;53:185-90.  Back to cited text no. 1
    
2.
Röllig C, Ehninger G. How I treat hyperleukocytosis in acute myeloid leukemia. Blood 2015;125:3246-52.  Back to cited text no. 2
    
3.
Hölig K, Moog R. Leukocyte depletion by therapeutic leukocytapheresis in patients with leukemia. Transfus Med Hemother 2012;39:241-5.  Back to cited text no. 3
    
4.
Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med 2011;364:1844-54.  Back to cited text no. 4
    
5.
Kaufman RM, Djulbegovic B, Gernsheimer T, Kleinman S, Tinmouth AT, Capocelli KE, et al. Platelet transfusion: A clinical practice guideline from the AABB. Ann Intern Med 2015;162:205-13.  Back to cited text no. 5
    
6.
Stahl M, Pine A, Hendrickson JE, Litzow MR, Luger SM, Stone RM, et al. Beliefs and practice patterns in hyperleukocytosis management in acute myeloid leukemia: A large U.S. web-based survey. Leuk Lymphoma 2018;59:2723-6.  Back to cited text no. 6
    
7.
Padmanabhan A, Connelly-Smith L, Aqui N, Balogun RA, Klingel R, Meyer E, et al. Guidelines on the use of therapeutic apheresis in clinical practice – Evidence-based approach from the Writing Committee of the American Society for Apheresis: The Eighth special issue. J Clin Apher 2019;34:171-354.  Back to cited text no. 7
    
8.
Choi MH, Choe YH, Park Y, Nah H, Kim S, Jeong SH, et al. The effect of therapeutic leukapheresis on early complications and outcomes in patients with acute leukemia and hyperleukocytosis: A propensity score-matched study. Transfusion 2018;58:208-16.  Back to cited text no. 8
    
9.
Ganzel C, Becker J, Mintz PD, Lazarus HM, Rowe JM. Hyperleukocytosis, leukostasis and leukapheresis: Practice management. Blood Rev 2012;26:117-22.  Back to cited text no. 9
    
10.
Porcu P, Danielson CF, Orazi A, Heerema NA, Gabig TG, McCarthy LJ. Therapeutic leukapheresis in hyperleucocytic leukaemias: Lack of correlation between degree of cytoreduction and early mortality rate. Br J Haematol 1997;98:433-6.  Back to cited text no. 10
    
11.
Jin Y, Guo S, Cui Q, Chen S, Liu X, Wei Y, et al. A hospital based retrospective study of factors influencing therapeutic leukapheresis in patients presenting with hyperleukocytic leukaemia. Sci Rep 2018;8:294.  Back to cited text no. 11
    
12.
Porcu P, Farag S, Marcucci G, Cataland SR, Kennedy MS, Bissell M. Leukocytoreduction for acute leukemia. Ther Apher 2002;6:15-23.  Back to cited text no. 12
    
13.
Parra Salinas IM, González Rodriguez VP, García-Erce JA. Therapeutic leukapheresis: 9-year experience in a University Hospital. Blood Transfus 2015;13:46-52.  Back to cited text no. 13
    
14.
Tan D, Hwang W, Goh YT. Therapeutic leukapheresis in hyperleukocytic leukaemias-the experience of a tertiary institution in Singapore. Ann Acad Med Singap 2005;34:229-34.  Back to cited text no. 14
    
15.
De Santis GC, de Oliveira LC, Romano LG, Almeida Prado Bde P Jr., Simoes BP, Rego EM, et al. Therapeutic leukapheresis in patients with leukostasis secondary to acute myelogenous leukemia. J Clin Apher 2011;26:181-5.  Back to cited text no. 15
    
16.
Bug G, Anargyrou K, Tonn T, Bialleck H , Seifried E, Hoelzer D, Ottmann OG. Impact of leukapheresis on early death rate in adult acute myeloid leukemia presenting with hyperleukocytosis. Transfusion 2007;47:1843-50.  Back to cited text no. 16
    
17.
Bewersdorf JP, Giri S, Tallman MS, Zeidan AM, Stahl M. Leukapheresis for the management of hyperleukocytosis in acute myeloid leukemia – A systematic review and meta-analysis. Transfusion 2020;60:2360-9.  Back to cited text no. 17
    

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Correspondence Address:
Veena Shenoy,
Amrita Institute of Medical Sciences and Research Centre, Ponekkara. P.O, Kochi - 682 041, Kerala
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajts.ajts_41_22




 
 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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