Emergency therapeutic leukapheresis: A single-center experience in a teaching hospital in Eastern India

Abstract

Hyperleukocytosis is a hematologic crisis caused by excessive proliferation of leukemic cells and has a relatively high early mortality due to a series of severe complications needing prompt and effective interventions. Leukapheresis performed using apheresis equipment to separate leukocytes from peripheral blood at the same time returns autologous plasma, platelets and erythrocytes to the patient and is applied clinically for treatment of hyperleukocytosis with symptoms of leukostasis. The aim of this study is to analyze the safety and effectiveness of therapeutic leukocytapheresis to alleviate symptoms of leukostasis in different types of hematological malignancies. The study is a retrospective review of procedures carried out for the treatment of hyperleukocytosis with symptoms of leukostasis at the Haematology Intensive Care Unit (ICU) and Critical Care ICU by the Transfusion Medicine Department of the institute from February 2019 to April 2024. Eleven patients underwent a total of 12 leukocytapheresis procedures. After an average of 1.09 sessions, a statistically significant drop in the initial leukocyte counts was observed (P = 0.0004), without any significant drop in Hemoglobin g% (P = 0.27%), hematocrit (P = 0.9%) and total platelet count (P = 0.15%). Despite the small size and limited homogeneity of our study, we can conclude that leukocytapheresis is a safe and effective adjuvant therapeutic measure for hematological malignancies, particularly acute lymphoid/myeloid leukemia, chronic myeloid leukemia with hyperleukocytosis and symptoms of leukostasis, especially in a patient who was not appropriate to cytoreduce with Ara-C or hydroxyurea.

Introduction

Hyperleukocytosis, defined as a white blood cell (WBC) count of 100 × 10⁹/L, is a complication seen in 5%–20% of patients with acute leukemia.[1,2] Risk factors for hyperleukocytosis include younger age, certain cytogenetic abnormalities and monocytic differentiation subtypes (acute myelomonocytic leukemia and acute monoblastic and monocytic leukemia).[2,3] Leukostasis secondary to hyperleukocytosis is associated with poor survival in specific subtypes of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Leukocytapheresis (leukapheresis) is often used prophylactically to prevent leukostasis or to improve its clinical symptoms.[4]

If it is not diagnosed and treated rapidly, the 1-week mortality rate is approximately 40%.[5] In a systematic review to determine if leukapheresis and low-dose chemotherapy reduced the incidence of early mortality, Oberoi et al. highlighted that the most common cause of early mortality is hemorrhage, followed by leukostasis, sepsis, respiratory failure and renal failure.[6]

The present study showed 11 patients who underwent emergency therapeutic leukapheresis and their outcomes pertaining to reduction in WBC counts and symptomatic improvement.

Materials and Methods

The present study was a retrospective analysis of records of all patients who have undergone therapeutic leukapheresis procedures in the Department of Transfusion Medicine in a tertiary care hospital, Bhubaneswar, India, from February 2019 to April 2024. The study has been approved by the institutional ethical committee with reference letter no. Ref no./DMR/IMS.SOA/2021/187. Due consent for all procedures was taken from all patients which are documented in the department as per guideline. The Spectra Optia (Terumo BCT, Lakewood, CO, USA) automated apheresis machine was used. Anticoagulant citrate dextrose solution A (ACD-A) was used as anticoagulant (AC), with ACD-A blood ratio of 1:12. Whole blood inlet flow rate and collection flow rate were adjusted by the system according to the size of the patient (gender, height, and weight) to reduce the risk of procedure-related complications such as citrate toxicity. The detailed information is as follows: total inlet processed was between 4250 ml and 10,496 ml, processing time was maintained between 3.5 and 4 h, and routine collect flow rate was maintained between 35 and 45 ml/min. The requirement for additional leukapheresis procedures was contingent upon the patient’s symptoms, peripheral WBC counts and plan for chemotherapy. Complete blood count (CBC) pre- and postprocedure was performed. Other preprocedural investigations included type and screen, triple H for HIV 1 and 2, hepatitis B and C, serum electrolytes, liver function test, kidney function test, and blood coagulation profile. Continuous monitoring of heart rate, oxygen saturation, respiration rate, blood pressure and any temperature rise was done throughout the procedures and all the procedures were performed in an intensive care unit setting by resident doctors of transfusion medicine under the supervision of senior faculty of transfusion medicine. Adequate hydration was maintained in all cases. No sedimenting agent was utilized for these procedures. Two ampules of 10% calcium gluconate in 500 ml NS were given as slow IV throughout the procedure. Indication for leukapheresis was mostly based on the presence of clinical symptoms of leukostasis and WBC counts as per the recent 2023 American Society for Apheresis (ASFA) guidelines. Most of the procedures were performed on an emergency basis (within 8 h post transfusion medicine notification as per the institutional protocol). Four patients (Cases-3, 5, 6, 10) with one patient blood group as A Rh D positive and others as O Rh D positive with Hct < 21% in which extra corporeal circuit of Apheresis Device was Primed with one unit ABO-specific, Anti Human Globulin (AHG)-compatible, leucodepleted, Packed Red Blood Cell (PRBCs) in order to avoid any hemodynamic instabilities of patients during procedures in which inlet line of apheresis kit was connected to compatible PRBC and return line was connected to an empty bag. After custom priming the procedure was started. Five patients reported central nervous system (CNS) symptoms such as dizziness, headache, and delirium; 3 patients had pulmonary symptoms such as dyspnea and hypoxia; and 3 patients had both CNS and pulmonary symptoms prior to the procedure.

Patients’ blood samples were sent immediately postprocedure within 10 min of its completion in all cases to check for efficacy of therapeutic leukapheresis. CBC was done by Fully automated Cell Counter SYSMEX XN-3111A. All our samples were run without any dilution for total WBC counts.

The percentage of reduction in WBC count postprocedure is calculated by the formula,

% of reduction = PreprocedureWBC count – Post procedure WBC count/Preprocedure WBC count × 100

Statistical analysis

Descriptive analyses of all variables determining the frequencies and percentages for qualitative variables and measures of central tendency (average ± standard deviation) for quantitative variables were done using the SPSS version 25 software (IBM SPSS Statistics for windows version 25, IBM Corp., Armonk, NY). Relationships between quantitative variables and categorical and quantitative variables were determined by applying the Student’s t-test and P < 0.05 in WBC reduction was considered to be statistically significant.

Results

A total of 11 patients with hyperleukocytosis with symptoms of leukostasis admitted in our hospital underwent emergency therapeutic leukocytapheresis procedure. Out of these, seven were females (63.63%) and the rest four (36.36%) were males. A total of 3 (27.27%) patients were in the age group of 11–20 years, 1 (9.09%) patient was in the age group of 21–30 years, 2 (18.18%) patients were in the age group of 31–40 years, 3 (27.27%) patients were in the age group of 51–60 years, and 2 (18.18%) patients were in the age group of 61–70 years. Out of 11 patients, only one patient underwent 2 cycles of therapeutic leukocytapheresis and the rest all underwent only one cycle of leukocytapheresis procedure.

Out of 11 patients, 4 (36.36%) patients were diagnosed as AML, 2 (18.18%) patients were diagnosed as ALL, 4 (36.36%) patients were diagnosed as chronic myeloid leukemia and 1 (9.09%) patient was diagnosed as hyperleukocytosis under evaluation. The details of the procedures performed are described in Tables 1-3. Age/gender, diagnosis, ABO Rh D type, vascular access, inlet blood volume processed, total blood volume, product volume collected and AC volume to the patient are shown in Table 1. The mean inlet processed was 6981 ml, the mean volume of product in collection bag was 639 ml, the mean volume of ACD used was 631 ml, and the mean volume of ACD to the patient was 592 ml.

Table 1.

Patient details

Case parameters	Case 1 (1st cycle)	Case 1 (2nd cycle)	Case 2	Case 3	Case 4	Case 5	Case 6	Case 7	Case 8	Case 9	Case 10	Case 11
Age and sex	18 years/female	18 years/female	13 years/female	53 years/male	25 years/male	56 years/male	17 years/female	69 years/female	66 years/female	52 years/male	36 years/female	34 years/female
Diagnosis	AML	AML	ALL	CML	AML	AML	CML-CP	AML	Acute lymphocytic leukemia with hyperthyroidism	Hyperleukocytosis under evaluation	CML	CML
ABO and RhD type	O positive	O positive	AB positive	A positive	O positive	O positive	O positive	O positive	O positive	B positive	O positive	O positive
Vascular access	Right IJV	Right IJV	Right IJV	Right IJV	Right IJV	Right IJV	Right femoral vein	Right femoral vein	Right femoral vein	Right femoral vein	Right IJV	Right IJV
TBV (mL)	3203	3203	2833	4179	6997	4006	2874	3635	2484	4406	2989	4060
Inlet processed (mL)	6406	6450	4250	6690	10,496	8012	6083	7270	4968	9570	6125	7462
Collected (mL)	729	626	620	700	742	747	590	585	455	402	700	774
TBV processed	2	2	1.5	1.6	1.5	2	2	2	2	2	2	2
Anticoagulant used (mL)	582	583	386	608	954	728	553	661	451	798	593	678
Anticoagulant to patient (mL)	543	551	352	575	915	692	496	632	430	740	544	640

AML=Acute myeloid leukemia, IJV=Internal jugular vein, TBV=Total blood volume, CML-CP=Chronic myeloid leukemia in the chronic phase

Table 3.

Percentage of white blood cell reduction postleukapheresis

Cases	Percentage of WBC count reduction
Case 1 (1st cycle + 2nd cycle)	70.64
Case 2	34.2
Case 3	36.2
Case 4	5.5
Case 5	42
Case 6	14.5
Case 7	57.1
Case 8	41.7
Case 9	36.8
Case 10	12.3
Case 11	53.8

WBC: White blood cell

Pre- and postprocedural laboratory investigation values of hemoglobin (Hb), hematocrit (Hct), platelet count and WBC count are shown in Table 2. The mean pre- and post-Hb were 7.28 g/dl and 7.56 g/dl, respectively (P = 0.27, t = 1.141). The mean pre- and post-Hct were 23.29% and 23.40%, respectively (P = 0.90, t = 0.127). The mean pre- and postplatelet counts were 117.33 × 10³/ml and 90.91 × 10³/ml, respectively (P = 0.15, t = 0.15). The mean pre- and post-WBC counts were 465.17 × 10³/ml and 305.29 × 10³/ml, respectively (P = 0.0004, t = 5.010). P values for WBC reduction were < 0.05 and considered to be statistically significant in all our procedures.

Table 2.

Pre- and postprocedural parameters

Cases	Hb (g/dL)		HCT (%)		WBC count (×1000/mL)		Platelet count (×1000/mL)
	Pre	Post	Pre	Post	Pre	Post	Pre	Post
Case 1 (1st cycle)	7.2	7.9	21	27	811.91	481	40	41
Case 1 (2nd cycle)	7.9	9.3	27	29.4	481	238.39	41	55
Case 2	7.7	7.5	29	27	791	520	44	35
Case 3	5.5	5.7	18.8	18	386.05	246.27	70	56
Case 4	7.9	7.9	27.6	24.9	308.55	291.47	108	91
Case 5	5	7.4	16.4	22	333	192.39	111	96
Case 6	7.6	7.2	19	20.2	685.81	585.77	244	172
Case 7	7.6	6.8	25	20.6	350.01	150.05	32	30
Case 8	7.9	7.9	24.6	23	129.11	75.2	28	28
Case 9	9	9	28	27	288.4	182.2	105	102
Case 10	7	7	19.6	19.1	558	489	494	292
Case 11	7.1	7.2	23.5	22.7	459.3	211.8	91	93
Mean	7.28	7.56	23.29	7.56	465.17	305.29	117.33	90.91
P	0.27		0.90		0.0004		0.15
t	1.141		0.127		5.010		0.15

Hb=Hemoglobin, HCT=Hematocrit, WBC=White blood cell

Procedure-related complications such as hypocalcemia symptoms like tingling around the mouth and paresthesia of extremities occurred in one patient for which inlet-to-AC ratio was increased from 12:1 to 13:1, following which the symptoms subsided and the procedure was continued. Other side effects such as chills and rigor were noted in one patient which was dealt using a warmer. Since one patient had a very high WBC count (811.11 × 10³/ml), she required two cycles of leukocytapheresis.

Table 3 shows postprocedure WBC depletion percentage.

Discussion

Hyperleukocytosis is associated with complications such as leukostasis, tumor lysis syndrome and disseminated intravascular coagulopathy which are associated with a high risk of early deaths in these patients.[7] The symptoms suggestive of leukostasis are confusion, dizziness, headache, tinnitus, visual disturbances such as blurred vision, mental status changes such as stupor, delirium, coma or respiratory symptoms such as dyspnea, tachypnea, and hypoxemia.[7] In our study, 5 patients reported CNS symptoms such dizziness, headache and delirium, 3 patients had pulmonary symptoms such as dyspnea and hypoxia and 3 patients had both CNS and pulmonary symptoms prior to the procedure.

According to Ganzel et al.,[7] leukapheresis needs to be initiated when there is a compromise in the functioning of either one of the respiratory, CNS or renal systems or when the leukocyte or blast count is more than 100,000/μL. The clinical efficacy of the procedure is best monitored with pre- and postprocedure total leukocyte count along with the patient’s clinical condition. They reported that a single procedure results in a 20%–50% reduction in leukocyte or blast count.[7]

According to the 2023 Guidelines on the use of Therapeutic Apheresis in Clinical Practice published by the ASFA, hyperleukocytosis secondary to AML and ALL is a category III recommendation for the treatment of leukostasis.[8] During a single procedure, WBC count can be reduced by 10%–70%.[9] In our study, in 10 out of 11 patients, a significant reduction in WBC counts was seen as suggested in the literature between 10% and 70%.[9] One case (case 4) out of 11 patients got a < 10% reduction in WBC counts [Table 3], but patients were observed with symptomatic improvement as the efficacy of leukocyte reduction correlates not only with the amount of cells removed but also with growth pattern and distribution kinetics of the leukemic blasts.[9] Blood loss is a known side effect of leukocytapheresis because contaminating RBCs are collected with WBCs.[10] In our study, one case (case 7) had a slight drop in Hb postprocedure [Table 2], which was managed with postprocedure PRBC transfusion along with one ABO-specific AHG-compatible PRBC transfusion in case 3 postprocedure along with custom priming keeping in view of low Hb g%. Transfusions before leukocytapheresis are not recommended because this may worsen hyperviscosity but custom priming of the apheresis machine with ABO-specific, AHG-compatible PRBCs was done prior to the start of the procedure in 4 cases out of 11 cases.[8]

Platelet loss is a similar concern in leukemic patients undergoing leukocytapheresis. In healthy, unstimulated mononuclear cell donors, platelets can decrease by as much as 44%.[11] This reinforces the importance of obtaining a postprocedure CBC to determine the need for blood product transfusions after leukocytapheresis. Postprocedure platelet reduction was not significant in this study. Hence, platelet transfusions were not given to any of the patients after procedure.

Out of 11 patients, 10 patients were managed by the combined effects of leukapheresis and induction chemotherapy and/or hydroxyurea which was found to be beneficial in our patients except the last one who was critical, developed hypotension and was on non invasive ventilator (NIV) due to respiratory insufficiency. Blood pressure could not be maintained even after on double vasopressor support, succumbed to disease next day after leukapheresis procedure. The patient (case 4), with 5.5% postprocedure WBC reduction, less than the desired reduction in WBC count, showed a significant improvement in his clinical symptoms and was discharged in a hemodynamically stable condition. In this study we did not observe any major complications during the procedure in any patients except two Cases (Case 2 and 7) who developed minor reactions such as chills, rigor, and tingling of the mouth respectively which were managed by using a warmer and increasing the ratio of inlet/AC from 12:1 to 13:1 effectively. All the 10 patients out of 11 were asymptomatic and doing well on 6-month follow-up with continuation of their disease-specific chemotherapies.

Conclusion

Leukostasis secondary to hyperleukocytosis in leukemic patients is a life-threatening medical emergency associated with significant morbidity and mortality. Hence, once hyperleukocytosis is present along with symptoms of leukostasis, it is very important to start therapeutic leukocytapheresis as early as possible as an adjuvant therapy along with more definitive treatment such as induction chemotherapy and cytoreductive agents. In conclusion, leukocytapheresis can rapidly reduce the leukocyte count, effectively decrease tumor burden, and reduce the incidence of complications as seen with our patients.

Limitations of the study

The study is a retrospective study, sample size is small, there is no control group and all procedures in this study are done as an adjuvant therapy along with disease-specific cytoreductive chemotherapies.

Ethical approval

The study has been approved by the Instructional Ethical Committee with reference letter no. Ref no./DMR/IMS. SOA/2021/187.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.