Therapeutic leukocytapheresis for leukostasis in chronic lymphocytic leukemia: A case report and literature review

Chronic lymphocytic leukemia (CLL) is a clonal mature B‐cell neoplasm with a typically indolent clinical course. Though most clinicians follow these neoplasms through observation alone, an aggressive transformation to prolymphocytic leukemia, diffuse large‐B‐cell lymphoma (Richter transformation) or classical Hodgkin lymphoma requires immediate attention. We present a case of extreme leukocytosis (>1 million/μL) in a previously diagnosed CLL patient. Due to symptomatic leukostasis, she was started on cytoreductive therapies including leukocytapheresis. After three rounds of leukocytapheresis (LCP) and concurrent chemotherapy, her white blood cell count decreased from a maximum 1262 × 103/μL to 574 × 103/μL. To our knowledge, CLL with symptomatic leukostasis that required therapeutic LCP is rarely reported in literature. We propose that therapeutic LCP is of value in such rare, yet dangerous settings like our case.

predilection and a greater incidence among individuals in Europe and North America. 2 While most CLL patients are asymptomatic, they may harbor an unrecognized hyperleukocytosis.Such a state of white blood cell (WBC) overproduction is classically defined by counts greater than 100 Â 10 3 /μL.If the numbers further increase, the patients may develop symptomatic hyperleukocytosis or leukostasis, leading to respiratory, neurologic, hematologic, and renal complications from viscosity-derived hindrances to tissue perfusion.Though exceedingly rare, such instances have occurred in CLL patients when WBC counts exceed 1000 Â 10 3 /μL. 3ere, we present a unique case of CLL, where the patient presented with symptomatic leukostasis after nearly 10 years of indolent history.The combination of therapeutic LCP and cytoreductive chemotherapy successfully reduced her WBC count from a maximum 1262 Â 10 3 /μL to 574 Â 10 3 /μL.Our case adds to the limited instances of CLL patients experiencing leukostasis treated effectively with leukocytapheresis.This presentation, in conjunction with others highlighted in our literature review, suggests the utility of therapeutic LCP as a promising modality to decrease morbidity and mortality in CLL patients with leukostasis.

| CASE REPORT
A 68-year-old female with pertinent past medical history of chronic kidney disease, type-2 diabetes mellitus, hypertension, and CLL diagnosed in 2013 presented to the emergency department for abdominal pain.She reported abdominal pain beginning 3 months prior, and most recently had developed new constipation with no bowel movements for 6 days.Upon further questioning, she mentioned a 30-pound weight loss accompanied by diminished appetite and night sweats in the prior threemonth period, increasing blurry vision for 1 week, and newly developed tachypnea.She had not received prior treatment for CLL.
While in the emergency department, initial workup indicated an elevated WBC count of 1146 Â 10 3 /μL and a severe anemia (hemoglobin, 5.0 g/dL; hematocrit, 24.5%).Transfusion of one unit packed red blood cells (pRBC) was initiated and she was intubated due to decline in cognition and lack of airway protection.Consultation with hematology raised consideration for cytoreductive therapy (hydroxyurea and cyclophosphamide) as well as LCP via apheresis to decrease the leukostasis burden and address the risk of tumor lysis.
As her WBC count rose to over 1296 Â 10 3 /μL, LCP was discussed with the pathology team and subsequently implemented.The Spectra Optia Apheresis System (TerumoBCT, Lakewood, CO, USA) was used for all the procedures.The blood volume processed for each round of leukoreduction was approximately 10 L, and an average of 1039 mL of WBC was removed via apheresis.Fivehundred milliliters of albumin was used consistently with adjusted amounts of 0.9% normal saline and anticoagulant citrate dextrose solution-formula A to average approximately 1250 mL of replaced volume.No sedimenting agent was utilized for the LCP procedures.The first round of apheresis dropped her WBC count to 927 Â 10 3 /μL.Two additional rounds conducted over the next 48 h successfully brought the WBC count down further to 857 Â 10 3 /μL (Figure 1).Additional procedures were halted due to hemodynamic instability, and chemotherapy with cyclophosphamide and bendamustine was initiated.
Hematologic workup confirmed the prior diagnosis of CLL.Specifically, peripheral blood smear interpretations revealed marked leukocytosis composed of monotonous small-to-medium sized lymphoid cells (>90%) with blocky chromatin and scant amounts of cytoplasm, macrocytic anemia with elliptocytes, dacrocytes and schistocytes with thrombocytopenia (Figure 2).Flow cytometry showed a population of mature B-cells expressing CD5, CD19, CD20, CD23, and low-density kappa light chains present at 99% of lymphocytes (Figure S1).Importantly, the peripheral smear and flow cytometry evaluation did not demonstrate increased prolymphocytes or large B-cells.Despite successful rounds of LCP and chemotherapy, the patient's need for vasopressor intervention continued to increase, leading to worsening encephalopathy, tumor lysis, and dependence on hemodialysis.The patient was transitioned to comfort measures only by the family.

| DISCUSSION
Over years of trial and error, treatment modalities for hematologic malignancies have changed.Newer options including monoclonal antibodies and immunomodulation now exist as alternatives to historical options of chemotherapy, radiation, splenectomy, and leukapheresis.][6] Prior studies have examined the potential benefits of leukapheresis as a therapeutic option in CLL patients.These findings note mixed conclusions.One study examined 59 patients noting a reduction in lymphocytosis, lymphadenopathy, and hepatosplenomegaly among 50%-60% of cases, suggesting leukapheresis as a beneficial treatment option. 7Another study examined 12 patients with CLL using therapeutic leukapheresis and concluded that long-term therapies were ineffective in management of advanced CLL cases.They did note, however, that in an acute setting requiring the removal of an abnormal cell burden within the circulation, the lowering of tumor cells could be beneficial as noted in our case. 80][11] The first theory proposes that the rigidity of a larger population of leukemic cells in comparison to their fellow leukocytes causes a nonturbulent flow and allows for stasis.This ultimately leads to end-organ damage through micro-obstruction.It is important recognize that this theory suggests worse outcomes in patients who receive RBC transfusion or diuresis during their leukostasis as these procedures increase blood viscosity and subsequent micro-obstruction.The second theory proposes that leukemic cells secrete cytokines that alter adhesion molecules and lead to aggregation within vessel lumens that induces a local hypoxic state which damages surrounding tissues.
3][14] The greater amount of cited leukostasis events in these subpopulations speaks to the rarity of similar events occurring in CLL patients.Upon review of the literature, limited cases of CLL patients experiencing leukostasis were noted and few received leukapheresis as a treatment (Table 1).6][17][18][19][20][21] While others like Singh et al. suggest beneficial though temporary improvements from LCP use in managing elevated WBC counts, our patient demonstrated continued improvements in her WBC counts without a rapid rebound. 18Additionally, the quick reduction of tumor burden can reduce additional concerns from tumor lysis syndrome, which can complicate the hospital course through metabolic disturbance, as seen in our patient.
According to the American Society for Apheresis (ASFA), there are incidences and indications for which clinicians should consider leukapheresis in the setting of hyperleukocytosis. 22Specifically, the group suggests WBC greater than 100 Â 10 3 /μL for AML patients and greater than 400 Â 10 3 /μL for ALL patients.The rationale proposed for therapeutic apheresis, while indeed applicable to such AML and ALL patient populations, seems equally viable for CLL patients also experiencing hyperleukocytosis.A single round of leukapheresis can reduce WBC counts by 30%-60%, and the rapid reduction of intravascular tumor burden improves tissue perfusion and potentially reverses end-organ manifestations of hypoxic distress.
In summary, our patient presented with extreme leukocytosis and leukostasis in the setting of CLL, without evidence of transformation to prolymphocytic leukemia or diffuse large cell lymphoma.In conjunction with cytoreductive therapies, leukapheresis was successfully performed in our patient to significantly decrease the white cell number.This strengthens the evidence for utilizing therapeutic LCP in patients with symptomatic leukostasis in CLL.

| CONCLUSIONS
Though rare for CLL patients, leukostasis can occur and is life-threatening.As seen both in our case and those referenced in our literature review, the signs and symptoms can vary by affected organ system.Leukapheresis reduces WBC counts rapidly, allowing improved tissue perfusion as concurrent chemotherapy is initiated.Though not recognized in the current ASFA guidelines, we highlight the benefits of leukapheresis as a treatment option for symptomatic hyperleukocytosis in CLL patients.

F I G U R E 1
Effect of leukapheresis on the patient's white blood cell counts.Black arrows indicate the days when the procedure was performed.

F I G U R E 2
Peripheral blood smear showing monomorphic lymphocytes with soccer-ball chromatin.Smear images taken under oil with 20Â magnification (A) and 60Â magnification (B).
T A B L E 1