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Correspondence: Dong Wook Jekarl, MD, PhD, Department of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, 06591, Seocho-gu, Seoul, Republic of Korea.
Department of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaResearch & Development Institute of In Vitro Diagnostic Medical Device of Catholic University of Korea, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
Department of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaResearch & Development Institute of In Vitro Diagnostic Medical Device of Catholic University of Korea, College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaCatholic Genetic Laboratory Center, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea
In acute promyelocytic leukemia (APL), increased cell burden in the peripheral blood due to either the disease itself or early treatment with all-trans retinoic acid could cause hyperleukocytosis (HL) before induction chemotherapy. However, therapeutic leukapheresis has seldom been used because of concerns of subsequent coagulopathy after this invasive procedure. The aim of this study was to evaluate the effects of leukapheresis in APL, especially for efficacy and safety.
Methods
We retrospectively analyzed newly diagnosed patients with APL from January 2009 to March 2022. Among 323 patients, 85 had white blood cell count above 40 × 109/L before induction chemotherapy. Thirty-nine patients were initially treated with leukapheresis, whereas the other 46 were not. Clinical and laboratory parameters between these groups were compared.
Results
There was a trend toward favorable 30-day survival rate for the leukapheresis group compared with the non-leukapheresis group (76.9% and 67.4%; P = 0.24). The complications including subsequent intensive unit care (P = 0.23), severe hemorrhagic events (P = 0.13) showed no significant differences between the two groups. The patients were divided into subcohorts, and the survival rates of the leukapheresis and non-leukapheresis groups were 92.3% (95% confidence interval [CI], 77.8%–100.0%) versus 58.3% (95% CI, 38.6%–78.1%) (P = 0.03) in “sequential HL” and 76.7% (95% CI, 61.5%–91.8%) versus 54.8% (95% CI, 37.3%–72.4%) (P = 0.03) in “symptomatic HL,” respectively. Moreover, in the “sequential HL” subcohort, the cumulative incidence of differentiation syndrome and following adverse events were significantly lower in the leukapheresis group.
Conclusions
In APL with “sequential HL” or “symptomatic HL” from either the disease itself or the effect of all-trans retinoic acid, therapeutic leukapheresis could be applied to reduce leukemic cell burden without significant risks.
]. Acute promyelocytic leukemia (APL) is no exception, and HL could occur from either disease progression or early treatment with all-trans retinoic acid (ATRA) or arsenic trioxide (ATO).
These two origins of HL are quite different from each other but converge to an unfavorable prognosis. The former is a native phenomenon for most acute leukemia, as the growing leukemic cell burden in bone marrow is released into peripheral blood (PB). One article stated that HL in the initial stage of APL could give rise to a much worse condition than non-HL [
Progressive hyperleukocytosis is a relevant predictive marker for differentiation syndrome, early death, and subsequent relapse in acute promyelocytic leukemia.
Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups: Presented in part at the 41st meeting of the American Society of Hematology, New Orleans, LA, December 3-7, 1999.
The latter origin of HL is an induced phenomenon as a result of the treatment regimen. Even though most patients with APL initially show leukocytopenia in PB, sequential HL could develop soon after starting ATRA or ATO treatment. These regimens induce terminal differentiation of leukemic cells, and those mature cells and residual leukemic cells can be massively released into PB [
]. Further, although the association between this sequential HL and differentiation syndrome (DS) is not clear, an increasing WBC count frequently is observed at the onset of DS symptoms [
Progressive hyperleukocytosis is a relevant predictive marker for differentiation syndrome, early death, and subsequent relapse in acute promyelocytic leukemia.
Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PMN/RAR-alpha isoform, and CD13 expression in patients treated with all-trans retinoic acid.
These “initial HL” and “sequential HL” could devastate the patient's condition. The aforementioned article showed that 8-week early death rates of “initial HL (n = 32)” and “sequential HL (n = 30)” in patients with APL were 40.6% and 30.0% and 8-week DS cumulative incidences of these were 34.4% and 26.7%, respectively [
Progressive hyperleukocytosis is a relevant predictive marker for differentiation syndrome, early death, and subsequent relapse in acute promyelocytic leukemia.
], and leukapheresis could be the one of options that can immediately reduce the leukemic cell burden in PB in a mechanical manner. However, in APL, leukapheresis has seldom been tried because of concerns about coagulopathy after this invasive procedure [
Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PMN/RAR-alpha isoform, and CD13 expression in patients treated with all-trans retinoic acid.
Thus, there have been few studies attempting leukapheresis in APL. Our institution had treated, using leukapheresis, some patients with APL accompanying HL, and a large amount of data were available. The aim of this study was to evaluate the effects of leukapheresis in APL, comparing clinical and laboratory parameters between leukapheresis and non-leukapheresis groups.
Methods
This study was a retrospective, single-center study performed with patients with APL from January 2009 to March 2022. The electronic medical records were searched for hematologic patients who had morphologic and cytogenetic studies from bone marrow. Informed consent for study participation was waived by the institutional review board (KC20RISI0340) of Seoul St. Mary's Hospital, which approved our study. Our protocol was in accordance with the Declaration of Helsinki.
Patients
Some patients with APL showed HL on initial laboratory findings, but other patients showed HL on follow-up laboratory findings after ATRA treatment, although their initial WBC count was low. In this study, the former and latter groups are termed “initial HL” and “sequential HL,” respectively.
From the cytogenetic study records from January 2009 to March 2022, 323 patients with “t(15;17)(q24.1;q21.2)” were searched. Among those, we excluded relapsed patients with APL to avoid bias from previous intervention, as well as pediatric (younger than 18 years) and palliative cases to focus on curative adults (Figure 1).
A cut-off WBC value for participants was necessary because there is no internationally agreed-on value for HL in APL. In our institution's records, most patients whose WBC count was greater than 50 × 109/L had been treated with leukapheresis, and we also found patients whose WBC count was in the 40∼50 × 109/L range who underwent the procedure depending on the clinician's decision. Moreover, Yoon and colleagues [
Progressive hyperleukocytosis is a relevant predictive marker for differentiation syndrome, early death, and subsequent relapse in acute promyelocytic leukemia.
] emphasized that either an initial or sequential WBC count greater than 43 × 109/L correlated with adverse outcomes. By arbitration, a WBC count greater than 40 × 109/L was chosen as the cut-off value in this study, as this value could be accepted as an approximation to 43 × 109/L and retain the cohort as much as possible. To sum up, all the leukapheresis were performed as soon as their WBC counts exceeded 40 × 109/L, to maintain those below 40 × 109/L regardless of their origins either “initial HL” or “sequential HL.”
Thirty-nine patients received at least one leukapheresis before induction chemotherapy, and all of their pre-initial leukapheresis WBC counts were greater than 40 × 109/L. In addition, 46 patients did not receive leukapheresis, even though their initial or sequential WBC count reached 40 × 109/L before induction chemotherapy. As our initial approach, we compared these two groups.
Furthermore, we divided the entire cohort into two subcohorts of “initial HL” and “sequential HL.” As our second approach, leukapheresis and non-leukapheresis groups in each subcohort were compared to reveal the effectiveness of the procedure depending on the origin of HL.
We also divided the entire cohort into two subcohorts according to the presence of any symptoms that could be derived from leukostasis [
Grading of symptoms in hyperleukocytic leukaemia: a clinical model for the role of different blast types and promyelocytes in the development of leukostasis syndrome.
Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors.
]. As our third approach, the leukapheresis and non-leukapheresis groups in each subcohort were compared with reveal the effectiveness depending on accompanying symptoms.
Leukapheresis
Procedures were performed using the COBE SPECTRA (Terumo BCT, Lakewood, CO, USA) continuous-flow blood cell separator. Acid citrate dextrose was added for anticoagulation at a citrate to blood ratio of 1:13. All procedures were continued until about 1.5∼2.0-fold total blood volume had been processed [
]. First procedures from each patient were analyzed for the study. Each first procedure lasted a median (range) of 165 (150–215) minutes, and the median volume (range) of products collected was approximately 725 (491–834) mL, with a coefficient of variation of 9.3% (see supplementary Figure 1).
Thirty-day survival rates
We tried to verify an association between leukapheresis and early mortality. Thus, data on day 30 from the date of first leukapheresis procedure were collected.
Follow-up for DS
We assumed a preventive effect of leukapheresis against DS after ATRA treatment. Therefore, data during the early admission period before induction chemotherapy were collected. Of those, only data for patients whose first leukapheresis procedure preceded DS diagnosis were included. Signs and symptoms used to diagnose DS are listed in Table 1 [
Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors.
Follow-up for intensive care and severe hemorrhage
We tried to examine adverse events potentially caused by leukapheresis. The number of patients with subsequent intensive care with a mechanical ventilator or continuous renal-replacement therapy or following severe hemorrhage (defined as any degree of bleeding occurred in any of three specific sites that could lead to fatal and massive hemorrhage; central nervous system or pulmonary or gastrointestinal tract) was the parameter of exacerbation. Thus, data during the 30 days from the date of the first leukapheresis procedure were collected.
Statistical methods
Categorical variables were presented as frequency and were compared using the χ2 test among the groups. If more than 20% of cells had less than the expected frequency of 5, the Fisher exact test was alternatively used for analysis.
Continuous variables were presented as median (range) and were compared using the Student's t-test or Mann–Whitney U test. Thirty-day survival rates and DS cumulative incidences were analyzed using the Kaplan–Meier method and the log-rank test.
The level of statistical significance was set at a P value of 0.05. Data were analyzed using the statistical programs SPSS 24 (IBM Corp., Armonk, NY, USA) and GraphPad Prism 9 (GraphPad Software, San Diego, CA, USA).
Results
Biological and clinical characteristics
All results are based on univariate analysis. Of the 85 patients enrolled in the whole cohort, the leukapheresis (n = 39) and non-leukapheresis (n = 46) groups did not significantly differ in age, sex, body weight, and complete blood count, especially WBC count (Table 2). Complete blood counts were measured just before the first leukapheresis procedure in the leukapheresis group and reached the maximum value during an ongoing upward trend in the non-leukapheresis group.
Table 2Baseline characteristics of the APL with hyperleukocytosis (≥40 × 109/L) whole cohort.
Patients who had at least one symptom outnumbered the subjects without symptoms in each group, but there was no significant difference between the two groups (P = 0.33). Most patients experienced DIC at the initial period or during ATRA treatment, but there was no significant difference between the two groups (P = 0.66). Patients who took concurrent cytoreductive low-dose hydroxyurea, which could possibly act as a confounding bias, outnumbered subjects who did not receive hydroxyurea in each group, and there was no significant difference between the two groups (P = 0.34). Some patients in each group could not start induction chemotherapy due to their sustained or aggravated poor conditions, but the number of those patients was not significantly different between the two groups (P = 0.41). The comparison data between the two groups only in these patients are summarized in supplementary Table 1.
Parameter data of the entire cohort divided into subcohorts are described in Table 3. Most parameters were not significantly different from each other, except for age in the “symptomatic HL” subcohort and sex in the “asymptomatic HL” subcohort (P = 0.03 and 0.02, respectively).
Table 3Baseline characteristics of the APL with hyperleukocytosis (≥40 × 109/L) subcohorts.
Initial HL subcohort (n = 48)
Sequential HL subcohort (n = 37)
Leukapheresis (n = 26)
Non-leukapheresis (n = 22)
Leukapheresis (n = 13)
Non-leukapheresis (n = 24)
A. The subcohort according to the origin of hyperleukocytosis
In the entire cohort, the WBC fluctuation due to serial leukapheresis or rebound phenomenon is displayed in Figure 2A,B. In the leukapheresis group, 12 patients underwent only one procedure, and three patients received more than seven procedures. The 30-day survival rates (95% confidence interval [95% CI]) of the leukapheresis and non-leukapheresis groups were 76.9% (95% CI, 63.7%–90.1%) and 67.4% (95% CI, 53.8%–80.9%), respectively (Figure 2C).
Fig. 2Changes in leukocyte count and 30-day survival curve for the whole hyperleukocytosis (HL) cohort. (A) Changes in leukocyte count in the leukapheresis group for the whole HL cohort. Each line means leukocyte count fluctuation in one patient. Especially in cases of "sequential HL," the lines start at the time of initial laboratory tests. Three cases exceeding seven procedures are omitted. Each error bar represents the range from the 25th to 75th percentiles of each group. (B) Changes in leukocyte count in the non-leukapheresis group for the whole HL cohort. Likewise, in cases of "sequential HL," the lines start at the time of initial laboratory tests. (C) 30-day survival curve in the leukapheresis and non-leukapheresis groups for the whole HL cohort.
For the subcohorts of “initial HL” or “sequential HL,” the WBC fluctuation is displayed in Figure 3A,B,D,E. In the “initial HL” subcohort, the 30-day survival rate was 69.2% (95% CI, 51.5%–87.0%) for leukapheresis and 77.3% (95% CI, 59.8%–94.8%) for non-leukapheresis (Figure 3C). In the “sequential HL” subcohort, there was a significant difference among the two groups (P = 0.03), with 30-day survival rates of 92.3% (95% CI, 77.8%–100.0%) and 58.3% (95% CI, 38.6%–78.1%), respectively (Figure 3F).
Fig. 3Changes in leukocyte count and 30-day survival curve for subcohorts of “initial hyperleukocytosis (HL)” or “sequential HL.” (A) Changes in leukocyte count in the leukapheresis group for the “initial HL" subcohort. Each line means leukocyte count fluctuation in one patient. Three cases exceeding seven procedures are omitted. Each error bar represents the range from the 25th to 75th percentiles of each group. (B) Changes in leukocyte count in the non-leukapheresis group for the “initial HL" subcohort. (C) 30-day survival curve in the leukapheresis and non-leukapheresis groups for the “initial HL" subcohort. (D) Changes in leukocyte count in the leukapheresis group for the “sequential HL" subcohort. (E) Changes in leukocyte count in the non-leukapheresis group for the “sequential HL" subcohort. (F) 30-day survival curve in the leukapheresis and non-leukapheresis groups for the “sequential HL" subcohort.
For the subcohorts of “symptomatic HL” or “asymptomatic HL,” the WBC fluctuation is displayed in Figure 4A,B,D,E. In the “symptomatic HL” subcohort, there was a significant difference among the two groups (P = 0.03), with 30-day survival rate of 76.7% (95% CI, 61.5%–91.8%) for leukapheresis and 54.8% (95% CI, 37.3%–72.4%) for non-leukapheresis (Figure 4C). In the “asymptomatic HL” subcohort, the 30-day survival rates of the two groups were 88.9% (95% CI, 68.4%–100.0%) and 93.3% (95% CI, 80.7%–100.0%), respectively (Figure 4F).
Fig. 4Changes in leukocyte count and 30-day survival curve for subcohorts of “symptomatic hyperleukocytosis (HL)” or “asymptomatic HL.” (A) Changes in leukocyte count in the leukapheresis group for the “symptomatic HL" subcohort. Each line means leukocyte count fluctuation in one patient. Especially in cases of "sequential HL," the lines start at the time of initial laboratory tests. Three cases exceeding seven procedures are omitted. Each error bar represents the range from the 25th to 75th percentiles of each group. (B) Changes in leukocyte count in the non-leukapheresis group for the “symptomatic HL" subcohort. Likewise, in cases of "sequential HL," the lines start at the time of initial laboratory tests. (C) 30-day survival curve in the leukapheresis and non-leukapheresis groups for the “symptomatic HL" subcohort. (D) Changes in leukocyte count in the leukapheresis group for the “asymptomatic HL" subcohort. (E) Changes in leukocyte count in the non-leukapheresis group for the “asymptomatic HL" subcohort. (F) 30-day survival curve in the leukapheresis and non-leukapheresis groups for the “asymptomatic HL" subcohort.
Five patients were excluded because their onset of DS preceded the first leukapheresis procedure, and the preventive effect of leukapheresis against DS could not be analyzed. Among the total of 80 patients, the number of patients diagnosed with DS was four in the leukapheresis group (n = 34) and 12 in the non-leukapheresis group (n = 46) (hazard ratio [HR] = 0.42; 95% CI, 0.15–1.14), P = 0.09] (Figure 5A).
Fig. 5Cumulative incidence of differentiation syndrome (DS). (A) Cumulative incidence of DS in the leukapheresis and non-leukapheresis groups for the whole hyperleukocytosis (HL) cohort. Early death patients are censored. (B) Cumulative incidence of DS in the leukapheresis and non-leukapheresis groups for the “initial HL" subcohort. (C) Cumulative incidence of DS in the leukapheresis and non-leukapheresis groups for the “sequential HL" subcohort.
Among 45 patients of the “initial HL” subcohort, the number of patients diagnosed with DS was four in the leukapheresis group (n = 23) and four in the non-leukapheresis group (n = 22) (HR = 0.93; 95% CI, 0.23–3.78), P = 0.92] (Figure 5B). In contrast, among 35 patients of the “sequential HL” subcohort, there was no patients diagnosed with DS in the leukapheresis group (n = 11) compared with eight patients in the non-leukapheresis group (n = 24) (HR = 0.18; 95% CI, 0.04–0.74), P = 0.02] (Figure 5C).
Follow-up for intensive care and severe hemorrhage
Among a total of 85 patients (Table 4A), 12 patients of the leukapheresis group (n = 39) and 20 patients of the non-leukapheresis group (n = 46) needed intensive care using a mechanical ventilator or continuous renal-replacement therapy. The difference was not significant (P = 0.23). The numbers of patients who experienced at least one severe hemorrhage event were 10 and 19 in the leukapheresis and non-leukapheresis groups, respectively (P = 0.13).
Table 4Comparisons of clinical parameters that represent general condition after leukapheresis.
Among 48 patients of the “initial HL” subcohort (Table 4B), 11 in the leukapheresis group (n = 26) and seven in the non-leukapheresis group (n = 22) required intensive care (P = 0.45), and nine patients in each group had at least one severe hemorrhage event (P = 0.65). In contrast, among 37 patients of the “sequential HL” subcohort (Table 4B), only 1 patient in the leukapheresis group required intensive care (n = 13) compared with 13 patients in the non-leukapheresis group (n = 24) (P < 0.01), and only 1 patient in the leukapheresis group had a severe hemorrhage event compared with 10 patients in the non-leukapheresis group (P = 0.03).
Among 61 patients of the “symptomatic” subcohort (Table 4C), 10 in the leukapheresis group (n = 30) and 17 in the non-leukapheresis group (n = 31) required intensive care (P = 0.09), and 10 and 17 respective patients had at least one severe hemorrhage event (P = 0.09). On the other hand, among 24 patients of the “asymptomatic” subcohort (Table 4C), 2 in the leukapheresis group (n = 9) and 3 in the non-leukapheresis group (n = 15) required intensive care (P = 0.90). No patient in the leukapheresis group experienced at least one severe hemorrhage event compared with two patients in the non-leukapheresis group, although the difference was not significant (P = 0.25).
Discussion
Theoretically, therapeutic leukapheresis can be beneficial against HL in acute leukemia patients for two reasons. First, by reducing peripheral leukemic cell mass, mechanical obstruction due to those masses causing leukostatic symptoms can temporarily be relieved [
]. Second, as leukapheresis induces most leukemic cells to enter S-phase especially in acute myeloid leukemia, concomitant chemotherapy targeting the S-phase can be more effective [
In APL, although the effects in this disease entity have not been well-defined, therapeutic leukapheresis could be an ideal option due to the more detrimental characteristic of circulating promyelocytes. Pathologically, APL cells could induce coagulopathy through either thrombosis due to elevated tissue factor [
]. Thus, to minimize these complications, timely removal of APL cell seems reasonable and necessary.
However, there has been hesitancy to perform therapeutic leukapheresis against HL in APL due to concerns of further coagulopathy. This trend is based on a study published in 1994 [
Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PMN/RAR-alpha isoform, and CD13 expression in patients treated with all-trans retinoic acid.
]. This previous article opposed therapeutic leukapheresis in APL based on early death events in a small cohort (three events in total eight patients who underwent leukapheresis) without a control group. Their conclusion, combined with further scarcity of hyperleukocytosis in APL and the hindrance of performing a randomized controlled trial around the world, became a norm and still has been referred to in some expert-panel recommendations and guidelines [
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. 2019;34(3):171-354.
]. Of course, coagulopathy frequently was observed among patients with APL, and leukapheresis could be regarded as an invasive procedure, but we carefully considered whether patient safety has been overwhelmingly emphasized compared to the potential benefits from leukapheresis.
Our institution has experienced many cases of hematologic malignancy; therefore, we gathered valuable data from newly diagnosed patients with APL who underwent therapeutic leukapheresis during their pre-induction chemotherapy period. In addition, as data from newly diagnosed APL patients who did not undergo leukapheresis also had accumulated, a control study was feasible and designed to reveal the influence of leukapheresis in APL.
As mentioned in “Methods,” a WBC count greater than 40 × 109/L was set as the cut-off value for HL in this study. Among patients whose leukocyte count in the early admission period was greater than this cut-off, 39 who underwent at least one leukapheresis procedure and 46 who never underwent the procedure showed no significant difference at the starting point (Table 2).
We chose 30-day survival rate as the most reliable short-term outcome. For the entire cohort, although a greater survival rate was observed for the leukapheresis group compared with the non-leukapheresis group, a statistically significant difference was not observed (Figure 2C). When we divided the whole cohort into two subcohorts of “initial HL” or “sequential HL,” only 1 among 13 “sequential HL” patients in the leukapheresis group died, with statistical significance (Figure 3F). Moreover, the cumulative incidence of DS (Figure 5C) and following adverse events including intensive care or severe hemorrhage (Table 4B) was significantly lower in the leukapheresis group than the non-leukapheresis group among “sequential HL” patients. APL cells treated with ATRA secrete interleukin-1b and granulocyte colony-stimulating factor, causing HL in vivo [
], and have a tendency to aggregate via adhesive properties mediated by leukocyte function-associated antigen-1 and intercellular adhesion molecule-2 molecules [
Progressive hyperleukocytosis is a relevant predictive marker for differentiation syndrome, early death, and subsequent relapse in acute promyelocytic leukemia.
]. Some additional results in concept of more subdivided pools from “sequential HL” (e.g., FLT3 mutation-positive patients in “sequential HL,” female patients in “sequential HL”) are mentioned in supplementary Figure 2 and supplementary Figure 3, although the numbers of patients in the both groups were too small to be analyzed.
In contrast, when we divided the whole cohort into two subcohorts of “symptomatic HL” or “asymptomatic HL,” in “symptomatic HL,” a significant difference in 30-day survival rate was observed between the leukapheresis and non-leukapheresis groups (Figure 4C). Any symptoms that could potentially be derived from either leukostasis or pre-DS condition are indicative of an exacerbated condition in which proper intervention should be initiated. Currently, in cases of symptomatic HL in other acute leukemias, therapeutic leukapheresis is accepted as a second-line therapy (Category II recommendation; disorders for which apheresis is accepted as second-line therapy, either as a standalone treatment or in conjunction with other modes of treatment) in the American Society for Apheresis guidelines [
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. 2019;34(3):171-354.
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. 2019;34(3):171-354.
Interestingly, most of the leukapheresis group within the whole cohort or the subcohorts did not show inferior results in severe hemorrhage than non-leukapheresis group (Table 4A,B,C). Contrary to universal concern, the odds ratio for severe hemorrhage was 0.50, 0.77, 0.12, 0.41 and 0.00 in the whole HL cohort and the “initial HL,” “sequential HL,” “symptomatic HL” and “asymptomatic HL” subcohorts, respectively. Considering the positive correlations between HL and either hemorrhage [
Early hemorrhagic death before starting therapy in acute promyelocytic leukemia: association with high WBC count, late diagnosis and delayed treatment initiation.
] in APL, cytoreductive effects of leukapheresis in APL might help reduce risk of those coagulopathies.
As stated previously, HL from either disease itself or a regimen (ATRA or ATO) effect remains problematic during treatment of patients with APL. As it could be difficult to simply reduce HL, the decisions whether and how to reduce leukemic cell burden could be complicated. If the clinician decides on cytoreduction, we anticipate that therapeutic leukapheresis alone or combined with low-dose hydroxyurea could be administered without severe adverse reaction. Of course, leukapheresis could not be an absolute solution, especially in an extreme HL case, accompanying the trend “the higher WBC, the worse survival rates” we observed even in the leukapheresis group (supplementary Figure 4). However, our results suggest the safe and beneficial effects in most cases, especially according to the origin of HL. In the article by Daver et al. [
], which found a non-significant difference for long-term 3-year overall survival between the leukapheresis group and the non-leukapheresis group in APL, the authors also described that the decision to initiate leukapheresis in APL should be made on a case-by-case-basis. Further studies with a randomized controlled design are necessary to verify the potential benefits of leukapheresis.
Our study has several limitations. First, this study is retrospective, and all clinical data depended entirely on reviews of medical charts. Second, the reason why some patients in the control group did not undergo leukapheresis were unclear because it depended entirely on the clinician's determination. Third, the number of study participants was not sufficient to be split into numerous subcohorts (e.g., initial asymptomatic, sequential asymptomatic). Fourth, symptoms could not be clearly attributed to either leukostasis or pre-DS condition because some features overlapped. Nevertheless, ours is the first comparative study examining the short-term effect of therapeutic leukapheresis in APL and offers information that should be considered in a clinical situation. In the current clinical climate in which such a procedure is unwilling to be challenged, we hope that our study will be of help to clinicians worldwide.
In summary, we compared the influence of therapeutic leukapheresis between leukapheresis and non-leukapheresis groups in an APL cohort and further divided subcohorts. In the entire HL cohort, there was no significant difference in 30-day survival rates between the two groups. However, in cases of “sequential HL” or “symptomatic HL,” the leukapheresis group showed a more favorable outcome than the non-leukapheresis group. Moreover, in cases of “sequential HL,” the leukapheresis group showed a lower cumulative incidence of DS and less following adverse events (e.g., intensive care or severe hemorrhage) than the non-leukapheresis group. Thus, therapeutic leukapheresis was effective, especially in the “sequential HL” or “symptomatic HL” subcohort in APL, without major complication.
Declaration of Competing Interest
The authors have no commercial, proprietary or financial interest in the products or companies described in this article.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.
Author contributions
H.L. and D.W.J. collected the raw data, designed the study, performed the statistical analyses, interpreted the analysed data, and drafted the article. J.Y., B.C., H.K. treated acute promyelocytic leukemia patients with leukapheresis. Y.K. diagnosed acute promyelocytic leukemia.
Acknowledgments
We thank the apheresis unit staff members for their contributions.
Progressive hyperleukocytosis is a relevant predictive marker for differentiation syndrome, early death, and subsequent relapse in acute promyelocytic leukemia.
Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups: Presented in part at the 41st meeting of the American Society of Hematology, New Orleans, LA, December 3-7, 1999.
Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PMN/RAR-alpha isoform, and CD13 expression in patients treated with all-trans retinoic acid.
Grading of symptoms in hyperleukocytic leukaemia: a clinical model for the role of different blast types and promyelocytes in the development of leukostasis syndrome.
Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors.
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. 2019;34(3):171-354.
Early hemorrhagic death before starting therapy in acute promyelocytic leukemia: association with high WBC count, late diagnosis and delayed treatment initiation.
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