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Presence of Promyelocytes in Peripheral Blood As a Novel Predictor of the Optimal Timing for Single-Step Peripheral Blood Stem Cell Collection

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Presence of Promyelocytes in Peripheral Blood As a Novel Predictor of the Optimal Timing for Single-Step Peripheral Blood Stem Cell Collection Journal of Nippon Medical School J-STAGE Advance Publication (March 31, 2020) Original Articles 1.Title page Presence of promyelocytes in peripheral blood as a novel predictor of the optimal timing for single-step peripheral blood stem cell collection Atsushi Marumo1, Hiroki Yamaguchi1, Tsuneaki Hirakawa1, Kazuki Inai1, Daishi Onai1, Ikuko Omori1, Satoshi Yamanaka1, Yusuke Fujiwara1, Masahiro Sakaguchi1, Satoshi Wakita1, Muneo Okamoto1, Shunsuke Yui1, Koiti Inokuchi1 1 Department of Hematology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-Ku, Tokyo 113- 8603, Japan Running Title: Predictor of PBSC collection timing *Correspondence to: Hiroki Yamaguchi MD, PhD Department of Hematology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-Ku, Tokyo 113- 8603, Japan Tel: +81-3-3822-2131, Fax: +81-3-5685-1793, E-mail: [email protected] 1 Journal of Nippon Medical School J-STAGE Advance Publication (March 31, 2020) 2. Abstract and key words Background: Peripheral blood stem cell (PBSC) collection places a burden on the patient and ideally should be completed in a single procedure. Consequently, a convenient predictive factor is needed for clinical use. Methods: This retrospective study included 72 patients who underwent autologous PBSC collection. A median volume of 3.9×106 CD34-positive cells/kg (range: 0.3–47.4×106 cells/kg) was collected on the first day. We defined failure as an inability to collect 2.0×106 cells/kg on the first day. Patients were classified into failure (n = 25, 34.7%) and success groups (n = 47, 65.3%), and their clinical backgrounds were analyzed. Results: The success group included a significantly larger number of cases in which a differential white blood cell count of the peripheral blood on the day of PBSC collection detected promyelocytes (n = 34, 72.3% vs. failure group: n = 11, 44.0%; P＝0.008). Sixty-two patients underwent autologous PBSC transplantation with a median of 5.6×106 transplanted cells/μL (range: 1.60–47.4×106 cells/µL). Among transplanted patients, no significant differences were observed between the success and failure groups in terms of the intervals until neutrophil, platelet, and red blood cell engraftment. Conclusion: The presence of promyelocytes in peripheral blood may be a useful indicator of the 2 Journal of Nippon Medical School J-STAGE Advance Publication (March 31, 2020) optimal timing for single-step PBSC collection. Key Words: peripheral blood stem cell transplantation, malignant lymphoma, multiple myeloma, stem cell collection 3 Journal of Nippon Medical School J-STAGE Advance Publication (March 31, 2020) 3.Main text Introduction Autologous peripheral blood stem cells (PBSCs) are transplanted into patients who have received a maximum dose of anticancer agents, with the aims of amplifying the antitumor effect of treatment and relieving protracted myelosuppression. The efficacy of PBSC transplantation has been confirmed in various malignancies such as multiple myeloma, recurrent malignant lymphoma, recurrent acute promyelocytic leukemia, and related diseases [1-3]. To prepare for transplantation, granulocyte colony-stimulating factor (G-CSF) is administered alone or in combination with chemotherapy to mobilize hematopoietic stem cells into the peripheral blood as PBSCs prior to collection via apheresis. An important PBSC yield is essential, as the collected number was shown to correlate with early post-transplantation engraftment [4]. Generally, PBSC transplantation requires a minimum of 1.0×106 CD34-positive PBSCs/kg, although 2.0×106/kg is preferred. As previous studies reported that 9.5–18.7% of patients are poor mobilizers and cannot produce sufficient PBSCs for collection [5,6], multiple harvesting procedures are often performed to ensure a sufficient yield. However, these expensive procedures impose a burden on patients, who must remain immobilized for 3−5 hours, as well as on nurses, clinical technicians, and medical resources. Ideally, therefore, 4 Journal of Nippon Medical School J-STAGE Advance Publication (March 31, 2020) collection would be completed during a single procedure. Plerixafor has been approved in recent years which made it possible to efficiently harvest peripheral blood stem cells. However, plerixafor is an expensive drug, so there is a need for clinical considerations such as limiting its use in cases where peripheral blood stem cell collection proves to be difficult. The optimal timing of PBSC collection needs to be determined to ensure success. Currently, several institutions use the total number of CD34-positive cells in the peripheral blood as an indicator of the total stem cells that could potentially be collected [7]. However, many institutions do not have in-house facilities able to measure CD34-positive cells in the peripheral blood. Consequently, a more convenient predictive factor is needed for use in clinical settings. In this study, therefore, we conducted a retrospective analysis of patients with hematopoietic malignancies who underwent autologous PBSC collection at our institution. We aimed to identify the factors predictive of the optimal timing for the collection of sufficient PBSCs in a single procedure. Materials and Methods Patient selection This retrospective study included 72 patients with malignant lymphoma, multiple 5 Journal of Nippon Medical School J-STAGE Advance Publication (March 31, 2020) myeloma, or acute promyelocytic leukemia who underwent autologous PBSC collection at Nippon Medical School Hospital from 2006 to 2016. The study was performed in accordance with the Declaration of Helsinki. The study protocol was approved by the appropriate institutional ethics committee (30-09-991). Patients who underwent autologous PBSC transplantation during the treatment of solid tumors were excluded. For all included patients, G-CSF monotherapy or G-CSF subsequent to chemotherapy was used to prepare for autologous PBSC collection. PBSCs were collected once the blood cells had begun to recover, according to the judgment of the attending physician. Cases in which plerixafor was used to mobilize hematopoietic stem cells were also excluded from the study. The white blood cell (WBC) count, differential WBC, platelet count, and lactate dehydrogenase (LDH) concentration in peripheral blood were determined on the day of collection. Subsequently, we assessed the presence of promyelocytes after technicians evaluated the ratio of these cells in the peripheral blood. Three cases in which a manual blood count could not be performed on the day of collection were excluded from testing for the presence of promyelocytes. The COM.TEC blood cell apheresis system (Fresenius Kabi, Bad Homburg, Germany) was used to collect autologous PBSCs from 10-L samples of peripheral blood (500 mL × 20 times). Patients 6 Journal of Nippon Medical School J-STAGE Advance Publication (March 31, 2020) whose initial yield of CD34-positive cells was <2.0×106/kg on the first day were subjected to collection on the second day and, if necessary, the third day. All 62 cases in which sufficient stem cells were collected underwent autologous transplantation. Statistical analysis In this study, we defined cases of success as those with a yield of 2.0×106 cells/kg during a single procedure were defined; all others were defined as failures. Differences in clinical background factors between the success and failure groups were analyzed using the t-test and χ- squared test. The correlation between the number of promyelocytes and the number of CD34 cells was analyzed using Pearson's correlation coefficient. Additionally, the 62 patients who underwent autologous transplantation were divided into success and failure groups, and the numbers of days required for neutrophil engraftment, platelet engraftment, and red blood cell (RBC) engraftment were analyzed using the log-rank test. The dates of neutrophil, platelet, and RBC engraftment were defined as the first of 3 successive days when the neutrophil level exceeded 500/μL, when the platelet level exceeded 20,000/μL without blood transfusion or 50,000/μL with blood transfusion, and when the hemoglobin concentration exceeded 8.0 g/dL without blood transfusion, respectively. The two-sided level of significance was set at a P value 7 Journal of Nippon Medical School J-STAGE Advance Publication (March 31, 2020) <0.05. The statistical analysis was performed using EZR version 1.27 (Saitama Medical Center, Jichi Medical University, Shimotsuke, Japan) [8]. Results Analysis of background factors The subjects had a median age of 56 years (range: 17–70 years) and comprised 42 male and 30 female subjects. Fifty-one patients had malignant lymphoma, while 15, 3, and 3 had multiple myeloma, acute promyelocytic leukemia, and other diseases, respectively. Fifteen patients with malignant lymphoma exhibited bone marrow involvement, and the PBSCs collected from 1 patient were contaminated with malignant lymphoma cells. At the time of PBSC collection, the following outcomes were observed in the lymphoma group: complete response (CR), 27 cases; complete response/unconfirmed (CRu), 3; partial response (PR), 17; stable disease (SD), 2; and progressive disease (PD), 2. In the myeloma group, 2, 6, 5, and 2 cases achieved a CR, very good partial response (VGPR), PR, and SD, respectively. Prior to collection, patients in the lymphoma and myeloma groups had received a median of 9 (range: 2– 21) and 4 (3–7) chemotherapy cycles, respectively. The preparative regimens for PBSC collection differed somewhat between the 8 Journal of Nippon Medical School J-STAGE Advance Publication (March 31, 2020) disease groups. In the lymphoma group, G-CSF was administered in combination with chemotherapy in 49 (96.1%) and alone in 2 cases (3.9%), In the multiple myeloma group, G- CSF was administered in combination with cyclophosphamide (CY) in 13 (72.2%) and alone in 5 cases (27.8%). All 3 cases in the acute promyelocytic leukemia group received G−CSF alone (100.0%; Table 1). The following median values were recorded on the day of PBSC collection: WBC count, 206×102/μL (range: 96–753×102/μL); platelet count, 7×103/μL (1.6–39.0×103/μL); and LDH concentration, 400 IU/L (158–1737 IU/L).
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