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ORIGINAL ARTICLE  
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Is neutropenic fever an obstacle to effective stem cell harvesting?


1 Department of Hematology and Bone Marrow Transplantation Center, Ankara Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital, University of Health Sciences, Ankara, Turkey
2 Department of Clinical Biochemistry, Ankara Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital, University of Health Sciences, Ankara, Turkey

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Date of Submission09-Oct-2021
Date of Decision29-Jul-2022
Date of Acceptance07-Aug-2022
Date of Web Publication26-Sep-2022
 

   Abstract 

INTRODUCTION: Autologous stem cell transplantation (ASCT) is a well-established consolidation treatment for many hematologic cancers which delivers prolonged survival. A subset of patients' adequate stem cell harvest is not achievable with a solitary use of granulocyte colony-stimulating agents (G-CSF). Generally, chemomobilization is employed for patients failing G-CSF and its most feared complication febrile neutropenia (FN).
MATERIALS AND METHODS: Here, we aimed to investigate the impact of the FN in chemomobilization on apheresis outcomes and engraftment. One hundred and eighty-three patients with the diagnosis of lymphoma or myeloma who underwent chemomobilization between 2015 and 2020 were included in the study.
RESULTS: Forty-three patients experienced FN. All patients received G-CSF. All myeloma patients were mobilized with 4 g/m2 cyclophosphamide, but it was heterogeneous for lymphoma patients. The precollection blood counts, harvested CD34+ hematopoietic stem cells (HSCs)/kg, apheresis count, and engraftment durations were recorded. Preapheresis leukocyte and platelet were lower in the FN group (P = 0,004 and P = 0,001). Peripheral CD34 HSCs and total harvested CD34 HSCs were similar among groups (P = 0.25 and P = 0.9). More apheresis was needed in the FN group, but it was not significant (P = 0.07). Undergoing ASCT was similar (P = 0.7); however, platelet and neutrophil engraftment durations were slower in the FN group (P = 0.05 and P = 0.001).
CONCLUSION: Harvesting sufficient CD34+ HSCs from patients with FN is still feasible; however, FN treatment should begin promptly, and further apheresis sessions may be required.

Keywords: Autologous stem cell transplantation, chemomobilization, febrile neutropenia, neutropenic fever, stem cell mobilization


How to cite this URL:
Basci S, Bozan E, Yaman S, Ulu BU, Bakırtaş M, Yiğenoğlu TN, Kılınç A, Özcan N, Dal MS, Çakar MK, Altuntaş F. Is neutropenic fever an obstacle to effective stem cell harvesting?. Asian J Transfus Sci [Epub ahead of print] [cited 2022 Dec 4]. Available from: https://www.ajts.org/preprintarticle.asp?id=356862



   Introduction Top


Autologous stem cell transplantation (ASCT) is a well-established consolidation treatment for many hematologic cancers which delivers prolonged survival.[1],[2] The ideal peripheral stem cell mobilization (PBSC) method has not been yet established, and it varies broadly among centers.[3] For ASCT, minimum collected CD34+ hematopoietic stem cells (HSCs/kg) was regarded as 2 × 106 and optimal collected CD34+ HSCs/kg defined as 4 × 106 by previous reports.[4]

The use of granulocyte colony-stimulating agents (G-CSF) alone for PBSC has resulted in decreased risks linked to morbidity, death, and hospitalization. However, for a subset of patients' adequate stem cell harvest is not achievable with a solitary use of G-CSF. Chemomobilization has its own advantages and limitations. It is appropriate to initiate stem cell mobilization after most chemotherapy regimens that are primarily used to treat the underlying disease. Compared with G-CSF alone, the extra advantages of chemomobilization include fewer apheresis processes and yields greater CD34+ HSCs.[5],[6] In addition, particularly in lymphoma, it reduces tumor burden and diminishes the risk of tumor cell contamination in the apheresis product. Indeed, chemomobilization takes place frequently as a part of the induction or salvage treatment cycle for patients with lymphoma, therefore, reducing increased costs and complications involved in using additional mobilization chemotherapy.[6] For multiple myeloma (MM), it is generally used cyclophosphamide for chemomobilization. High-dose cyclophosphamide has an increased risk of adverse events such as febrile neutropenia (FN), prolonged antibiotic therapy, need for transfusions, and prolonged hospitalization with no additional benefit to tumor burden.[7] Another issue regarding chemomobilization is the increased variability among patients to figure out the precise timing of mobilization and it requires close follow-up for blood counts and peripheral CD34+ HSCs counts to determine the commencement of the apheresis process.[5] Chemomobilization is associated with increased stem cell harvest but also with severe toxicities such as FN, which must be weighed against the benefits.[3],[8],[9]

The development of neutropenia is a frequent complication observed in cancer patients. Neutrophils are essential for warranting host defense against infections, particularly for bacterial and fungal agents. The prevalence of infections increases with the severity and duration of neutropenia.[10] Avoidance of FN and prompt intervention with antibiotics and supportive care is crucial since the frequency of severe conditions such as end-organ failure is high, and mortality can be observed up to 11% and in cases of sepsis, mortality may rise to 50%.[11],[12],[13]

Predisposing aspects of FN and its effect on the stem cell harvest and the capacity to undergo ASCT have not been well defined. Here, we aimed to investigate the impact of the FN in chemomobilization on apheresis outcomes and engraftment.


   Materials and Methods Top


Patients

Patients aged 18 years and older with the diagnosis of lymphoma or myeloma who underwent chemomobilization between 2015 and 2020 were included in the study. One hundred and eighty-three patients enrolled in the study, with 43 patients who experienced FN and 140 patients with no FN during chemomobilization. Treatment details before mobilization were recorded. After mobilization, patients were followed up to ASCT and engraftment durations were recorded. Patients who failed second mobilization and patients who had successfully mobilized with a solitary use of G-CSF were excluded from the study.

The study was carried out under the principles outlined in the Helsinki declaration. All patients signed informed consent and local institutional ethical approval was obtained.

Mobilization regimens and stem cell mobilization

Chemomobilization was utilized for myeloma patients failing to mobilize with only G-CSF and for relapsed/refractory lymphoma patients during their salvage treatments.

All patients were admitted and followed up in the in-patient setting from initiation of mobilization regimen to the achievement of stem cell collection. All myeloma patients (n = 38, 100%) were mobilized with 4 g/m2 cyclophosphamide, but it was very heterogeneous for lymphoma patients. Lymphoma patients were mobilized mostly with their induction or salvage treatment regimen. The most prevalent regimens utilized were GDP ± R (n = 63, 43.4%), DHAP ± R (n = 18, 12.4%), and cyclophosphamide (n = 17, 11.7%). Plerixafor was used in a few patients with the on-demand strategy.

After the mobilization, regimen was initiated, patients were followed up to the white blood count nadir and then G-CSF was initiated. All patients received G-CSF, mostly filgrastim or lenograstim, and their biosimilar equivalents were given subcutaneously as a total dose of 10 μg/kg/day for 4–6 days until the apheresis procedure is completed. Leukocyte count was monitored and when it is above 1 × 109/L, flow cytometry peripheral blood CD34+ HSCs count was performed. Leukapheresis was started after confirming flow cytometry peripheral blood CD34+ HSCs count is on target (>20/μL was used as institutional practice). If peripheral CD34+ HSCs count is not on target, G-CSF was carried on, and the leukapheresis was commenced again on the following day. The apheresis procedure was performed mostly by peripheral venous access (61.7%). Leukapheresis was implemented over a continuous flow cell separator (Fresenius Kabi, COM. TEC, Germany). For each leukapheresis, the processed blood volume was two- and three-fold of patients' blood volume.

Neutropenic fever and treatment

Neutropenia was described as an absolute neutrophil count (ANC) <1000/μL (<1.0 × 109/L), severe neutropenia as ANC <500/μL (<0.5 × 109/L), and profound neutropenia as < 100/μL (<0.1 × 109/L). FN is identified by the above-defined neutropenia accompanying a single oral temperature of ≥38.3°C (101°F) or a temperature of ≥38.0°C (100.4°F) continued over 1 h.[14] Cefoperazone/sulbactam or piperacillin/tazobactam was administered initially for patients with FN and no focus on infection. Patients with persistent fever for >3 days were switched to meropenem. For patients with persistent fever for >5 days, amphotericin B was administered additionally as empirical antifungal treatment. Patients with identified infection focus and patients with identified pathogens in cultures were treated accordingly.

Treatment response and autologous stem cell transplantation

All patients had treatment response evaluation before ASCT, patients with progressive disease did not advance to ASCT. Bone marrow biopsy, serum, urinary protein electrophoresis, and immunofixation tests are employed for MM patients, whereas positron emission tomography–computed tomography is employed for lymphoma patients. Upfront ASCT after induction therapy was performed for MM patients. For Hodgkin's lymphoma (HL) patients, ASCT was performed for relapsed/refractory patients with chemosensitive responses to the salvage therapy. For non-HL, it was heterogeneous, for patients with mantle cell lymphoma, primary central nervous system lymphoma, and peripheral T-cell lymphoma (except anaplastic lymphoma kinase-positive) received ASCT as in upfront strategy but other non-HLs such as diffuse large B-cell lymphoma, follicular lymphoma received ASCT in relapsed/refractory setting.

Engraftment durations

The engraftment definition for neutrophils was defined as the 1st day when the ANC was ≥500/μL for 3 consecutive days, and for platelets, it was defined as the 1st day when platelet count was ≥20,000/μL without transfusion for 7 consecutive days.[15]

Statistical analyses

Analyses were processed with IBM SPSS Statistics for Windows (Version 26.0. Armonk, NY, USA) software. Demographical and clinical data were summarized with descriptive statistics. Categorical variables were displayed as a ratio; numerical variables were displayed as median (minimum–maximum). Differences between FN groups for continuous variables were analyzed with Mann–Whitney U and for categorical variables with the Chi-square test. P < 0.05 were considered statistically significant.


   Results Top


Patients

The study included a total of 183 patients with 43 (23.5%) developing FN and 140 (77.5%) having no FN. The median age of the FN group was 53 (19–71) and for the non-FN group, it was 43 (17–72), which was similar between groups (P = 0.1). The distribution of gender and body mass index among groups were comparable (P = 0.8 and P = 0.9). The diagnosis of patients between groups was nonhomogenous with more myeloma patients and fewer HL patients observed in the FN group (P = 0.001). The rate of radiotherapy implementation and premobilization disease status were similar among groups (P = 0.1 and P = 0.5, respectively). Bone marrow infiltration was more frequent in the FN group (P = 0.001). Characteristics of the patients were displayed in [Table 1].
Table 1: Patient characteristics

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Febrile neutropenia group

The median day of hospitalization for the FN group was 19.5 (13–36). Fever occurred on the median 11th day (3–17) after initiation of mobilizing regimen. Pathogen identification was possible in 13 cases and the focus of infection was evident in four cases. The details of the FN group are given in [Table 2].
Table 2: Febrile neutropenia patients' details

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Mobilization and transplant outcomes

Peripheral venous access was used for most procedures (61.7%). The rate of usage for central venous access was similar among groups (P = 0.6). Chemomobilization was applied to all cohorts, but for some patients, there was a need for plerixafor, plerixafor usage among groups was homogenous (P = 0.9). Peripheral CD34+ HSCs/μL count and total harvested CD34+ HSCs/kg were comparable in groups (P = 0.25, P = 0.9). In the FN group, more apheresis procedures were needed to reach adequate stem cell harvest, but it was not statistically significant (P = 0.07).

ASCT was not feasible for some of the cohorts due to various reasons. ASCT treatment frequency was similar between groups (P = 0.7). Both platelet and neutrophil engraftment were slower in the FN group (P = 0.05 and P = 0.001). The details of the mobilization and transplant outcomes are demonstrated in [Table 3].
Table 3: Mobilization details

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   Discussion Top


We have observed peripheral blood CD34+ HSCs/kg and total harvested CD34+ HSCs/kg was comparable among groups. The apheresis count to reach adequate harvest was higher in the FN group; however, this did not reflect statistical significance. Precollection white blood count, hemoglobin, and platelet were lower in the FN group.

Occasionally, stem cell mobilization with G-CSF does not yield sufficient CD34+ HSCs for a group of patients. Although G-CSF alone has advantages such as less toxicity and no requirement of hospitalization. G-CSF with chemotherapy – chemomobilization – has unique aspects. It is demonstrated that chemomobilization yields greater CD34+ HSCs and ensures fewer apheresis procedures.[5],[6] Furthermore, debulking tumor load is feasible with chemomobilization.[6] The risk of prolonged hospitalization, transfusion need, and serious infections such as FN are arising with chemomobilization.[3],[7],[8],[9],[16],[17] The timing of apheresis procedure in solitary use of G-CSF is almost definite and clear, but it is not anywhere near chemomobilization with various protocols and patient-related factors make the operation very indecisive, raising a need for close follow-up.[5]

In earlier studies, poor mobilization was described as the yield of <4 × 106 CD34+ HSCs/kg over 5 apheresis days, or the requirement of >two mobilization cycles to reach the target.[18],[19],[20] There are several unfavorable risk factors for the lessened yield after stem cell mobilization such as advanced age, multiple line chemotherapies, radiotherapy, prolonged lenalidomide therapy, thrombocytopenia, and bone marrow involvement.[4],[16],[21],[22] Poor mobilization is regarded as an adverse factor and poor mobilizers were reported to have reduced survival.[20],[23]

Khouri et al. observed occurrence of FN in chemomobilization was related to reduced CD34+ HSCs harvest and greater need for apheresis processes.[3] Similarly, another study revealed patients who experienced FN in mobilization were associated with lessened stem cell yield with more frequent apheresis needs.[24] Conversely, Topcuoglu and Ozcan observed no effect of FN on total harvested CD34+ and the number of apheresis processes.[25] We found no difference between groups regarding total harvested CD34+ HSCs. The requirement of >1 apheresis process was observed more frequently in the FN group, but it was not statistically significant.

FN occurrence in chemomobilization was suggested as could be related to a lessened chance of advancing to ASCT. However, earlier studies have conflicting results.[3],[25] We observed no effect of FN on advancing to ASCT. Engraftment durations might be affected as patients with FN in chemomobilization are suggested to have poor bone marrow reserve. Although another study revealed no effect of FN on engraftment durations, our findings were contradictory with longer neutrophil and platelet engraftment durations in the FN group.[25] However, in our FN cohort, there were proportionally more myeloma patients and more patients with bone marrow involvement which might be the cause of longer engraftment durations.

Blood counts might be predictive of poor mobilization or FN. As Khouri et al. found that premobilization blood counts revealed lower hemoglobin and platelet counts.[3] Another study reported leukocyte and peripheral CD34+ HSCs count were not affected by FN.[25] We detected significantly lower white blood count and hemoglobin in preapheresis in the FN group compared with the non-FN group, although platelet counts were lower in the FN group, it was not statistically significant.

Jillella et al. observed 14/54 (26%) frequency of FN attack in their research, it was similar in our cohort 43/183 (23.5%).[9] However, in their cohort, there were 32% of solid cancer patients and mobilizing regimens were different from our cohort.

Our study has some limitations. Our cohort was heterogeneous regarding mobilizing regimen and patient and disease characteristics.


   Conclusion Top


Chemomobilization is a common practice for stem cell mobilization, and it has unique pros and cons. FN is the most feared complication of chemomobilization. Harvesting sufficient CD34+ HSCs from patients with FN is still feasible; however, FN treatment should begin promptly, and further apheresis sessions may be required.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Majhail NS, Weisdorf DJ, Defor TE, Miller JS, McGlave PB, Slungaard A. Long-term results of autologous stem cell transplantation for primary refractory or relapsed hodgkin's lymphoma. Biol Blood Marrow Transplant 2006;12:1065-72.  Back to cited text no. 1
    
2.
Schmitz N, Pfistner B, Sextro M, Sieber M, Carella AM, Haenel M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive hodgkin's disease: A randomised trial. Lancet 2002;359:2065-71.  Back to cited text no. 2
    
3.
Khouri J, Rybicki L, Majhail N, Kalaycio M, Copelan E, Pohlman B, et al. Neutropenic fever during peripheral blood progenitor cell mobilization is associated with decreased CD34+ cell collection and increased apheresis collection days. J Clin Apher 2018;33:303-9.  Back to cited text no. 3
    
4.
Giralt S, Costa L, Schriber J, Dipersio J, Maziarz R, McCarty J. Optimizing autologous stem cell mobilization strategies to improve patient outcomes: Consensus guidelines and recommendations. Biol Blood Marrow Transplant 2014;20:295-308.  Back to cited text no. 4
    
5.
Bensinger W, DiPersio JF, McCarty JM. Improving stem cell mobilization strategies: Future directions. Bone Marrow Transplant 2009;43:181-95.  Back to cited text no. 5
    
6.
Lemoli RM. New strategies for stem cell mobilization. Mediterr J Hematol Infect Dis 2012;4:e2012066.  Back to cited text no. 6
    
7.
Fitoussi O, Perreau V, Boiron JM, Bouzigon E, Cony-Makhoul P, Pigneux A. A comparison of toxicity following two different doses of cyclophosphamide for mobilization of peripheral blood progenitor cells in 116 multiple myeloma patients. Bone Marrow Transplant 2001;27:837-42.  Back to cited text no. 7
    
8.
Toor AA, van Burik JA, Weisdorf DJ. Infections during mobilizing chemotherapy and following autologous stem cell transplantation. Bone Marrow Transplant 2001;28:1129-34.  Back to cited text no. 8
    
9.
Jillella AP, Ustun C, Robach E, Sertkaya D, DiPiro C, Kallab AM, et al. Infectious complications in patients receiving mobilization chemotherapy for autologous peripheral blood stem cell collection. J Hematother Stem Cell Res 2003;12:155-60.  Back to cited text no. 9
    
10.
Taplitz RA, Kennedy EB, Bow EJ, Crews J, Gleason C, Hawley DK, et al. Outpatient management of fever and neutropenia in adults treated for malignancy: American society of clinical oncology and infectious diseases society of America clinical practice guideline update. J Clin Oncol 2018;36:1443-53.  Back to cited text no. 10
    
11.
Carmona-Bayonas A, Jiménez-Fonseca P, Virizuela Echaburu J, Antonio M, Font C, Biosca M, et al. Prediction of serious complications in patients with seemingly stable febrile neutropenia: Validation of the clinical index of stable febrile neutropenia in a prospective cohort of patients from the FINITE study. J Clin Oncol 2015;33:465-71.  Back to cited text no. 11
    
12.
Kuderer NM, Dale DC, Crawford J, Cosler LE, Lyman GH. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer 2006;106:2258-66.  Back to cited text no. 12
    
13.
Legrand M, Max A, Peigne V, Mariotte E, Canet E, Debrumetz A. Survival in neutropenic patients with severe sepsis or septic shock. Crit Care Med 2012;40:43-9.  Back to cited text no. 13
    
14.
Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America. Clin Infect Dis 2011;52:427-31.  Back to cited text no. 14
    
15.
Politikos I, Devlin SM, Arcila ME, Barone JC, Maloy MA, Naputo KA, et al. Engraftment kinetics after transplantation of double unit cord blood grafts combined with haplo-identical CD34+cells without antithymocyte globulin. Leukemia 2021;35:850-62.  Back to cited text no. 15
    
16.
Ataca Atilla P, Bakanay Ozturk SM, Demirer T. How to manage poor mobilizers for high dose chemotherapy and autologous stem cell transplantation? Transfus Apher Sci 2017;56:190-8.  Back to cited text no. 16
    
17.
Malik S, Bolwell B, Rybicki L, Copelan O, Duong H, Dean R. Apheresis days required for harvesting CD34+cells predicts hematopoietic recovery and survival following autologous transplantation. Bone Marrow Transplant 2011;46:1519-25.  Back to cited text no. 17
    
18.
Moreb JS, Byrne M, Shugarman I, Zou F, Xiong S, May WS. Poor peripheral blood stem cell mobilization affects long-term outcomes in multiple myeloma patients undergoing autologous stem cell transplantation. J Clin Apher 2018;33:29-37.  Back to cited text no. 18
    
19.
Sevindik OG, Korkmaz S, Altuntas F. Current status of art mobilization in myeloma. Transfus Apher Sci 2017;56:850-3.  Back to cited text no. 19
    
20.
Yiğenoğlu TN, Başcı S, Ulu BU, Bakırtaş M, Kılınç A, Şahin D, et al. Inferior prognosis in poor mobilizing myeloma patients. Transfus Apher Sci 2020;59:102722.  Back to cited text no. 20
    
21.
Goker H, Ciftciler R, Demiroglu H, Turgut M, Sayınalp N, Haznedaroglu IC. Predictive factors for stem cell mobilization failure in multiple myeloma patients: A single center experience. Transfus Apher Sci 2020;59:102595.  Back to cited text no. 21
    
22.
Altuntaş F, Korkmaz S. Hematopoietic progenitor cell mobilization. Transfus Apher Sci 2017;56:787.  Back to cited text no. 22
    
23.
Brioli A, Perrone G, Patriarca F, Pezzi A, Nobile F, Ballerini F. Successful mobilization of PBSCs predicts favorable outcomes in multiple myeloma patients treated with novel agents and autologous transplantation. Bone Marrow Transplant 2015;50:673-8.  Back to cited text no. 23
    
24.
Duong H, Bolwell BJ, Rybicki L, Sweetenham JW, Pohlman B, Dean R, et al. Available from: https://www.sciencedirect.com/science/article/pii/S0006497119619798 https://doi.org/10.1182/blood.V118.21.4053.4053.  Back to cited text no. 24
    
25.
Topcuoglu P, Ozcan M. Neutropenic fever and stem cell mobilization. J Clin Apher 2019;34:517-8.  Back to cited text no. 25
    

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Correspondence Address:
Semih Basci,
Department of Hematology and Bone Marrow Transplantation Center, Ankara Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital, University of Health Sciences, Ankara
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajts.ajts_152_21




 
 
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