|Year : 2022 | Volume
| Issue : 1 | Page : 18-22
Influence of Pretransplant Anemia on Red Blood Cell Transfusions in Myeloma Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation
Merline Augustine1, Mohandoss Murugesan2, Chandran K Nair3, Sangeetha Keloth Nayanar4
1 Department of Transfusion Medicine, Goa Medical College, Bambolim, Goa, India
2 Department of Transfusion Medicine, Malabar Cancer Centre, Thalassery, Kerala, India
3 Department of Clinical Hematology and Medical Oncology, Malabar Cancer Centre, Thalassery, Kerala, India
4 Department of Oncopathology, Malabar Cancer Centre, Thalassery, Kerala, India
|Date of Submission||06-Aug-2021|
|Date of Decision||23-Mar-2022|
|Date of Acceptance||26-Mar-2022|
|Date of Web Publication||29-Apr-2022|
Dr. Mohandoss Murugesan
Department of Transfusion Medicine, Malabar Cancer Centre, Thalassery, Kerala
Source of Support: None, Conflict of Interest: None
Background and Objectives: Anemia during peripheral blood stem cells (PBSCs) transplant is considered a bad prognostic marker. The study aimed to determine whether pretransplant anemia influence peritransplant transfusion requirements in myeloma patients. Methods: Myeloma patients planned for PBSC transplant were stratified based on hemoglobin levels at time of mobilization, PBSC collection, and PBSC infusion. Univariate and multivariate analysis was performed to study the predictors for good mobilization, adequate CD34 yield by apheresis, and red blood cell (RBC) transfusion in the peritransplant period. Results: Of 67 patients, the prevalence of anemia at mobilization, PBSC collection, and PBSC infusion was 37%, 58%, and 70%, respectively. Eighty-five percent had good mobilization with peripheral blood CD34 count of 50 cells/μl (8–123) and 81% had adequate CD34 yield with first apheresis. Thirty-two percent patients received peritransplant RBC transfusion with the median of one unit (range: 0–5). Anemia on the day of infusion did influence the RBC transfusions in the peritransplant period (P = 0.03). Conclusion: One third of myeloma patients require RBC transfusion support in the peritransplant period. We identified pretransplant anemia neither influenced mobilization nor PBSC collection but increased the risk for RBC transfusion in the peritransplant period.
Keywords: Anemia, myeloma, peripheral blood stem cell transplant, red blood cell transfusion
|How to cite this article:|
Augustine M, Murugesan M, Nair CK, Nayanar SK. Influence of Pretransplant Anemia on Red Blood Cell Transfusions in Myeloma Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation. Glob J Transfus Med 2022;7:18-22
|How to cite this URL:|
Augustine M, Murugesan M, Nair CK, Nayanar SK. Influence of Pretransplant Anemia on Red Blood Cell Transfusions in Myeloma Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation. Glob J Transfus Med [serial online] 2022 [cited 2023 Mar 30];7:18-22. Available from: https://www.gjtmonline.com/text.asp?2022/7/1/18/344339
| Introduction|| |
Anemia is a common presentation in patients with malignancies planned for peripheral blood stem cells (PBSCs) transplantation and blood transfusion forms an essential support during the transplantation. Mobilization in iron depleted marrow stimulates erythropoietin and thereby resulting in more erythroid series than granulocytic series, which in turn leads to lesser PBSC collection in allogenic donors. Similarly, the collection of increased vascular progenitor cells is seen in patients with higher hemoglobin (Hb) levels on day of PBSC apheresis. Pretransplant anemia may reflect unfavorable hematopoietic micro-environment, resulting in increased red blood cell (RBC) transfusion requirements during the transplant period.
Transfusion has an immunomodulatory effect and RBC transfusion is associated with increased morbidity and longer hospital stays in the intensive care setting.,
Aims and objectives
The main objective of the study was to estimate RBC transfusion requirements in myeloma patients during autologous PBSC transplantation. The secondary objectives were to determine whether pretransplant anemia influence RBC transfusion during the peritransplant period. We also aimed to the study the association between pretransplant anemia on PBSC mobilization and PBSC collection.
| Methodology|| |
Study design and Ethical clearance
The study included all myeloma patients who underwent PBSC collection in the center from January 2014 to June 2020. Institutional Review Board (IRB) approved this retrospective study without ethical consideration through Ref. No: 1616/1RB-SRC/13/MCC/13-06-2020/1 dated: June 24, 2020. Myeloma patients were placed into CRAB criteria at diagnosis. The demographic and clinical details of patients were retrieved from record of case papers available in the medical records department and abstracted in a data collection sheet.
All patients uniformly received granulocyte-colony-stimulating factor (G-CSF) 300 μg subcutaneous twice daily for five consecutive days. From 2014 to 2017, peripheral blood (PB) CD34 count was not practiced before apheresis collection. For these patients, if the CD34 product yield found inadequate with first apheresis, patients received an additional dose of G-CSF and/or plerixafor 0.24 mg/kg in single dose approximately 11 h before next apheresis. From 2018, all patients underwent PB CD34 count on the 5th day of G-CSF administration in Beckman coulter FC500 flow-cytometer using Stem kit reagent. The mobilization failure was defined as PB CD34 cell count <20 cells/μl, and these patients were offered an additional dose of G-CSF and/or plerixafor 0.24 mg/kg single dose approximately 11 h before initiation of apheresis.
PBSC collection was performed using Spectra Optia, Terumo BCT, Version 11 (MNC and CMNC collection protocol) or MCS+®, Haemonetics (PBSC A.2-EN-000331 protocol) apheresis equipment. Total blood volume (BV) processed was fixed at two BVs for patients without PB CD34 counts and patients with adequate mobilization. In patients with borderline PB CD34 counts, the target apheresis was increased to 2.5–3 BV. Post collection CD34 enumeration was performed similar to PB CD34 enumeration protocol. Adequate CD34 cell yield was defined as CD34 dose ≥2 × 106 cells/kg body weight of the recipient. Collected product was stored at 4°C in the refrigerator and was infused the subsequent day. If the CD34 dose was found to be <2 × 106/kg, subsequent apheresis procedures were performed. If the cumulative yield of CD34 <2 × 106/kg despite repeated apheresis procedure, the products were cryopreserved and procedure was planned at a later stage.
Conditioning and infusion
All patients who had an adequate cumulative CD34 dose were conditioned with Melphalan 200 mg/m2 and the dose was advised as per transplant physician's discretion. Stem cells were infused intravenously on the next day. RBC and platelet transfusion support were given whenever required. Neutrophil engraftment day was defined as first of the three consecutive days with sustained absolute neutrophil count ≥500/μl and platelet engraftment day was defined as first of the three consecutive days with sustained platelet count ≥20 × 109 without a transfusion for at least 7 days.
Peritransplant red blood cell transfusions
The median Hb was determined by determining daily Hb levels from transplant till the day of discharge. The RBC transfusion requirement during the peritransplant period counted from day 1 to day 30 was noted.
The operational definition for pretransplant anemia was Hb <12 g/dL. To understand the association of anemia, patients were stratified based on hemoglobin (Hb) levels at time of mobilization, PBSC collection and PBSC transplant into low (Hb <10 g/dL), intermediate (Hb 10–12 g/dL) and normal (Hb >12 g/dL). The categorical variables were expressed as frequency (percentage) and continuous variables expressed as median (range). Paired-t test was performed to assess the degree of pretransplant anemia by comparing mean differences in Hb during mobilization, PBSC collection, and PBSC infusion. To determine whether pretransplant anemia influence RBC transfusion during peritransplant period, the Hb on the day of transplant was analyzed against RBC transfusions using the Chi-square test. Univariate and multivariate analysis (predictors with P < 0.2 in univariate) was performed to determine the influence of clinical factors on PB CD34 count mobilization. The analysis was performed in IBM SPSS statistics for Windows, version 20.0. Armonk, NY; with P < 0.05 was considered significant.
| Results|| |
A total of 67 participants were included in the study (n = 67).The patient demographic details are displayed in [Table 1]. Median age was 51 (33–63) years and 61% were males. All cases were multiple myeloma except one which was diagnosed as solitary plasmacytoma. Thirty-nine (59%) patients presented with anemia at diagnosis as per CRAB criteria (Hb <10 g/dL) and majority were normocytic anemia (84%). Lenalidomide chemotherapy was administered in 39 (58%) patients.
|Table 1: Clinical and demographic details of myeloma patients undergoing autologous peripheral blood stem cell transplantation|
Click here to view
Distribution of blood counts
The prevalence of anemia before mobilization, PBSC collection, and PBSC infusion was 37%, 58%, and 70%, respectively. [Figure 1] shows the mean differences in Hb between mobilization and collection was 0.45 g/dL (P < 0.01) and between PBSC collection and infusion was 0.57 g/dL (P < 0.01). Similarly, the platelet count before collection (182 ± 71 × 109/μl) and during transplant (118 ± 47 × 109/μl) showed a significant reduction from the mobilization counts (223 ± 72 × 109/μl) (P < 0.01) may be attributed to thrombocytopenic effect of granulocyte-colony-stimulating factor (G-CSF). There was a seven fold increase in white blood cell (WBC) count from mobilization (6523 ± 2068/μl) to collection (41,759 ± 13,382/μl).
|Figure 1: Distribution of pretransplant anemia in myeloma during autologous peripheral blood stem cell transplantation|
Click here to view
Mobilization and peripheral blood stem cell collection
Fifty-seven patients were mobilized with G-CSF only, while ten were mobilized with plerixafor in addition to G-CSF either during first or subsequent apheresis collection. Out of 57 patients mobilized, two patients received G-CSF for 6 days before the first collection. Only 44 patients had PB CD34 count available. Four patients received plerixafor along with G-CSF during the first collection and they were excluded for analyzing the extent of mobilization with anemia. The median PB CD34 count for these patients with G-CSF mobilization was 50 cells/μl (8–123). Among them, 34 (85%) had adequate PB CD34 count. And remaining six patients had to be mobilized with plerixafor for an additional day to attain an adequate PB CD34 count. CD34 yield was adequate in 54 (81%) patients following first apheresis collection with median cells harvested was 3.4 × 106/kg (0.4–13 × 106/kg). Repeat collection was performed in 13 (19%) patients of whom only one patient required three apheresis collections. The overall median cumulative CD34 yield obtained was 4.0 × 106/kg (0.8–13 × 106/kg). In four patients, stems cells harvested were cryopreserved and transplant was not performed.
Red blood cell transfusions in peritransplant period
Out of 63 patients who underwent transplant, RBC transfusion was required in 20 (32%) patients during peritransplant period. Majority (65%) received single unit RBC transfusion (range 0–5 units). Only one patient required five events of RBC transfusions in the peritransplant period. The median Hb levels was significantly lower among patients transfused with respect to Hb levels at time of mobilization (P = 0.004), PBSC collection (P = 0.001) and PBSC transplant (P = 0.004) [Table 2]. When patients stratified based on Hb levels at the time of transplant, there was significant differences in RBC transfusions between the groups (P = 0.03) [Table 3].
|Table 2: Relationship between hemoglobin levels at stages of transplant and red blood cell transfusion in peritranplant period|
Click here to view
|Table 3: Relationship between hemoglobin levels at time of peripheral blood stem cells transplant and red blood cell transfusion|
Click here to view
Predictors for mobilization and peripheral blood stem cell collection
In univariate analysis, only mobilization regimen significantly associated with PB CD34 counts (P = 0.049). Multivariate analysis was performed with factors (where P < 0.2 in univariate) such as sex, chemotherapy regimen, number of cycles of chemotherapy, and mobilization regimen to predict PB CD34 count mobilization. However, no clinical factors significantly predicted CD34 cells mobilization in the regression model. Only PB CD34 count significantly influenced adequate CD34 yield with first apheresis collection (P = 0.049).
[Table 4] displays the clinical outcomes between the transfused and nontransfused groups. The WBC and platelet engraftment were similar among the transfused and nontransfused group. Similarly, there was no difference in hospital stay during the peritransplant period among the transfused and nontransfused groups (P = 0.73). The median Hb levels during the hospital stay were significantly lower in transfused group (P = 0.04). However, there was no difference in discharge Hb levels between the transfused and nontransfused groups (P = 0.99). There was one patient with transplant-associated mortality (1.5%). 14 (23%) patients were shown to have progression following transplant.
|Table 4: Influence of red blood cell transfusion during peritransplant period on clinical outcomes|
Click here to view
| Discussion|| |
This study observed pretransplant anemia influenced peritransplant RBC transfusion requirements in myeloma patients undergoing PBSC transplantation. There was a significant drop in Hb levels during mobilization, collection and during the transplant shown in [Figure 1]. The fall in Hb following G-CSF mobilization was explained in the murine model which hypothesized that there exists a competition between granulopoietic and erythropoietic lineages for differentiating stem cells. With G-CSF administration, there is the stimulation of granulopoeisis and relative depletion of stem cell pool, thereby a comparative reduction in erythroid progenitors. Reduction in Hb levels following PBSC collection may be attributed to apheresis and conditioning chemotherapy given to the patients. Furthermore, reduction in platelet count before collection may be partly due to thrombocytopenic effect of G-CSF administration and possibly due to apheresis during the transplant period.
It was observed that in healthy allogenic donors with iron depleted marrow, G-CSF mobilization could worsen anemia and affect mobilization of PBSC. They hypothesized that in anemic donors, there is more differentiation toward erythroid progenitor cells than hematopoietic stem cells, which may affect the PB CD34 mobilization. In multivariate analysis, only mobilization regimen predicted mobilization of PB CD34 count. This difference in response to G-CSF in the healthy donors as in case of allogenic transplant and the patients in autologous PBSC transplant can be explained by exposure of patient marrow to different chemotherapy agents.
Studies have shown in the past that biologic nature of disease and long exposure to prior alkylating agents can have an adverse effect on adequate mobilization of stem cells., In the study group, neither chemotherapy regimen nor number of chemotherapy cycles influenced mobilization of stem cells. In the present study, 85% mobilized with G-CSF achieved adequate CD34 mobilization in PB and 81% patients attained adequate target dose 2 × 106 cells/kg in the first collection. Only 19% study patient's required repeat collection and need for plerixafor therapy. The overall median cumulative CD34 yield obtained among the patients was 4.0 × 106/kg. DiPersio et al. with a target yield of 6 × 106 cells/kg observed that around half of the myeloma patients treated with plerixafor and G-CSF reached target CD34 yield after one apheresis, whereas only G-CSF group required four apheresis collections to reach the target yield. The use of plerixafor eliminated the need for additional apheresis collections, thereby reducing procedure cost and improving quality of life.
In the previous study by Duggan et al., low Hb did not correlate with CD34 cell collection by univariate analysis. Similarly, Ray et al. also observed that, Hb levels did not influence stem cell yield during large volume leukapheresis in myeloma patients with Cox-regression analysis (P = 0.84). The present study also observed that Hb levels did not affect CD34 collection yield by apheresis. Only PB CD34 count significantly influenced adequate CD34 yield with first apheresis collection (P = 0.049).
Kasbia et al. observed that pretransplant reduction in Hb levels may reflect an impaired ability of the damaged marrow for erythropoeitic engraftments and hence can predict future RBC transfusion requirements in PBSC transplant. Kumar et al. observed that Hb <10 g/dL is a predictor of inferior PFS among myeloma patients with PBSC transplant. In the present study, 32% patients received RBC transfusions. Peritransplant RBC transfusion requirements were influenced by degree of anemia, as shown in [Table 2]. However, RBC transfusions during peritransplant period did not out affect clinical outcomes such as WBC/platelet engraftment and length of stay during transplant. As both autologous patients and allogenic donors are associated with a relative erythropoietin deficiency, it could be hypothesized that anemia worsens during the transplant process, thereby increasing the risk of RBC transfusion in peritransplant period. The study has several limitations in general as it was retrospective.
To conclude, the prevalence of RBC transfusion was 32% in the peritransplant period in myeloma patients. We identified pretransplant anemia neither influenced mobilization nor PBSC collection but increased the risk for RBC transfusion in the peritransplant period.
The authors acknowledge Dr. Soumya Das for reviewing the manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kindwall-Keller TL, Ballen KK. Is anemia a harbinger of poorer outcomes after allogeneic hematopoietic cell transplant? Bone Marrow Transplant 2020;55:275-7.
Kasbia G, Al-Gahtani F, Tay J, Labonté L, Tinmouth A, Ramsay T, et al.
Reduced hemoglobin on day of peripheral blood progenitor cell collection is associated with low graft content of vascular progenitors and increased toxicity after autologous hematopoietic stem cell transplantation. Transfusion 2008;48:2421-8.
Hosoba S, Waller EK, Shenvi N, Graiser M, Easley KA, Al-Kadhimi Z, et al.
Peritransplantation red blood cell transfusion is associated with increased risk of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2018;24:973-82.
Youssef LA, Spitalnik SL. Transfusion-related immunomodulation: A reappraisal. Curr Opin Hematol 2017;24:551-7.
Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009;23:3-9.
Goker H, Ciftciler R, Demiroglu H, Turgut M, Sayınalp N, Haznedaroglu IC, et al.
Predictive factors for stem cell mobilization failure in multiple myeloma patients: A single center experience. Transfus Apher Sci 2020;59:102595.
Kulkarni U, Devasia AJ, Korula A, Fouzia N, Nisham P, Samoon YJ, et al.
Clinical outcomes in multiple myeloma post-autologous transplantation – A single centre experience. Indian J Hematol Blood Transfus 2019;35:215-22.
Bungart B, Loeffler M, Goris H, Dontje B, Diehl V, Nijhof W. Differential effects of recombinant human colony stimulating factor (rh G-CSF) on stem cells in marrow, spleen and peripheral blood in mice. Br J Haematol 1990;76:174-9.
Papaldo P, Ferretti G, Di Cosimo S, Giannarelli D, Marolla P, Lopez M, et al.
Does granulocyte colony-stimulating factor worsen anemia in early breast cancer patients treated with epirubicin and cyclophosphamide? J Clin Oncol 2006;24:3048-55.
Schlenke P, Frohn C, Steinhardt MM, Kirchner H, Klüter H. Clinically relevant hypokalaemia, hypocalcaemia, and loss of hemoglobin and platelets during stem cell apheresis. J Clin Apher 2000;15:230-5.
Pornprasertsud N, Niparuck P, Kidkarn R, Puavilai T, Sirachainan N, Pakakasama S, et al.
The use of hematocrit level for predicting the efficiency of peripheral blood CD34(+) cell collection after G-CSF Mobilization in Healthy Donors. J Clin Apher 2015;30:329-34.
Tricot G, Jagannath S, Vesole D, Nelson J, Tindle S, Miller L, et al.
Peripheral blood stem cell transplants for multiple myeloma: Identification of favorable variables for rapid engraftment in 225 patients. Blood 1995;85:588-96.
Perea G, Sureda A, Martino R, Altés A, Martínez C, Cabezudo E, et al
. Predictive factors for a successful mobilization of peripheral blood CD34+cells in multiple myeloma. Ann Hematol 2001;80:592-7.
Zubair AC, Grant R, Wu W, Tun H, Rivera C, Moreno-Aspitia A, et al
. Platelet count is a sensitive predictor of autologous peripheral blood progenitor cell collection yield in previously treated plasma cell disease patients. Transfusion 2008;48:1106-14.
DiPersio JF, Stadtmauer EA, Nademanee A, Micallef IN, Stiff PJ, Kaufman JL, et al
. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood 2009;113:5720-6.
Duggan PR, Guo D, Luider J, Auer I, Klassen J, Chaudhry A, et al.
Predictive factors for long-term engraftment of autologous blood stem cells. Bone Marrow Transplant 2000;26:1299-304.
Ray GK, Jena RK, Panda T, Sethy S. Prospective identification of potential factors influencing stem cell mobilization and the necessity for plerixafor use in newly diagnosed multiple myeloma patients undergoing autologous stem cell transplantation. Hematol Transfus Cell Ther 2021;43:402-9.
Kumar L, Ramavath D, Kataria B, Tiwari A, Raj A, Chellapuram S, et al
. High-dose chemotherapy followed by autologous stem cell transplant for multiple myeloma: Predictors of long-term outcome. Indian J Med Res 2019;149:730-9.
] [Full text]
Miller CB, Lazarus HM. Erythropoietin in stem cell transplantation. Bone Marrow Transplant 2001;27:1011-6.
[Table 1], [Table 2], [Table 3], [Table 4]