Asian Journal of Transfusion Science
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ORIGINAL ARTICLE  
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Influence of blood transfusion during induction chemotherapy on treatment outcomes in acute myeloid leukemia


1 Department of Clinical Hematology and Medical Oncology, Malabar Cancer Centre, Thalassery, Kerala, India
2 Department of Transfusion Medicine, Malabar Cancer Centre, Thalassery, Kerala, India
3 Department of Oncopathology, Malabar Cancer Centre, Thalassery, Kerala, India

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Date of Submission26-Aug-2021
Date of Decision29-Nov-2021
Date of Acceptance11-Dec-2021
Date of Web Publication26-Sep-2022
 

   Abstract 

BACKGROUND: Transfusion is an integral part of supportive care in patients undergoing aggressive chemotherapy for acute myeloid leukemia (AML). As transfusion induces immune modulation, the objective of the study was to assess whether the intensity of red blood cell (RBC) and platelet (PLT) transfusion during induction chemotherapy influences complete remission (CR) and overall survival (OS) in newly diagnosed AML patients.
METHODS: Details of the number of RBC units and PLT events transfused from diagnosis till completion of induction chemotherapy were collected. Patients were stratified as high or low intensity for transfusion based on median RBC units and PLT events transfused per week. The influence of transfusion intensity on CR and OS was estimated using multivariate analysis and log-rank test, respectively.
RESULTS: Among 90 patients analyzed, the median RBC unit required was 1.7 units/week and PLT transfused was 1.5 events/week. Patients requiring transfusion at disease presentation had significantly higher intensity of RBC and PLT transfusions. Only high intensity for RBC transfusion (P = 0.016) appeared among prognostic factors for achieving CR. The OS was not affected in patients requiring high intensity of RBC (P = 0.314) and PLT (P = 0.504) transfusions.
CONCLUSION: Transfusion support was higher in patients with a high disease burden at diagnosis. The lower intensity of RBC transfusion goes along with the response to chemotherapy in terms of CR but not OS.

Keywords: Acute myeloid leukemia, platelet transfusion, red blood cell transfusion, survival, transfusion intensity


How to cite this URL:
Raghavan V, Murugesan M, Nair CK, Nayanar SK. Influence of blood transfusion during induction chemotherapy on treatment outcomes in acute myeloid leukemia. Asian J Transfus Sci [Epub ahead of print] [cited 2022 Dec 4]. Available from: https://www.ajts.org/preprintarticle.asp?id=356854



   Introduction Top


Aggressive chemotherapy has been shown to improve treatment outcomes in acute myeloid leukemia (AML) patients.[1] During induction chemotherapy, care of these patients warrants a prolonged hospital stay because of chemotherapy-induced pancytopenia.[1] Majority of the AML patients present with anemia and thrombocytopenia, and hence, transfusion support is necessary for the management of these patients.[2],[3]

In myelodysplastic syndrome (MDS) patients, survival outcomes are optimal in patients who are transfusion independent as compared to the dependent ones.[4] Transfusion status was shown to have prognostic significance in MDS.[4] Similarly, AML patients who receive an intensive blood transfusion during induction therapy have shown to have a negative treatment outcome.[2] Previous studies have shown that certain immunomodulatory effects induced by transfusion might be a reason for poor survival outcomes in transfusion-dependent patients.[4] Underlying disease severity, relative chemotherapy resistance, and frequent transfusion-induced iron overload and organ dysfunction may also result in an increased red blood cell (RBC) transfusion requirement during induction chemotherapy.[4],[5]

Induction mortality in AML patients in an Indian setting (18%–25%) is relatively higher than in the Western world (10%).[6] With limited literature on blood transfusion in AML, the objective of the study was to estimate the transfusion needs and to assess whether the intensity of transfusion during induction chemotherapy influences treatment outcomes such as complete remission (CR) status and overall survival (OS) in newly diagnosed AML patients of Indian demographics.


   Methods Top


This was a retrospective audit on newly diagnosed patients (aged ≥14 years) with AML who underwent induction chemotherapy between January 2011 and December 2018. The study was undertaken after obtaining permission from an institutional review board from a tertiary care cancer center in South India. The patients were treated by standard induction chemotherapy regimens consisting of cytarabine and anthracycline (7 + 3 regimens). The marrow response status was determined on day 14 and after completion of induction therapy between days 28 and 35. CR was defined as not more than a 5% blast in bone marrow with the restoration of peripheral blood counts.[2] The patient underwent one or two courses of induction chemotherapy depending on day 14 marrow response. The patient age, sex, chemotherapy regimen, baseline blood counts, blast percentage, cytogenetic risk, response to therapy, and inpatient duration were retrieved from medical records.

The number of RBC units and platelet (PLTs) events transfused was noted for each patient from diagnosis till completion of induction chemotherapy.[7] The treating physician would decide the transfusion triggers based on clinical judgment. The transfusion triggers were consistent and RBC transfusion was given when hemoglobin (Hb) level was <7 g/dL. Prophylactic PLT transfusion was given when PLT count <10,000 in asymptomatic patients and PLT count <20,000 in patients with fever, mucocutaneous bleed, etc. Transfusion event was defined as either a single unit of RBC transfusion or one adult dose of PLTs (either five units of random donor PLTs or one unit of apheresis PLTs). Weekly transfusion requirements for RBC units and PLT events were estimated. The RBC and PLT transfusions were dichotomized as low intensity and high intensity (median units transfused per week taken as cutoff) among the patients to estimate the transfusion intensity. The OS was calculated from the date of initial diagnosis to the end of data collection, death, or earliest date of loss to follow-up. Patients with insufficient data on treatment or transfusion records were excluded from the study.

Statistics

Descriptive data were represented in frequency with percentage for categorical variables and median with range for continuous variables. To study the differences between groups, the Chi-square test or Fisher's exact test was used for categorical variables and the Mann–Whitney U test was used in continuous variables. OS was estimated by the Kaplan–Meier survival curves, and differences in survival function based on transfusion intensity were tested using the log-rank test. Multiple logistic regression analysis was performed for CR status. Cox proportional hazard model was used to assess hazard ratios (HR) and 95% confidence intervals (CI) for OS with transfusion holding other clinical factors constant. P = 0.05 was considered statistically significant. Statistical analysis was done using IBM, Statistical Package for the Social Sciences (SPSS), Chicago, IL, USA version 20.0.


   Results Top


A total of 96 patients underwent induction chemotherapy during the study period. Only 90 patients had complete records and were considered for further analysis. Among the group, the median RBC transfused per week was 1.7 (mean 1.8; range 0–6.5) units and the median PLT transfused per week was 1.5 (mean 1.8; range 0–10.1) events. For determining transfusion intensity, the median units transfused were rounded and the groups were classified as low RBC (<2 RBC units per week) and high RBC (≥2 RBC units per week) intensity, similarly low PLT (<2 PLT events per week) and high PLT (≥2 PLT events per week) intensity for transfusion. [Table 1] displays clinical characteristics such as body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) status, baseline Hb, white blood cell (WBC) counts, and inpatient days significantly differ among AML patients based on transfusion intensity during the induction period.
Table 1: Clinical Characteristics of acute myeloid leukemia patients undergoing induction chemotherapy categorized based on transfusion intensity at a tertiary care cancer center in India

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The intensity of RBC and PLT transfusions was not associated with day 14 response to induction chemotherapy (P = 0.281; P = 0.268, respectively). [Figure 1] shows that high-intensity RBC and PLT transfusion was associated with low blood counts at the time of presentation (P = 0.050; P = 0.002, respectively).
Figure 1: Box plot displays patients with red blood cell (RBC) and platelets (PLT) transfusion at diagnosis and intensity of transfusion during induction period in acute myeloid leukemia patients

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[Table 2] compares RBC and PLT transfusions among patients with CR status and induction mortality. Weekly RBC and PLT requirements were significantly higher in patients who did not achieve CR status (P = 0.014 and P = 0.008, respectively). There was a strong association between RBC transfusion intensity and PLT transfusion intensity during the induction period (P < 0.001). Similarly, patients with induction mortality received higher intensity of blood transfusion for RBC and PLTs (P = 0.107; P = 0.039, respectively). Multivariate analysis was performed to study factors affecting CR status with prognostic variables in univariate analysis: BMI, RBC/PLT transfusion at presentation, day 14 response, RBC transfusion/week, and PLT transfusion/week during the induction period. RBC transfusion at presentation (P = 0.013) and RBC transfusion intensity (P = 0.016) appeared among prognostic factors for CR status.
Table 2: Volume and intensity of transfusion in acute myeloid leukemia patients during induction chemotherapy on complete remission status and induction mortality

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There was no association between the intensity of RBC transfusion during the induction period over transfusion requirements during consolidation (P = 0.238). However, patients with high intensity of PLT transfusion during the induction period continued to receive relatively higher PLT transfusion during consolidation (low vs. high: 1.7 vs. 4 PLT events/consolidation, P = 0.082).

[Table 3] shows the survival outcomes based on transfusion intensity. [Figure 2]a shows the median OS for the entire cohort with patients requiring low- and high-intensity RBC transfusion as 18 months versus 5 months, respectively (P = 0.314). The median OS for patients with low and high intensity platelet transfusion was 18 months and 12 months respectively (P = 0.504) [Figure 2]b. In the Cox model, with transfusion as the independent prognostic variable with other clinical factors constant for OS, HR = 1.08 for every unit of RBC transfusion (CI 0.91–1.29; P = 0.353) and every event of PLT transfusion the HR was 0.87 (CI: 0.79–0.95; P = 0.004).
Table 3: Intensity of red blood cell and platelet transfusion during induction chemotherapy in acute myeloid leukemia patients on overall survival

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Figure 2: Kaplan–Meier plot showing transfusion intensity in acute myeloid leukemia patients during induction chemotherapy on overall survival. (a) Describes low and high red blood cell (RBC) transfusion intensity; (b) describes low and high platelet (PLT) transfusion intensity

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   Discussion Top


The effect of blood transfusion on a patient's immunity and clinical outcomes were studied extensively but mostly restricted to surgical settings. Leukemia patient care involves supportive measures with substantial amount of blood transfusions, especially during the induction phase of therapy.[8],[9] Little has been published that discusses the relationship between blood transfusion and survival in adult AML patients in an Indian setting. The present study observed that higher intensity of RBC and PLT transfusions during induction therapy negatively affected CR status (P = 0.014 and P = 0.008, respectively).

Transfusion is required in almost every adult acute leukemia patient.[1] The induction period is critical in the management of acute leukemia therapy, and any additional immune suppression could adversely affect patient outcomes.[3] The median weekly transfusion requirements in adult AML patients during the induction period were 1.7 RBC units/week and 1.5 PLT events/week for the entire cohort. In a similar study, Cannas et al. observed higher median RBC requirements (median 2.5 RBC units/week) in AML patients who attained CR, while the PLT needs were similar (median 1.6 PLT/week).[2]

Patients with a high disease burden manifesting with poor ECOG status, high WBC counts, and low PLT counts at presentation required higher transfusion intensity (P = 0.001). The likelihood of RBC transfusion increases in patients with prechemotherapy Hb levels <11 g/dL.[10] Harnan et al. observed that transfusion requirements may depend on disease severity at diagnosis.[4] The present study also observed that patients who required transfusion at diagnosis for lower blood counts subsequently received higher intensity of RBC (P = 0.050) and PLT (P = 0.002) transfusion during the induction period as well.

Previous studies on childhood ALL had demonstrated an association between transfusion needs and poor survival outcomes.[2] However, few other studies on childhood ALL failed to demonstrate the effect of transfusion during the induction period on clinical outcomes.[9] Cannas et al. observed that increased transfusion requirements at diagnosis affected CR status in AML patients.[2] In the present study, univariate analysis revealed that intentisty of RBC and PLT transfusions affected CR status. In multivariate analysis, RBC transfusion at presentation and RBC transfusion intensity during the induction period appeared among prognostic factors for achieving CR status. Patients who did not achieve CR after induction therapy received higher intensity of RBC transfusions (2.0 vs. 1.5 units/week; P = 0.014) and PLT transfusions (1.7 vs. 1.3 units/week; P = 0.008). Patients with induction mortality also received higher intensity of blood transfusions (RBC/week = 2.1 vs. 1.5 units and PLT/week = 1.7 vs. 1.3 events/week). There was no difference in median units of transfusions given to patients who are alive during induction as compared to otherwise. As the duration of hospital stay for patients with induction mortality was comparatively lower as compared to the groups who survived, these patients received similar transfusions within a short period of hospital stay.

There was no clear relationship between the RBC transfusion pattern observed during the induction period and consolidation period. However, patients with higher PLT intensity during induction continued to receive higher PLT transfusion during consolidation period.

Blood transfusion leads to immunomodulatory changes by downregulation of Th1 immunity and reciprocal activation of Th2 immunity.[1] Moreover, increased blood transfusion might alter the immune function, which is important in eradicating residual disease with induction therapy in acute leukemia.[1],[2],[11] Blumberg et al. observed an inverse relationship with increasing doses of PLT transfusion and survival during induction in patients with CR.[7] The present study observed reduced OS in patients requiring high RBC (18 vs. 5 months) and high PLT (18 vs. 12 months) intensity transfusions; however, the difference was not significant. In the Cox model, the expected hazard was 9% (HR = 1.09; P = 0.353) higher for one unit increase in RBC transfusion, while for PLT transfusions, the expected hazard was 13% lower for one event of PLT transfusions (HR = 0.87; P = 0.004) during the induction period, holding other factors constant. Few hypothesized transfusion-associated microchimerism in combination with immunomodulation might explain reduced survival in acute leukemia patients with frequent transfusions.[3]

High intensity of RBC transfusion during the induction period negatively affected CR status but not OS. There was no clear relationship between high PLT transfusion intensity and CR status as significance was observed only in univariate analysis. The study observed that transfusion is associated with poor outcomes, possibly due to the secondary effect of disease severity and could not confirm the inverse relationship between the intensity of transfusions and OS in these patients. The study had limitations in general as it was a retrospective record-based review.


   Conclusion Top


Transfusion support was significantly higher in patients with a high disease burden at diagnosis. The lower intensity of RBC transfusion accompanies the response to chemotherapy in terms of CR status but not OS.

Acknowledgments

The author's acknowledge Jesu Pandian, Gayathrir K Chellaiya, and Merline Augustine for assisting in data collection and proofreading the manuscript.

Ethical approval

Being a retrospective study, Institutional Review Board (IRB) approved the present study without ethical approval through Ref. No: 1616/1RB-SRC/13/MCC/23-11-2019/1 dated: 12 December 2019.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Vaughn JE, Othus M, Powell MA, Gardner KM, Rizzuto DL, Hendrie PC, et al. Resource utilization and safety of outpatient management following intensive induction or salvage chemotherapy for acute myeloid leukemia or myelodysplastic syndrome: A nonrandomized clinical comparative analysis. JAMA Oncol 2015;1:1120-7.  Back to cited text no. 1
    
2.
Cannas G, Fattoum J, Raba M, Dolange H, Barday G, François M, et al. Transfusion dependency at diagnosis and transfusion intensity during initial chemotherapy are associated with poorer outcomes in adult acute myeloid leukemia. Ann Hematol 2015;94:1797-806.  Back to cited text no. 2
    
3.
Lee S, Parra P, Udoyen I, Grover K, Kane K, Desai P, et al. Factors affecting transfusion utilization in acute myeloid leukemia (AML) patients undergoing initial therapy. Blood 2017;130 Suppl 1:3870.  Back to cited text no. 3
    
4.
Harnan S, Ren S, Gomersall T, Everson-Hock ES, Sutton A, Dhanasiri S, et al. Association between transfusion status and overall survival in patients with myelodysplastic syndromes: A systematic literature review and meta-analysis. Acta Haematol 2016;136:23-42.  Back to cited text no. 4
    
5.
Komrokji RS, Khan AM, Al Ali NH, List AF, Lancet JE. Impact of red blood cell (RBC) transfusion during induction chemotherapy in newly diagnosed patients with acute myeloid leukemia (AML). Blood 2011;118:3600.  Back to cited text no. 5
    
6.
Pandian J, Raghavan V, Manuprasad A, Shenoy PK, Nair CK. Infection at diagnosis – A unique challenge in acute myeloid leukemia treatment in developing world. Support Care Cancer 2020;28:5449-54.  Back to cited text no. 6
    
7.
Favre G, Fopp M, Gmür J, Tichelli A, Fey MF, Tobler A, et al. Factors associated with transfusion requirements during treatment for acute myelogenous leukemia. Ann Hematol 1993;67:153-60.  Back to cited text no. 7
    
8.
Alwan AF, Alrahal NK, Alnuaimi MA. A one year anticipated blood transfusion requirements among patients with acute leukemia undergoing chemotherapy in the National Center of Hematology in Baghdad. Iraqi J Hematol 2019;8:25-9.  Back to cited text no. 8
  [Full text]  
9.
Alkayed K, Al Hmood A, Madanat F. Prognostic effect of blood transfusion in children with acute lymphoblastic leukemia. Blood Res 2013;48:133-8.  Back to cited text no. 9
    
10.
Bryer E, Henry D. Chemotherapy-induced anemia: Etiology, pathophysiology, and implications for contemporary practice. Int J Clin Transfus Med 2018;6:21-31.  Back to cited text no. 10
    
11.
Blumberg N, Heal JM, Liesveld JL, Phillips GL, Rowe JM. Platelet transfusion and survival in adults with acute leukemia. Leukemia 2008;22:631-5.  Back to cited text no. 11
    

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Correspondence Address:
Mohandoss Murugesan,
Department of Transfusion Medicine, Malabar Cancer Centre, Thalassery, Kerala
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajts.ajts_123_21



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