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ORIGINAL ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 6  |  Page : 981-988

Analysis of factors affecting initial cyclosporine level and its impact on post transplant outcomes in acute leukemia


1 Department of Medical Oncology, Bone Marrow Transplant Unit, Tata Memorial Centre, Mumbai, Maharashtra, India
2 Department of Biostatistics, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Mumbai, Maharashtra, India

Date of Web Publication13-Dec-2017

Correspondence Address:
Dr. Navin Khattry
Department of Medical Oncology, Bone Marrow Transplant Unit, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Mumbai - 410 210, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.157338

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 > Abstract 

Background: Trough cyclosporine (CsA) blood level can influence incidence of graft-versus-host disease (GVHD) and relapse in patients with acute leukemia undergoing allogeneic hematopoietic stem cell transplant (HSCT). We sought to determine factors affecting initial trough CsA level (CsA-1) and its impact on transplant outcome in acute leukemia.
Materials and Methods: Seventy-seven patients underwent HSCT for acute leukemia between January 2008 and March 2013 and were included. GVHD prophylaxis included CsA + methotrexate. (MTX) in 53 patients and CsA + mycophenolate mofetil (MMF) in 24 patients CsA-1 was measured on day 3–5 of starting CsA and subsequent dose was modified to achieve therapeutic level of 150–200. ng/mL. According to CsA-1, patients were divided into three groups - 27 in Group A (dose escalated), 13 in Group B (dose de-escalated), and 37 in Group C (same dose continued).
Results: On univariate analysis, cyclophosphamide with total-body irradiation (TBI) based conditioning regimen and lower body mass index (BMI) were associated with lower CsA-1, while use of fludarabine and higher BMI were associated with higher CsA-1. On multivariate analysis, only fludarabine use and BMI affected CsA-1. Incidence of acute and chronic GVHD (aGVHD and cGVHD), transplant-related mortality, relapse incidence, and relapse-free and overall survival (OS) were similar in the three groups.
Conclusion: While fludarabine use in conditioning regimen and higher BMI leads to higher CsA-1, transplant outcomes are not affected by CsA-1.

Keywords: Acute leukemia, cyclosporine, graft-versus-host disease, hematopoietic stem cell transplantation


How to cite this article:
Gupta A, Punatar S, Gawande J, Mathew L, Kannan S, Khattry N. Analysis of factors affecting initial cyclosporine level and its impact on post transplant outcomes in acute leukemia. J Can Res Ther 2017;13:981-8

How to cite this URL:
Gupta A, Punatar S, Gawande J, Mathew L, Kannan S, Khattry N. Analysis of factors affecting initial cyclosporine level and its impact on post transplant outcomes in acute leukemia. J Can Res Ther [serial online] 2017 [cited 2019 Dec 11];13:981-8. Available from: http://www.cancerjournal.net/text.asp?2017/13/6/981/157338


 > Introduction Top


Allogeneic hematopoietic stem cell transplant (HSCT) remains one of the most effective treatment strategies in the management of patients with acute leukemia. The ability of HSCT to cure acute leukemia is attributed to the antileukemic effects of the conditioning regimen and the graft versus leukemia (GVL) effect of the donor derived lymphocytes.[1] However, this beneficial effect is limited by transplant related mortality (TRM), which is mainly attributed to the toxicity of conditioning regimen, infectious complications and development of severe GVHD. Both acute and chronic GVHD (aGVHD and cGVHD) results in significant morbidity and mortality post HSCT.[2] Use of reduced intensity conditioning (RIC) regimens,[3],[4] improvement in supportive care, and use of GVHD prophylaxis [5] have resulted in decrease in TRM and improved transplant outcomes in acute leukemia.

CsA in combination with either methotrexate (MTX) or mycophenolate mofetil (MMF) remains two of the most widely used immunosuppressive regimens for GVHD prophylaxis.[6],[7],[8] Trough CsA blood level is known to influence incidence of GVHD and incidence of relapse in acute leukemia patients undergoing HSCT. Higher CsA levels decrease incidence and severity of GVHD, but may increase risk of relapse while lower levels is a risk factor for severe GVHD.[9],[10],[11] Large variation seen in initial CsA levels from patient to patient may be attributed to interindividual differences in CsA metabolism and disposal. Tailoring CsA dose based on regular trough level monitoring is required to maintain a balance between the risk of GVHD and risk of relapse.[12]

Due to availability and routine use of CsA level monitoring in transplant centers around the world, CsA blood levels are now kept within the therapeutic range over prolonged periods posttransplant. However, in the immediate posttransplant period it may take few weeks of CsA dose adjustment before CsA levels are in the therapeutic range. Two studies have suggested that lower CsA levels during initial 1–3 weeks posttransplant were more significantly associated with increased incidence of severe aGVHD compared to CsA levels during later period.[13],[14] However, it remains to be established whether initial CsA levels measured during 1st week posttransplant (CsA-1) had an impact on various transplant outcomes including aGVHD and cGVHD, relapse, and survival. Also, despite being in use for more than 30 years, factors affecting CsA-1 are not well known. This study sought to determine factors that may affect CsA-1 and also to assess the impact of CsA-1 on incidence of severe aGVHD and cGVHD, TRM, relapse incidence, relapse-free survival (RFS) and overall survival (OS) in acute leukemia patients undergoing HSCT.


 > Materials and Methods Top


Patient characteristics

Seventy-seven patients underwent HSCT for acute leukemia between January 2008 and March 2013 and were included in this retrospective study [Table 1]. Written informed consent for HSCT was obtained from all patients. In addition, written informed consent was obtained from patients who received CsA + MMF based GVHD prophylaxis as a part of an ongoing MMF pharmacokinetic study. Others received CsA + MTX as per the institutional practice. The median age was 30 years (range 6–51). These included 52 (67.5%) patients with acute myeloid leukemia (AML), 23 (29.9%) with acute lymphpoblastic leukemia (ALL), and two (2.6%) with biphenotypic leukemia. Forty-two (54.5%) patients were in first complete remission (CR1), 20 (26%) in second complete remission (CR2), and 15 (19.5%) in relapsed/refractory state (RR) at the time of HSCT. Seventeen (73.9%) patients with ALL had high risk disease at transplant which was characterized by at least one of the following: Total leukocyte count (TLC) > 100 × 109/L at baseline, poor risk cytogenetics, not achieving CR after induction, persistent disease at transplant or disease stage ≥ CR-2. Twenty-two (42.3%) patients with AML had poor risk disease at transplant which was characterized by at least one of the following: TLC > 100 × 109/L at baseline, unfavorable cytogenetics, not achieving CR after induction, persistent disease at transplant or disease stage ≥ CR-2), while 21 (40.4%) patients had intermediate risk disease according to cytogenetics. All patients received azole antifungal prophylaxis, starting on day 1 of transplant [Table 1].
Table 1: Baseline characteristics (n=77)

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Human leukocyte antigen (HLA) matching and source of stem cells

Low resolution HLA typing for HLA antigen loci A, B, and DRB1 was done for all patients and siblings using polymerase chain reaction with sequence specific primers (SSP). Those with mismatch at one locus were further tested for antigen match at HLA-C and HLA-DQB1. Patients who did not have HLA-matched sibling donor underwent high resolution HLA typing for HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 to find the most appropriate matched unrelated donor (MUD). Sixty-five (84.4%) patients received hematopoietic stem cells from matched related donor (MRD), 10 (13%) from MRD, and two (2.6%) from haploidentical donor (HID). Forty (51.9%) patients underwent gender mismatched transplants which included female donor to male recipient in 23 (29.8%) cases. Source of stem cells was granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood stem cells (PBSCs) in 70 (90.9%) transplants, bone marrow in five (6.5%), and cord blood in two (2.6%) transplants. Ex vivo T-cell depletion was not done for any patient [Table 1].

Conditioning regimen and GVHD prophylaxis

Total-body irradiation (TBI) based conditioning regimen (TBI dose ≥ 12 Gy + cyclophosphamide (TBI-Cy)) was used in 26 (34%) patients and fludarabine based conditioning regimen was used in 50 (65%) patients [Table 1]. One patient received busulfan and cyclophosphamide based conditioning regimen. TBI-Cy included TBI at a dose of 12–14.4 Gy in eight fractions over 4 days from day 7 to 4 and cyclophosphamide at a dose of 60 mg/kg on day 3 and 2. TBI of 2 Gy was given with fludarabine based reduced intensity regimens in six patients. Though various fludarabine based regimen were used in our cohort of patients, the dose of fludarabine was 30 mg/m 2 from day 7 to 3 in all patients with a cumulative dose of 150 mg/m 2 [Table 1]. Four patients received conditioning with 2 Gy TBI, fludarabine, and cyclophosphamide (day 3 and 2 at 60 mg/kg/day). GVHD prophylaxis consisting of CsA + MTX was used in 53 (68.8%) patients and CsA + MMF was used in 24 (31.2%) patients [Table 1]. CsA and MMF was started on day 1 of transplant at 1.5 mg/kg/twice daily and 600 mg/m 2/twice daily, respectively. CsA was initially administered as an intravenous infusion over a period of 2 h. Intravenous CsA was changed to oral CsA upon resolution of mucositis and diarrhea. CsA was tapered from day + 90 and stopped by day + 180. In high risk patients, CsA was tapered from day + 45 to + 60 and stopped by day + 90 to + 120. MTX was given intravenously at 15 mg/m 2 on day + 1 and 10 mg/m 2 on day + 3, +6, and + 11, each dose followed 24 h later by leucovorin rescue. MMF was administered per orally and was continued till day + 30. Individual modification in dose of CsA was made depending on its level in blood, risk of relapse, development of GVHD, and toxicity. Posttransplant cyclophosphamide (50 mg/kg on day + 3 and + 4 was added as GVHD prophylaxis along with CsA + MMF (started on day + 5) in two patients who underwent HID transplant. Antithymocyte globulin (ATG) was added in patients who underwent MUD transplant or one antigen mismatched sibling donor transplant.

CsA blood level measurement

Trough CsA level was assessed in whole blood which was collected immediately prior to morning dose of CsA at 06.00 AM (fixed time). CsA blood level was measured by chemiluminiscence assay (Architect Analyser, Abbott Healthcare). The limit of detection was 25 ng/mL. First CsA level, that is, CsA-1 was measured from day 3 to 5 of starting CsA. Thereafter, the CsA blood level was measured twice weekly and monitoring was continued till the start of CsA tapering.

CsA dose modification

CsA dose was modified depending on CsA-1 to achieve therapeutic level of 150–200 ng/mL subsequently. Subsequently at all time points until CsA tapering, CsA dose was modified whenever the levels were out of therapeutic range. CsA was omitted for two doses and decreased by 25 and 50% for levels between 300–400 ng/mL and >400 ng/mL, respectively. Patients were monitored for potential CsA toxicities including nephrotoxicity (decrease in glomerular filtration rate > 25%), neurotoxicity (clinically), and hypertension (rise in blood pressure (BP) to systolic > 140 mmHg or diastolic > 90 mmHg in previously normotensive patients or rise in systolic BP by > 20 mmHg or diastolic BP by >10 mmHg in previously hypertensive patients). CsA was replaced by MMF in patients who developed clinically significant nephrotoxicity or neurotoxicity.

GVHD

aGVHD was defined as GVHD developing in first 100 days of transplant. Diagnosis and grading of aGVHD was done according to standard criteria [15] and treatment was initiated with methylprednisolone 1–2 mg/kg/day given intravenously, followed by tapering upon clinical improvement. cGVHD was defined as GVHD developing after 100 days of transplant and was classified as limited or extensive stage according to standard criteria.[16] Treatment of cGVHD was initiated with local steroids with or without addition of systemic steroids depending on the site of cGVHD and response to local steroids.

Definitions

Time to myeloid engraftment was defined as first of 3 consecutive days with an absolute neutrophil count of ≥ 0.5 × 109/L.[17] Time to platelet engraftment was defined as first of 7 consecutive days when the platelet count is maintained ≥ 20 × 109/L without platelet transfusion. TRM was defined as death occurring in the posttransplant period not related to relapse of leukemia. RFS was defined as the time interval between date of transplant and date of relapse or death or last follow-up if in CR. OS was defined as the time interval between date of transplant and date of death or last follow-up.

Statistical considerations

For analysis, patients were divided into three groups based on initial modification of CsA dose - Group A (dose escalated), Group B (dose de-escalated), and Group C (same dose continued). The primary objective was to determine factors associated with higher or lower CsA-1. Secondary objectives were to determine and compare the following outcomes in patients with high, low, or normal CsA-1: Incidence of a GVHD and cGVHD, severity of aGVHD, TRM, incidence of relapse, RFS, and OS.

Comparisons were done between three groups for discrete variables which may affect CsA-1 by Chi-square test, while continuous variables were compared by Kruskal–Wallis test. Multivariate analysis was carried out using logistic regression to determine factors predicting low or high CsA-1 between Groups A (dose escalated) and B (dose de-escalated). The factors were split into two separate models due to small sample size. Model 1 included patient-related factors, that is, age, gender, diagnosis (AML, ALL, and biphenotypic leukemia), disease status at transplant (CR-1, CR-2, and RR), and pretransplant patient parameters (hemoglobin, albumin, creatinine, bilirubin, alkaline phosphatase, and BMI). Model 2 included transplant related factors, that is, type of conditioning regimen (TBI-Cy based, fludarabine based), individual drugs used in conditioning (fludarabine, melphalan, cyclophosphamide, busulfan, mitoxantrona, cytarabine, and treosulfan), GVHD prophylaxis regimen used (CsA + MTX and CsA + MMF), and concomitant antifungal prophylaxis used. Comparisons were done between three groups for transplant related outcomes, which included incidence of aGVHD and cGVHD, incidence of relapse, TRM, RFS, and OS. Survival outcomes were compared by Kaplan–Meier method.


 > Results Top


Factors affecting initial CsA level

Twenty-seven (35%) patients in the study population had low CsA-1 requiring CsA dose escalation (Group A), 13 (17%) patients had high CsA-1 requiring CsA dose de-escalation (Group B), and 37 (48%) patients had CsA-1 in therapeutic range requiring no CsA dose modification (Group C). Median time to achieve therapeutic CsA levels was 10 days in Groups A and B. Factors potentially affecting CsA-1 were analyzed and compared between three groups [Table 2].
Table 2: Analysis of potential factors affecting CsA-1

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On univariate analysis, use of cyclophosphamide with TBI based conditioning regimen (P = 0.003) and lower BMI (P = 0.038) were associated with lower CsA-1. Use of fludarabine in conditioning regimen (P = 0.014) and higher BMI (P = 0.038) were associated with higher CsA-1. On multivariate analysis, only fludarabine based conditioning regimen (P = 0.038) and higher BMI (P = 0.025) were associated with higher CsA-1 requiring CsA dose de-escalation [Table 3].
Table 3: Multivariate analysis of potential factors affecting CsA-1

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Transplant outcomes

Median time to myeloid engraftment was 13 days in Group A, 13 days in Group B, and 14 days in Group C (P = not significant (NS)). Median time to platelet engraftment was 12 days in Group A, 10 days in Group B, and 13 days in Group C (P = NS).

Thirty-four (44%) patients developed aGVHD and median time to onset was 30 days. Incidence of grade II–IV aGVHD was 27%. The most common site of aGVHD was gastrointestinal tract, seen in 20 (59%) patients. Skin GVHD was seen in 11 (32%) patients, while no patient developed associated liver GVHD. Systemic steroids were used in 28 patients, of which 26 patients (93%) responded. Median duration of steroid usage was 10 weeks. Incidence of all grade and grade II–IV aGVHD was 48 and 11% in Group A, 38 and 31% in Group B, and 43 and 19% in Group C, respectively (P = NS).

Forty patients (52%) developed cGVHD and median time to onset was 5 months. Sixteen (21%) patients had limited, while 24 (31%) patients had extensive cGVHD. Most common site of cGVHD was oral cavity (62.5%), followed by liver (42.5%), skin (40%), lung (30%), eye (27.5%), and gut (20%). Systemic steroids were used in 23 (57.5%) patients. Median duration of steroid use was 17 weeks. Incidence of cGVHD was 52% in Group A, 38% in Group B, and 57% in Group C (P = NS).

Incidence of relapse was 41% in Group A, 23% in Group B, and 32% in Group C (P = NS). TRM was 7% in Group A, 38% in Group B, and 11% in Group C (P = NS). OS [Figure 1] and RFS [Figure 2] at 4 years was 33 and 29% in Group A, 43 and 46% in Group B, and 53 and 45% in Group C, respectively (P = NS). There was no difference in the incidence of CsA toxicity between the three groups [Table 4].
Figure 1: Impact of cyclosporine CsA-1 on overall survival (OS). CsA-1 = Initial trough cyclosporine A level

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Figure 2: Impact of CsA-1 on relapse-free survival (RFS)

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Table 4: Impact of CsA-1 on transplant-related outcomes

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 > Discussion Top


In last 2 decades, significant efforts have been made to exploit the antileukemic mechanism of GVL effect in HSCT for acute leukemia. One such strategy involves tailoring the dose and duration of immunosuppressive agents used in GVHD prophylaxis. CsA in combination with another immunosuppressive agent has become the standard GVHD prophylaxis regimen used worldwide. Immunosuppressive effect of CsA is mediated through suppression of calcineurin-mediated T-cell activation. Therapeutic drug level monitoring of CsA along with careful dose titration to achieve the desired therapeutic levels has become an integral component of HSCT in acute leukemia. This has helped in optimizing the balance between GVHD and GVL effect, leading to improved transplant outcomes. However, despite regular monitoring and keeping CsA blood levels within therapeutic range for larger part of the posttransplant period, significant variation is seen in the incidence and severity of GVHD from patient-to-patient. One potential explanation for this may be provided by the difference in the intensity of immunosuppression in the early posttransplant period before therapeutic CsA levels are achieved. Few studies have highlighted the importance of trough CsA levels and indirectly the intensity of immunosuppression in the pre-engraftment period on the development of aGVHD.[13],[14] The present study has made an attempt to determine whether such a correlation exists between initial CsA levels and incidence of GVHD. The study had also sought to determine factors affecting initial CsA level and its impact on incidence of relapse and survival.

All patients received same initial CsA dose as per body weight, but only 48% had CsA-1 in the therapeutic range. Fifty-two percent patients in our study had CsA-1, which was either lower (35%) or higher (17%) than the therapeutic range. CsA blood level variability had been linked to differences in CsA pharmacokinetics from patient-to-patient.[18] Factors such as patient age,[18],[19] concurrently used drugs chiefly azole antifungals,[20],[21] transplant type,[18] and hepatic function [19] can influence metabolism of CsA and CsA blood level. Bioavailability of oral CsA is highly variable (20–50%) and it becomes even more erratic in the posttransplant period due to conditioning regimen-induced mucositis.[22],[23] This variability is overcome by intravenous route of administration. However, in our study we did not find patient age, gender, transplant type, diagnosis, and type of azole antifungal used as factors affecting CsA-1. On the contrary, use of cyclophosphamide with TBI in conditioning regimen and lower BMI were associated with lower CsA-1 in our study. This finding is in concordance with similar finding reported in a study from Japan.[24] High doses of cyclophosphamide used in conditioning caused autoinduction of hepatic enzymes, CYP3A4, CYP2C9, and CYP2B6.[25],[26] CYP3A4 is the primary enzyme involved in the metabolism of CsA. Induction of CYP3A4 by cyclophosphamide has been shown to be associated with reduced CsA levels [27] and may also contribute to lower CsA-1 seen in our study.

Factors which were significantly associated with higher CsA-1 included use of fludarabine in conditioning regimen and higher BMI. The mechanism by which fludarabine resulted in higher CsA-1 remains unexplained. However, at this stage it can be hypothesized that one of the metabolites of fludarabine might have inhibitory effect on CYP3A4 resulting in higher CsA-1. Higher CsA-1 associated with higher BMI may be a reflection of higher total dose of cyclosporine administered in patients with higher BMI. This might suggest that CsA dose estimation based on body weight might not be the best method of CsA dosing. However, whether higher CsA-1 seen in patients with higher BMI have an impact on transplant outcome is not known; and since this is only an observation, we recommend not to draw any firm conclusions from same. CsA dosing based on body weight should still be the standard until pharmacokinetic studies suggest otherwise.

Various studies have demonstrated an inverse relationship between trough CsA levels and incidence of GVHD.[9],[11],[12] At the same time others have failed to demonstrate any relationship between trough CsA levels and incidence of GVHD.[28],[29],[30],[31] Based on existing level of evidence, the association between trough CsA levels and incidence of aGVHD might not be very strong. None of these studies have looked at the impact of initial CsA levels on aGVHD. Also, data regarding the impact of initial CsA levels on other treatment outcomes including relapse and survival is not robust. In our study, we found that CsA-1 did not have an impact on the incidence of severe aGVHD, incidence of cGVHD, incidence of relapse, TRM, RFS, and OS. This finding (with respect to aGVHD) is contrary to what has been reported in another similar study.[13] No effect of CsA-1 on transplant outcomes seen in our study can be explained by the fact that all patients eventually achieved therapeutic CsA levels within a median time of 10 days. This lack of association can also be explained by the finding that there exists significant patient-to-patient variability in the degree of calcineurin inhibition achieved by a constant dosing of CsA.[32] Thus, CsA-1 might not be an accurate reflection of the functional activity of CsA.

The limitation of this study is that CsA levels have been taken as a surrogate for immunosuppression, which is also the standard practice worldwide. However, keeping in view that CsA levels might not correlate with calcineurin inhibition and thus immunosuppression, definite conclusions regarding the impact of CsA levels on transplant outcomes cannot be drawn. Direct measurement of calcineurin activity could serve as a better therapeutic index of immunosuppression in future studies evaluating the impact of CsA on transplant outcomes.

In conclusion, the present study suggests that in patients undergoing HSCT for acute leukemia, cyclophosphamide with TBI based conditioning regimen and lower BMI are associated with lower initial CsA levels. Fludarabine based conditioning regimen and higher BMI are associated with higher initial CsA levels. However, transplant outcomes including incidence of aGVHD and cGVHD, TRM, relapse incidence, RFS, OS, and CsA toxicity are not significantly affected by initial CsA level.

 
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Bacigalupo A, Di Georgio F, Frassoni F, Van Lint MT, Raffo MR, Gogioso L, et al. Cyclosporin A serum and blood levels in marrow graft recipients: Correlation with administered dose, serum creatinine and graft-versus host disease. Acta Haematol 1984;72:155-62.  Back to cited text no. 30
    
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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