FACTORS AFFECTING INITIAL CYCLOSPORINE

A LEVEL AND ITS CORRELATION WITH

CLINICAL OUTCOME IN

ACUTE LEUKEMIA PATIENTS UNDERGOING

ALLOGENEIC STEM CELL TRANSPLANTATION

Alok Gupta 1, Sachin Punatar 1, Jayant Gawande 1, BhausahebBagal 1, Libin Mathew 1, Sadhana Kannan 2, Navin Khattry 1

1 Medical Oncology, Bone Marrow Transplant Unit, ACTREC, Tata Memorial Centre, 2Biostatistics, ACTREC, Tata Memorial Centre,

Mumbai, India

Introduction

• Trough Cyclosporine A (CsA) blood level is known to influence

incidence of Graft versus Host Disease (GVHD) and relapse in acute

leukemia patients undergoing allogeneic stem cell

transplantation(ASCT).

• 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.

• Tailoring CsA dose based on regular trough level monitoring is required

to maintain a balance between the risk of GVHD and risk of relapse.

• Few studies have suggested that trough CsA levels during the first

few weeks post transplant had more relevance to outcome

compared to levels during later period.

• Also, despite being in use for more than 30 years, factors affecting

initial CsA levels (CSA-1) are not well established.

• Therefore this study attempts to evaluate whether such a correlation

between CSA-1 & post transplant outcomes exists and to explore

potential factors affecting CSA-1.

Introduction

Aim

To determine factors that may affect initial trough CsA level (CSA-1)

& the impact of CSA-1 on acute and chronic GVHD, relapse and

overall survival in acute leukemia patients undergoing ASCT.

Objectives

• Primary: To determine factors associated with higher or lower CSA-1

• Secondary: To determine & compare the following parameters in

patients with high, low or normal CSA-1

Incidence of acute & chronic GVHD

Severity of acute GVHD

Transplant related mortality (TRM)

Incidence of relapse

Relapse Free Survival (RFS)

Overall Survival (OS)

Study Design

• Retrospective study

• Study Period: January 2008 to March 2013

• Study centre: Bone Marrow Transplant Unit, ACTREC, Tata Memorial

Centre, Mumbai, India

• Study population: All patients who underwent ASCT for acute

leukemia.

Methods

• GVHD prophylaxis

CsA and Methotrexate (MTX) or CsA and Mycophenolate Mofetil

(MMF) was used.

CsA and MMF was started on day -1 of transplant at 3 mg/kg/day

and 600 mg/m2 /twice daily respectively. MTX was given at 15

mg/m2 on day+1 and 10 mg/m2 on day+3, +6, +11.

CSA-1 was measured on day 4 or day 5 of starting CsA.

Dose of CsA was modified depending on CSA-1 to achieve

therapeutic level of 150-200 ng/ml subsequently.

• Patients were divided into three groups based on initial modification

of CsA dose –

Group A (CsA dose escalated)

Group B (CsA dose de-escalated)

Group C (CsA same dose continued)

Methods

• Comparisons were done between 3 groups for discrete variables

which may affect CSA-1 was done 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 high or low CSA-1 between Group A and

B. The factors were split into 2 separate models due to small sample

size. Model 1 included patient related factors and model 2 included

transplant conditioning regimen related factors.

• Comparisons were done between 3 groups for transplant outcomes

including incidence of acute and chronic GVHD, incidence of relapse,

TRM, RFS and OS. Survival outcomes were compared by Kaplan-

Meier method.

Results

ALL- HR- High Risk (TLC > 100 x 109 /L at baseline or poor risk cytogenetics or not achieving CR after induction or persistent disease at transplant or > CR-2 ), SR-

Standard Risk (according to cytogenetics)

AML- PR- Poor Risk (TLC > 100 x 109 /L at baseline or poor cytogenetics or not achieving CR after induction or persistent disease at transplant or > CR-2) , IR-

Intermediate Risk (according to cytogenetics), GR- Good Risk (according to cytogenetics)

NK- Not Known

M68%

F32%

Gender

ALL30%

AML67%

Biphenotypic

Leukemia3%

Diagnosis

Biphenotypic Leukemia (3%)

CR155%CR2

26%

19%

Disease status at transplant

Relapse/Refractory

Baseline Characteristics (n = 77)P

erc

en

t

GR

IR

PR

0

20

40

60

80

100

ALL AML

4 10

74

40

22

8

42 NK

HR

SR

Baseline Characteristics (n = 77)

0

20

40

60

80

100

Bo

ne

Ma

rro

w

Um

bilic

al c

ord

Peri

ph

era

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loo

d s

tem

cell

s

Ma

tch

ed

Rela

ted

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ns

pla

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Un

rela

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pla

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Hap

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tica

l tr

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Fu

ll In

ten

sit

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Red

uc

ed

In

ten

sit

y

Yes

No

Cyclo

sp

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ne

+ M

eth

otr

exa

te

Cyclo

sp

ori

ne

+ M

yc

op

hen

ola

tem

ofe

til

Cy

clo

sp

ori

ne

+ M

yc

op

hen

ola

te +

Cyclo

ph

osp

ham

ide

Stem cell source Transplant type Conditioningregimen

TBI used GVHD Prophylaxis

Percent

Analysis of potential factors affecting CSA-1

Group A – Dose

escalated

(n=27)

Group B – Dose

de-escalated

(n=13)

Group C –

Same dose

continued

(n=37)

P

value

Median age at transplant 27 34 25 0.309

Males, n (%) 20 (74) 5 (39) 27 (73) 0.050

ABO mismatched transplants, n (%) 12 (44) 4 (31) 16 (43) 0.684

Gender mismatched transplants, n(%) 12(44) 6(46) 22(60) 0.445

Diagnosis

Acute Lymphoid Leukemia (ALL), n(%)

Acute Myeloid Leukemia (AML), n (%)

Biphenotypic leukemia, n (%)

9 (33)

17 (63)

1 (4)

1 (8)

11 (85)

1 (8)

13 (35)

24 (65)

0 (0)

0.226

Baseline Risk (n=68)

ALL

Standard Risk

Poor Risk

AML

Good Risk

Intermediate Risk

Poor Risk

Biphenotypic Leukemia

0

9

2

10

4

1

0

1

1

5

5

1

1

7

2

6

13

0

0.718

Group A Group B Group C P value

Disease status at transplant

Complete remission – 1

Complete remission – 2

Refractory/Relapse (in disease)

15

4

8

5

5

2

21

11

5

0.375

Stem cell source, n (%)

Bone Marrow

Umbilical Cord

Peripheral blood stem cells

2 (7)

2 (7)

23 (85)

2 (15)

0 (0)

11 (85)

1 (3)

0 (0)

36 (97)

0.167

Type of transplant, n (%)

Matched Related transplant

Matched Unrelated transplant

Haplo-indentical transplant

20 (74)

6 (22)

1 (4)

12 (92)

1 (8)

0 (0)

33 (89)

3 (8)

1 (3)

0.443

Type of conditioning regimen, n (%)

Full intensity

Reduced intensity

18(67)

9(33)

2(15)

11(85)

22(60)

15(41)0.007

Total body irradiation used, n (%) 13 (48) 0 (0) 19 (52) 0.004

Analysis of potential factors affecting CSA-1

Group A Group B Group C P value

Drugs used in conditioning, n (%)

Fludarabine

Melphalan

Cyclophosphamide

Busulphan

Mitoxantrone

Cytarabine

Treosulfan

16(60)

11(41)

13(48)

3(11)

1(4)

6(22)

2(7)

13(100)

8(62)

0(0)

4(31)

0(0)

2(15)

1(8)

21(57)

12(32)

20(54)

4(11)

0(0)

5(37)

2(5)

0.014

0.183

0.003

0.176

0.391

0.648

0.932

GVHD prophylaxis, n (%)

Cyclosporine + Methotrexate

Cyclosporine + Mycophenolate mofetil

17 (63)

10 (37)

8 (62)

5 (39)

28 (76)

9 (24)

0.458

Analysis of potential factors affecting CSA-1

Pre- Transplant Group A Group B Group C P value

Hemoglobin gm/dl 9.3 9.5 10.4 0.033

Serum albumin gm/dl 3.9 3.9 3.87 0.466

Serum creatinine mg/dl 0.8 0.95 0.85 0.173

Serum bilirubin mg/dl 0.4 0.4 0.5 0.050

Alkaline phosphatase IU/ml 108 117 131 0.429

Body mass index (Mean) 20.56 24.83 22.41 0.038

GFR ml/min 93 79.8 81.29 0.246

Analysis of potential factors affecting CSA-1

Factor OR 95% CI p value

Model 1

BMI-Pre transplant * 0.835 0.708-0.986 0.034

Hemoglobin 0.914 0.521-1.603 0.753

Bilirubin 2.595 0.053-127.153 0.631

Model 2

TBI use 1.901 0.176-20.537 0.597

Fludarabine use * 0.184 0.011- 3.18 0.244

Cyclophosphamide use 0.678 0.039-11.686 0.789

Conditioning regimen- Full

Intensity2.28 0.456-11.389 0.315

Multivariate Analysis

* Factors significant in stepwise selection

Factor OR 95% CI p value

Model 1 BMI-Pre transplant * 0.83 0.705-0.977 0.025

Model 2 Fludarabine use * 0.101 0.012- .877 0.038

On univariate analysis

Use of FI regimen, cyclophosphamide and TBI and lower

Body Mass Index (BMI) were associated with lower CSA-1

Use of RI regimen, fludarabine, and higher BMI were

associated with higher CSA-1

On multivariate analysis

Fludarabine use and increased BMI predicted for higher CSA-

1 requiring CSA dose de-escalation.

Summary of factors affecting CSA-1

Analysis of transplant outcomes based

on CSA-1

Group A Group B Group C P value

Median days to achieve therapeutic CSA level 10 10 4 -

Median days to platelet engraftment 12 10 13 0.705

Median days to WBC engraftment 13 13 14 0.351

Incidence of acute GVHD (all grades), n (%) 13 (48) 5 (39) 16 (43) 0.836

Incidence of acute GVHD (grade III-IV), n (%) 3 (11) 4 (31) 7 (19) 0.316

Incidence of chronic GVHD, n (%)

Overall

Limited stage

Extensive stage

14 (52)

6(22)

9(33)

5 (39)

3(23)

2(15)

21 (57)

7(19)

13(35)

0.738

Incidence of relapse, n (%) 11 (41) 3 (23) 12 (32) 0.527

Slippage of chimerism, n (%) 10(31) 4(31) 8(22) 0.396

Treatment related mortality, n (%) 2 (7) 5 (39) 4 (11) 0.064

Median overall survival (years) 2.15 1.85 not reached 0.40

Toxicity of cyclosporine, n (%)

Nephrotoxicity

Hypertension

Neurotoxicity

7 (26)

11 (41)

1 (4)

2 (15)

7 (54)

0 (0)

12 (32)

14 (38)

4 (11)

0.485

0.599

0.304

Survival Analysis

RFS at 4 years

29% in group A

46% in group B

45% in group C (P=NS).

OS at 4 years

33% in group A

43% in group B

53% in group C (P=NS).

Conclusions

1. Cyclophosphamide based conditioning regimen and

lower BMI is associated with lower CSA-1 requiring

CSA dose escalation.

2. Fludarabine based conditioning regimen and higher BMI

is associated with higher CSA-1 requiring CsA dose de-

escalation.

3. Transplant outcomes including incidence of acute and

chronic GVHD, TRM, relapse incidence and overall

survival are not significantly affected by initial CsA level.

Thank You