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Chemotherapy Delays Are Associated with Inferior Outcome in Acute Lymphoblastic Leukemia: A Retrospective Study from a Tertiary Cancer Center in South India

Indian Journal of Medical and Paediatric Oncology 2021; 42(01): 051-060

DOI: 10.1055/s-0041-1729513

Author : Vineet Agrawal, Smita Kayal, Prasanth Ganesan, Biswajit Dubashi

Abstract
Background Treatment protocols for acute lymphoblastic leukemia (ALL) have evolved over time to give excellent cure rates in children and moderate outcomes in adults; however, little is known how delays in chemotherapy affect long-term survival.

Objectives To find the association of delays during different treatment phases on the survival outcomes.

Materials and Methods Data from 149 ALL cases treated between 2009 and 2015 were retrospectively analyzed. Treatment course in commonly used protocols was divided into three phases?induction, consolidation (postremission), maintenance, and also a combined intensive phase (induction plus consolidation) for the purpose of analysis, and delay in each phase was defined based on clinically acceptable breaks. Analysis was done to find the impact of treatment delay in each phase on the survival outcomes.

Results The median age was 12 years (range, 1?57). Multi-center Protocol-841 (MCP-841) was used for 72%, German Multicenter Study Group for Adult ALL (GMALL) for 19%, and Berlin, Frankfurt, Muenster, 95 protocol (BFM-95) for 9% of patients. Delay in induction was seen in 52%, consolidation in 66%, and during maintenance in 42% of patients. The median follow-up was 41 months, and 3-year survival outcomes for the entire cohort were event-free survival (EFS)?60%, relapse-free survival (RFS)?72%, and overall survival (OS)?68%. On univariate analysis, delay in induction adversely affected EFS (hazard ratio [HR] = 1.78, p = 0.04), while delay in intensive phase had significantly worse EFS and RFS (HR = 2.41 [p = 0.03] and HR = 2.57 [p = 0.03], respectively). On separate analysis of MCP-841 cohort, delay in intensive phase affected both EFS (HR = 3.85, p = 0.02) and RFS (HR = 3.42, p = 0.04), whereas delay in consolidation significantly affected OS with (HR = 4.74, p = 0.04) independently.

Conclusion Treatment delays mostly in intensive phase are associated with worse survival in ALL; attempts should be made to maintain protocol-defined treatment intensity while adequately managing toxicities.

Keywords
acute lymphoblastic leukemia - delay - relapse - survival - treatment interruption


Publication History
Publication Date:
28 May 2021 (online)

? 2021. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Thieme Medical and Scientific Publishers Private Ltd.
A-12, Second Floor, Sector -2, NOIDA -201301, India

Abstract
Background Treatment protocols for acute lymphoblastic leukemia (ALL) have evolved over time to give excellent cure rates in children and moderate outcomes in adults; however, little is known how delays in chemotherapy affect long-term survival.

Objectives To find the association of delays during different treatment phases on the survival outcomes.

Materials and Methods Data from 149 ALL cases treated between 2009 and 2015 were retrospectively analyzed. Treatment course in commonly used protocols was divided into three phases?induction, consolidation (postremission), maintenance, and also a combined intensive phase (induction plus consolidation) for the purpose of analysis, and delay in each phase was defined based on clinically acceptable breaks. Analysis was done to find the impact of treatment delay in each phase on the survival outcomes.

Results The median age was 12 years (range, 1?57). Multi-center Protocol-841 (MCP-841) was used for 72%, German Multicenter Study Group for Adult ALL (GMALL) for 19%, and Berlin, Frankfurt, Muenster, 95 protocol (BFM-95) for 9% of patients. Delay in induction was seen in 52%, consolidation in 66%, and during maintenance in 42% of patients. The median follow-up was 41 months, and 3-year survival outcomes for the entire cohort were event-free survival (EFS)?60%, relapse-free survival (RFS)?72%, and overall survival (OS)?68%. On univariate analysis, delay in induction adversely affected EFS (hazard ratio [HR] = 1.78, p = 0.04), while delay in intensive phase had significantly worse EFS and RFS (HR = 2.41 [p = 0.03] and HR = 2.57 [p = 0.03], respectively). On separate analysis of MCP-841 cohort, delay in intensive phase affected both EFS (HR = 3.85, p = 0.02) and RFS (HR = 3.42, p = 0.04), whereas delay in consolidation significantly affected OS with (HR = 4.74, p = 0.04) independently.

Conclusion Treatment delays mostly in intensive phase are associated with worse survival in ALL; attempts should be made to maintain protocol-defined treatment intensity while adequately managing toxicities.

Keywords
acute lymphoblastic leukemia - delay - relapse - survival - treatment interruption

Introduction
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer worldwide; it is relatively less common in adults. Contemporary series from India and other developing countries report overall outcomes far removed from Western figures. Whereas the long-term survival reported from high-income countries for pediatric ALL is close to 90%[1] and for adult ALL is ~40%,[2] the corresponding survival is 60 and 22%, respectively, in studies from India.[3] [4] [5] [6] The inferior outcomes in adults can be attributed mainly to adverse biologic features, along with the inability to tolerate chemotherapy, particularly in older adults. Some of the important factors for inferior outcomes in developing countries are delayed presentation, higher infections, poor social support system, inadequate treatment facilities, and treatment abandonment.

In addition, another important cause of poorer outcome can be delay and interruptions in chemotherapy delivery. ALL is treated with chemotherapy protocols spanning 2 to 3 years, with intensive therapy in the first few months.

In the course of this long treatment period, delays in chemotherapy administration and dose modifications commonly occur due to drug-related toxicity, infections, associated comorbidities, or patient noncompliance. Delaying chemotherapy due to toxicity is safer for patients in the short term, but its long-term impact on survival outcomes is not well established. While the need for dose-intense chemotherapy in curing ALL is well described, there is scant literature describing risk factors for and outcomes after chemotherapy delays in different phases.[7] [8] [9] In this study, we aim to evaluate whether delays in chemotherapy increase the risk of relapse or affect survival in patients undergoing treatment for ALL.

Materials and Methods

Patient Recruitment
All patients diagnosed and treated during May 2009 to December 2015 in the Department of Medical Oncology of a tertiary cancer center in Southern India were enrolled in the study. Baseline demographic features, clinical characteristics, disease parameters, treatment details and timelines, toxicities, and outcomes were collected retrospectively from medical case records. Cases with a diagnosis of lymphoblastic lymphoma, with insufficient documentation, or patients who had event (death or discharge against medical advice) before the start of chemotherapy, were excluded from the study. Institutional ethical committee approval for waiver of consent was obtained prior to conducting this study.

Treatment Protocol
Treatment protocol for ALL generally consists of multiagent chemotherapy in different schedules and combinations and is typically divided into three phases: induction, consolidation, and maintenance, along with central nervous system (CNS) prophylaxis during the first two phases. Induction and consolidation are intensive phases consisting of a combination of eight to ten chemotherapy drugs that are delivered intravenously or orally typically over a period of 4 to 6 months, with the first month being the induction phase. Orally delivered 6-mercaptopurine (6-MP) and methotrexate form the backbone of maintenance phase that continues for 18 to 24 months in different protocols. As per our department policy, Multi-center Protocol-841 (MCP-841)[10] was used for all cases up to 25 years of age and German Multicenter Study Group for Adult ALL (GMALL) protocol[11] for adults above 25 years, until 2014. From 2015 onward, in an attempt to move to a high-dose methotrexate-based modern protocol for pediatric and young adult patients, we started using Berlin, Frankfurt, Muenster, 95 protocol (BFM-95)[12] initially for cases of T cells ALL (T-ALL) ?25 years.

Definition for Treatment Delay in Different Phases
As the total treatment spans over 2 to 3 years, the primary objective of the study was to evaluate the effect of prolonged treatment delays on survival outcomes. The time duration between first presentation to the hospital and date of start of chemotherapy (first dose of steroid) was taken as the ?delay in initiation? of therapy. For evaluation of delay during ongoing treatment, duration of a particular phase was taken as the difference in dates between the initiation of the particular phase and the start of the next phase of treatment. Each of the three regimens used in our study (MCP-841, GMALL, and BFM-95) were divided into an induction phase, a consolidation phase (postremission), and a maintenance phase. Each of the protocols has a 28-day standard induction phase. Taking into consideration small interruptions due to delay in logistics and staffing or administrative practices, delays due to toxicities, time needed for performing bone marrow exam, and time required for recovery of counts after therapy, a duration of 35 days in induction was classified as ?no delay.? Durations of 36 to 42 days of induction were classified as ?mild delay? and 43 or more days were classified as ?severe delay? for descriptive purposes. For analysis, a cutoff of 42 days was taken, and survival outcomes were compared for two groups: patients with duration <42>42 days. Only patients who were started on consolidation after completion of induction were evaluated for delay in induction phase.

For MCP-841, the standard duration of consolidation phase is 16 weeks, and of maintenance phase is 21 months. Again taking into consideration small interruptions, durations of 20 weeks for consolidation (4 weeks over standard) and 22 months for maintenance (1 month over standard) were considered as acceptable. Using these durations as cutoffs, survival outcomes were analyzed for patients treated with MCP-841. On the other hand, for BFM-95/GMALL protocols, the standard duration of consolidation phase is 28 weeks, and of maintenance phase is 24 months. Again taking into consideration small interruptions, durations of 32 weeks for consolidation (4 weeks over standard) and 25 months for maintenance (1 month over standard) were considered as acceptable. Using these durations as cutoffs, survival outcomes were compared for patients treated with BFM-95/GMALL protocols. Irrespective of the protocol, only patients who completed consolidation phase were evaluated for delay in consolidation. Similarly, only patients with a documented date of completion of maintenance phase were evaluated for maintenance delay.

For analysis, a combined duration of induction and consolidation phase was taken as ?intensive phase.? For MCP-841, the cutoff taken was 26 weeks (42 days induction + 20 weeks consolidation) and for GMALL/ BFM-95, the cutoff taken was 38 weeks (42 days induction + 32 weeks consolidation). The causes for interruptions in chemotherapy were also recorded.

Definition of Survival Outcomes
Delay in individual treatment phases was evaluated for association with the following survival outcomes: event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS). EFS was defined as the duration from start of induction-phase chemotherapy to occurrence of any event (relapse or death from any cause). RFS was defined as the duration from attainment of complete remission (CR) to relapse. Patients dying without documented relapse were censored in the evaluation of RFS. OS was defined as the duration from the start of induction chemotherapy to death from any cause. Data for survival analysis were censored on May 31, 2018.

Statistical Analysis
Descriptive statistics were used to summarize baseline characteristics, and treatment timelines. Chi-squared test was used to find association between the baseline parameters and delay in induction phase. Kaplan?Meier survival analysis followed by univariate log rank test was used to compare the survival outcomes in different groups of patients. Univariate and multivariate Cox regression analysis was used to evaluate factors affecting survival outcomes. All statistical analyses were performed by using 5% level of significance, and p < 0>

Results
Baseline Characteristics
Out of 168 patients of ALL registered in our department from 2009 to 2015, 149 met the inclusion criteria. The baseline characteristics of the patients are shown in [Table 1]. The median age was 12 years (range, 1?57), with a male: female ratio of 1.86. MCP-841 was used for 72%, 19% patients were treated with GMALL, and 9% with BFM-95 protocols. The median white cell count at presentation was 16 ? 109/L, while 29% (n = 44) had baseline leukocyte count of >50 ? 109/L. Baseline CNS involvement was present in 13 patients (9%) and testicular involvement in 2 (1.3%).

Table 1: Baseline characteristics n = 149

Characteristics at diagnosis

n (%)

Age (y)

0?14

85 (57)

15?39

45 (30)

40?60

19 (12)

Median age (range)

12 (1?57)

Sex

Male

97 (65)

Female

52 (35)

TLC (?109/L)

<50>

100 (67)

>50

44 (29.5)

Unknown

5 (3.5)

Blasts

<50>

40 (27)

>50%

100 (67)

Unknown

9 (6)

Sub-type

B-ALL

101 (68)

T-ALL

48 (32)

Risk

Standard

52 (35)

High

97 (65)

Involvement

None

133 (89)

CNS

13 (9)

Testis

2 (1.3)

Both

1 (0.7)

Karyotype

Normal

104 (70)

Ph +

6 (4)

Complex

13 (9)

Unknown

26 (17)

Protocol

MCP-841

107 (72)

GMALL

28 (19)

BFM-95

14 (9)
Abbreviations: ALL, acute lymphoblastic leukemia; B-ALL, B cells ALL; BFM-95, Berlin, Frankfurt, Muenster, 95 protocol; CNS, central nervous system; GMALL, German Multicenter Study Group for Adult ALL; MCP-841, Multi-center Protocol-841; T-ALL, T cells ALL; TLC, total leukocyte count.
Duration of Treatment Phases and Reasons for Delay
The duration of chemotherapy phases of induction, consolidation, intensive phase (combined induction and consolidation), and maintenance in different treatment protocols is shown in [Table 2]. Delay in initiation of induction therapy of >7 days after presentation to hospital was seen in 64% patients; however, this delay was not associated with survival outcome (data not shown). Induction duration of >42 days was observed in 52% (n = 70) of patients in all the three protocols combined. On analysis of baseline factors affecting induction delay, pediatric age group of 0 to 14 years was found to have significantly higher delay though mild (36?42 days); other factors such as gender, presenting white cell count, risk group, subtype, and treatment protocol were not associated with delay during induction ([Supplementary Table S1], available online). A considerable number of patients had delay during subsequent phases of consolidation (65%) and maintenance therapy (42%), as shown in [Table 2].


Table 2: Duration of phases of chemotherapy

Outcome parameters

Total (n)

Duration, median (range)

Categories

n (%)

Delay in initiation (d)

147

9.0 (0?101)

?7 d

53 (36.1)

>7 d

94 (63.9)

Duration of inductiona (d)

134

43.0 (29?87)

?35 d

9 (7)

36?42 d

55 (41)

>42 d

70 (52)

Duration of consolidationa

MCP 841

93

22.3 (14.1?31.0)

<20>

27 (29)

>20 wk

66 (71)

GMALL

19

31.9 (22.3?36.9)

<32>

11 (57.9)

>32 wk

8 (42.1)

BFM 95

5

31.4 (24.4?39.7)

<32>

3 (60)

>32 wk

2 (40)

Duration of maintenancea

MCP 841

72

21.95 (20.1?29.4)

<22>

37 (51.4)

>22 mo

35 (48.6)

GMALL

10

23.55 (6.5?25.4)

<25>

9 (90)

>25 mo

1 (10)

BFM 95

3

23.8 (22.2?24.1)

<25>

3 (100)

>25 mo

0
Abbreviations: ALL, acute lymphoblastic leukemia; BFM-95, Berlin, Frankfurt, Muenster-95 protocol; GMALL, German Multicenter Study Group for Adult ALL; MCP-841, Multi-center Protocol-841. Includes patients only if they have completed the respective phase of chemotherapy.
The main causes for delay in intensive phase were febrile neutropenia (78%), Grade 3 or 4 neutropenia (58%), thrombocytopenia (32%), abnormal liver function tests (17%), and patient noncompliance (8%). The major causes for delay in maintenance included febrile neutropenia (95%), Grade 3 or 4 neutropenia (92%), thrombocytopenia (39%), liver toxicity (56%), and patient noncompliance (22%). Multiple factors were concurrently affecting treatment delays. Grade of toxicities was not always available in the records; however, in the available data, mostly the interruption was for Grade 3 or 4 toxicities.

Overall Outcomes
Postinduction, 134 of the 149 (89.9%) patients attained CR, whereas 12 patients (8%) died during induction. In the entire cohort, 38 relapses were documented at different time points, of which 6 (15.8%) were during consolidation, 24 (63.1%) during maintenance, and 8 (21%) during follow-up. Death without a documented relapse was seen in 13 patients (9.7% out of 134 patients who attained CR). The median follow-up for the entire cohort was 41 months. Protocol-specific distribution of events and survival (EFS, RFS, and OS) outcomes is shown in [Table 3]. For the entire cohort, EFS was 60%, RFS 72%, and OS was 68% at 3 years.

Table 3 : Overall outcome (n = 149)

Outcome

MCP-841 (n = 107)

GMALL (n = 28)

BFM-95 (n = 14)

Total (n = 149)

No event

69

12

5

86

Event

38

16

9

63

Induction death

5

5

2

12

Relapse

25

8

5

38

In consolidation

1

1

4

6

In maintenance

17

6

1

24

During follow-up

7

1

0

8

Died without documented relapse

8

3

2

13

EFS (%)

At 3 y

67.1

44.4

29.5

59.6

At 5 y

60.2

37.0

?

53.3

RFS (%)

At 3 y

77.1

64.0

45.9

72.7

At 5 y

69.1

53.3

?

64.9

OS (%)

At 3 y

74.5

53.1

44.5

68.0

At 5 y

72.8

53.1

?

66.6

Abbreviations: ALL, acute lymphoblastic leukemia; BFM-95, Berlin, Frankfurt, Muenster-95 protocol; EFS, event-free survival; GMALL, German Multicenter Study Group for Adult ALL; MCP-841, Multi-center Protocol-841; OS, overall survival; RFS, relapse-free survival.
Factors Affecting Survival Outcome
Role of treatment delay during different phases of therapy in affecting survival outcomes in the entire cohort is shown in [Table 4]. Delay in induction of >42 days adversely affected EFS (hazard ratio [HR] = 1.78; 95% confidence interval [CI], 1.01?3.14), while no significant difference was seen in RFS and OS. Patients with delay in intensive phase had significantly worse EFS and RFS with HR = 2.43 (95% CI, 1.05?5.55) and HR = 2.57 (95% CI, 1.05?6.29), respectively. Delay in maintenance therapy did not affect survival outcomes. However, in multivariate analysis, delay in any phase of treatment was not found to be independently affecting survival.


Table 4 : (continued)

Parameters

Categories

n

EFS

RFS

OS

HR (95% CI)

p-Value

HR (95% CI)

p-Value

HR (95% CI)

p-Value

Univariate analysis

Age (y)

0?14

85

1

1

1

15?39

45

1.345 (0.75?2.40)

0.318

0.984 (0.45?2.14)

0.97

1.358 (0.69?2.65)

0.369

40?60

19

3.632 (1.91?6.88)

<0>*

3.15 (1.33?7.42)

0.009

3.231 (1.52?6.85)

0.002

Sex

Male

97

1

1

1

TLC (?109/L) (n = 144)

Female

52

0.573 (0.32?1.01)

0.55

0.43 (0.19?0.94)

0.035

0.755 (0.40?1.41)

0.38

<50>

100

1

1

1

>50

44

1.958 (1.17?3.26)

0.01*

1.754 (0.97?3.18)

0.064

2.700 (1.41?5.16)

0.003

Subtype

B-ALL

101

1

1

1

T-ALL

48

1.423 (0.85?2.38)

0.178

1.346 (0.69?2.63)

0.385

1.805 (1.01?3.22)

0.046

Risk

Standard

52

1

1

1

High

97

2.594 (1.42?4.71)

0.002*

2.294 (1.11?4.73)

0.024

2.714 (1.34?5.49)

0.005

Delay in inductiona (d)

?42

64

1

1

1

> 42

70

1.780 (1.01?3.14)

0.047*

1.657 (0.86?3.18)

0.128

1.834 (0.92?3.65)

0.084

Delay in consolidationa

No delay

39

1

1

1

Delay seen

78

1.892 (0.88?4.05)

0.101

1.924 (0.86?4.32)

0.113

2.976 (0.96?9.20)

0.058

Delay in intensive phasea

No delay

37

1

1

1

Delay seen

80

2.413 (1.05?5.55)

0.038*

2.572 (1.05?6.29)

0.039

2.762 (0.89?8.58)

0.079

Delay in maintenancea

No delay

49

1

1

1

Delay seen

36

0.95 (0.25?3.56)

0.95

0.962 (0.26?3.59)

0.954

1.378 (0.19?10.09)

0.753

Multivariate analysis

Age (y)

0?14

85

1

1

15?39

45

0.813 (0.36?1.82)

0.616

1.07 (0.46?2.47)

0.876

0.552 (0.17?1.75)

0.313

TLC (?109/L) (n = 144)

40?60

19

3.179 (1.28?7.89)

0.013

3.80 (1.36?10.56)

0.011

3.30 (1.07?10.12)

0.037

?50

100

?

?

1

?

?

>50

44

?

?

2.44 (1.16?5.16)

0.019

?

?

Abbreviations: ALL, acute lymphoblastic leukemia; B-ALL, B cells ALL; CI, confidence interval; EFS, event-free survival; HR, hazard ratio; OS, overall survival; RFS, relapse-free survival; T-ALL, T cells ALL; TLC, total leukocyte count. Includes patients only if they have completed the respective phase of chemotherapy.

*factors taken for multivariate analysis.

In the entire cohort, age and presenting white cell count were the only baseline factors independently affecting survival outcomes on multivariate analysis as shown in [Table 5]. Kaplan?Meier survival curves with age-based outcomes for the entire cohort are shown in [Fig. 1A?C].


Table 5 : Cox regression univariate analysis: MCP-841 (n = 107)

Parameters

Categories

n

EFS

RFS

OS

HR (95% CI)

p-Value

HR (95% CI)

p-Value

HR (95% CI)

p-Value

Univariate analysis

Age (y)

0?14

79

1

1

1

>15

28

1.405 (0.69?2.83)

0.342

1.127 (0.45?2.82)

0.79

1.56 (0.70?3.47)

0.276

Sex

Male

65

1

1

1

TLC (?109/L) (n = 104)

Female

42

0.686 (0.35?1.36)

0.281

0.681 (0.29?1.58)

0.372

0.883 (0.41?1.92)

0.753

<50>

72

1

1

1

>50

31

2.144 (1.12?4.11)

0.021

2.518 (1.13?5.59)

0.023

1.867 (0.87?4.03)

0.112

Subtype

B-ALL

86

1

1

1

T-ALL

21

1.167 (0.53?2.60)

0.699

1.085 (0.41?2.91)

0.87

1.505 (0.64?3.54)

0.35

Risk

Standard

51

1

1

1

High

56

1.94 (1.00?3.75)

0.049

1.807 (0.81?4.03)

0.148

2.113 (0.97?4.62)

0.061

Delay in induction* (d)

?42

51

1

1

1

>42

49

2.474 (1.20?5.10)

0.014

1.911 (0.86?4.26)

0.113

2.384 (1.01?5.63)

0.048

Delay in consolidation* (wk)

?20

27

1

1

1

>20

66

3.20 (1.09?9.36)

0.034

2.82 (0.95?8.37)

 <
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