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HEMATOLOGIC MALIGNANCIES
original reports
Infection Prevalence in Adolescents and Adults
With Acute Myeloid Leukemia Treated in an
Indian Tertiary Care Center
Hasmukh Jain, MD, DM
1
; Karthik Rengaraj, MD
1
; Vibhor Sharma, DM
1
; Avinash Bonda, MD, DM
1
; Raajit Chanana, MD, DM
1
;
Jayashree Thorat, MD
1
; Ashwini Ronghe, MD
2
; Sanjay Biswas, MD
3
; Lingaraj Nayak, MD, DM
1
; Prashant Tembhare, MD
4
;
Papagudi Subramnian, MD
4
; Dhanalaxmi Shetty, PhD
5
; Nikhil Patkar, MD
3
; Bhausaheb Bagal, DM
1
; and Manju Sengar, DM, MD
1
abstract
PURPOSE Infections remain a major challenge in the treatment of acute myeloid leukemia (AML). Induction-
related mortality reported in the literature is approximately ,5% in clinical trials. However, the real-world
scenario is different, especially in developing countries, given the high incidence of multidrug-resistant (MDR)
organisms, high incidence of fungal pneumonia at baseline, and significant delay before initiation of che-
motherapy. We aimed to look at contemporary infections and infection-related mortality and analyze the patterns
of infections.
MATERIALS AND METHODS This retrospective study was conducted at a large tertiary care oncology center in
India. Patients with newly diagnosed AML who were older than age 15 years, considered fit for intensive therapy,
and treated in the general wards of the adult hematolymphoid unit from March 1, 2014, until December 31,
2015, were included.
RESULTS One hundred twenty-one patients were treated during the study period. The most common presenting
complaint was fever (85%). The focus of infection at presentation was found in 63% of patients, with respiratory
infection being the most common (47%). MDR organisms were isolated in 55% of patients during induction from
various foci. Klebsiella pneumoniae was the most common blood culture isolate (42.9%). Fungal pneumonia
was diagnosed in 55% of patients during induction despite antifungal prophylaxis. Treatment-related mortality
was 10.7% in all phases, with an induction mortality rate of 7.4%. Complete remission was attained in 69% of
patients. Of all patients who received induction chemotherapy, 74% completed all three consolidation cycles.
The 121 patients were followed up for a median period of 53 months. Four-year event-free survival was 35.8%,
and 4-year overall survival was 41.5%.
CONCLUSION Infections and infection-related mortality are major challenges during AML induction. Gram-
negative MDR and fungal infections are particularly common in our region.
JCO Global Oncol 6:1684-1695. © 2020 by American Society of Clinical Oncology
Creative Commons Attribution Non-Commercial No Derivatives 4.0 License
INTRODUCTION
The challenges in the management of acute myeloid
leukemia (AML) are treatment-related mortality as
a result of infections and bleeding and relapsed dis-
ease. Infections during therapy are associated with
mortality, morbidity, and increased health care ex-
penditure and can compromise the dose intensity of
chemotherapy. The induction mortality reported in the
literature is ,5% in clinical trials.
1-3
However,
induction-related mortality reported from tertiary care
centers in India ranges from 4.4%-24.7%.
4-8
The
higher mortality rate is a result of factors such as
presence of infections at presentation, multidrug-
resistant (MDR) organisms infection during in-
duction, invasive fungal infections at baseline,
8
and
significant delay before diagnosis and initiation of
chemotherapy. A study from India reported infections
in 46% of patients at baseline.
8
Another retrospective
study from southern India showed a 4-week gap from
onset of symptoms to first presentation to hospital.
4
To
improve outcomes, it is important to understand the
pattern of infections to devise an appropriate strategy.
Herein, we present the pattern of infections and
infection-related mortality in patients with AML from
a high-volume tertiary care center in India.
MATERIALS AND METHODS
Study Design
This is a retrospective study of patients with newly
diagnosed AML who were older than age 15 years,
received intensive therapy, and were treated in the
general wards from March 1, 2014, until December
31, 2015. This study was approved by the institutional
review board vide letter IEC/0319/3209/001. Patients
ASSOCIATED
CONTENT
Appendix
Author affiliations
and support
information (if
applicable) appear at
the end of this
article.
Accepted on
September 17, 2020
and published at
ascopubs.org/journal/
go on November 6,
2020: DOI https://doi.
org/10.1200/GO.20.
00240
1684
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Copyright © 2021 American Society of Clinical Oncology. See https://ascopubs.org/go/authors/open-access for reuse terms.
with antecedent hematologic disorder, acute promyelocytic
leukemia, and therapy-related AML were excluded as
a result of variable management and outcomes.
There are six beds in the general ward for AML induction.
Patients get waitlisted for admission from the leukemia
clinic. Priority is given to good-risk patients and then
according to age. These wards do not have high-efficiency
particulate air filters. The patients’beds are placed in a hall
with adequate spacing. Chemotherapy is delivered through
a peripherally inserted central catheter (PICC). The patients
are managed as inpatients until recovery of blood counts.
Granulocyte colony-stimulating factor injections were not
routinely used after induction chemotherapy. All patients
who did not have evidence of fungal pneumonia at baseline
received posaconazole as antifungal prophylaxis. As de-
partmental policy, routine antibiotic prophylaxis was not
given with the 7+3 induction regimen. Cotrimoxazole and
acyclovir prophylaxis was given if a cladribine-based reg-
imen was used.
9
All patients were treated with standard intensive therapy
with 7+3-based (cytarabine plus daunorubicin or idar-
ubicin) induction
1
or 7+5+3 (cytarabine plus cladribine
plus daunorubicin) induction.
10
Cladribine was used in
patients with high-risk features such as adverse cytoge-
netics on a case-by-case basis at the physician’s discretion.
The deciding factors included logistics, funds, and general
condition to tolerate 4 weeks of neutropenia.
All episodes of fever
9
were evaluated with detailed history
and physical examination directed at finding the focus of
infection, radiologic investigations if required, and cultures.
Cultures were taken from the PICC line and peripheral
blood at the onset of fever, escalation of antimicrobials,
and/or deterioration of general condition of patients at-
tributed to infection. Cultures were also taken from other
sites (eg, urine, stool) whenever clinically indicated. All
episodes of fever, unexplained tachycardia, hypotension,
infectious diarrhea, and soft tissue infections (eg, furuncle,
skin abscess, inflammation at site of PICC line insertion,
and/or perianal tenderness) were considered infections.
The choice of initial antibiotics and subsequent change or
total duration of antibiotics were consistent with the In-
fectious Diseases Society of America guidelines.
9
The only
difference was the use of cefoperazone-sulbactam and
amikacin as the preferred first-line agents based on our
hospital antibiogram and the higher incidence of drug-
resistant gram-negative infections.
Objectives
The primary objective was to evaluate the pattern and
frequency of infections and infection-related outcomes.
The secondary objectives were to estimate the treatment-
related mortality, response to chemotherapy (as defined
per the Cancer and Leukemia Group B working group
criteria
11
), antimicrobial usage, event-free survival (EFS),
and overall survival (OS). Exploratory objectives were to
correlate the risk of death with time to initiation of therapy,
multidrug-resistant infections, and fungal pneumonia.
EFS and OS were calculated. EFS was calculated from the
date of diagnosis to the date of treatment failure, relapse, or
death.
11
OS was calculated from the date of diagnosis to last
follow-up, death as a result of any cause, or probable death
as a result of advanced disease.
11
Methods
The details of the patients were retrieved from case files and
electronic medical records. Baseline details such as de-
mographic characteristics, presenting symptoms, clinical
findings, Eastern Cooperative Oncology Group perfor-
mance status, presence of comorbidities, infectious foci at
presentation (detected in baseline workup and symptom-
directed evaluation), and laboratory parameters were
recorded. AML disease-related characteristics such as
cytogenetics (fluorescence in situ hybridization and con-
ventional karyotyping) and molecular abnormalities were
recorded. As per the cytogenetics results, patients were
divided into favorable-, intermediate-, and poor-risk
CONTEXT
Key Objective
We analyzed the patterns of infection and infection-related mortality in patients with acute myeloid leukemia (AML) from
a region with a high incidence of drug resistance and fungal infections.
Knowledge Generated
A clinically evident focus at presentation was found in 63% of patients, with a respiratory focus being most common.
Multidrug-resistant organisms were isolated in 55% of patients during induction from various sources, with Klebsiella
pneumoniae being the most common blood culture isolate. Treatment-related mortality was 10.7% and induction mortality
was 7.4%, predominantly as a result of infections.
Relevance
Drug-resistant infections are a major challenge in the management of AML in our setting. They result in greater morbidity,
higher antimicrobial usage, and slightly higher mortality compared with rates reported in the literature.
Infection-Related Mortality in Acute Myeloid Leukemia
Journal of Global Oncology 1685
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groups.
12
The interval from diagnosis to the initiation of
induction chemotherapy and the type of chemotherapy
administered during induction and consolidation were
recorded. The type of infections, infection-related out-
comes, need for ICU admission, ventilator support, and
PICC line removal as a result of infection were recorded.
The response to induction and subsequent postremission
therapy was recorded. Minimal residual disease (MRD) was
assessed using bone marrow aspirate multicolor flow
cytometry with the residual blasts cutoff being ,0.1%.
13
The disease status at last follow-up was noted.
Analysis
Descriptive statistics were used to summarize the data,
including medians and standard deviations. Survival was
presented using Kaplan-Meier analysis. Correlation be-
tween survival and factors such as MDR infections, fungal
pneumonia, and time to initiation of therapy was estimated
using multivariable analysis. SPSS v25 (SPSS, Chicago, IL)
was used for statistical analysis.
RESULTS
One hundred twenty-one patients with AML were treated
during the study period. The median time from registration
to start of induction chemotherapy was 21 days (range,
1-75 days). The baseline characteristics are listed in
Table 1. For this study, individuals between the age of 15
and 30 years were considered adolescents and young
adults.
14
Seventy-seven patients had a focus of infection
(63%), with respiratory infections being the most common
site (47%). The 7+3 regimen was the most common in-
duction strategy. Consolidation therapy consisted of high-
dose cytarabine (HIDAC) as a 3-hour infusion every
12 hours on days 1, 3, and 5. The cause for attrition in each
phase is given in Figure 1.
Infections During Induction
All patients developed infections at some point in their
treatment course. Most of the infections (90%) were ob-
served during the induction phase. Organisms were iso-
lated from blood, stool, sputum, perianal swabs, wound
swabs, and pus cultures, which were sent from clinical
infectious foci (Table 2).
During induction, gram-positive cocci (GPCs) were isolated
from different sites in 25 patients (20%), with the most
common being enterococci (12% of patients; Table 3).
Gram-negative bacilli (GNBs) were observed in 91 patients
(75%), with Escherichia coli being the most common
isolate seen (35.4% of patients).
Twenty-seven patients (22%) had blood culture positivity
during induction. GNBs were more common (20 patients;
16%), followed by GPCs (six patients; 5%), Mixed infection
with GNBs and GPCs was seen in one patient, and one
patient had a Candida infection. Nineteen patients (16%)
had an isolate from the PICC, of whom six patients were
successfully treated with antibiotic lock, whereas 13
TABLE 1. Demographic and Clinical Characteristics at Baseline
Characteristic No. of Patients (%)
Sex
Males 76 (63)
Females 45 (37)
Age, years (median, 30 years)
,30 (AYA) 59 (48)
30-50 57 (47)
.50 5(4)
Comorbidities
a
None 100 (83)
At least one 18 (15)
Not known 3 (2)
Presenting complaints
Fever
b
103 (85)
Fatigue/weakness 62 (51)
Bleeding manifestations 22 (18)
Cervical lymphadenopathy 2 (2)
Gum swelling 2 (2)
Generalized lymphadenopathy 1 (1)
Paraparesis 2 (2)
Duration of illness before presenting to hospital, months
Range 0.13-16
c
Median 1
ECOG performance status at baseline
0-1 81 (67)
2-4 40 (33)
Infectious focus at presentation
None 44 (37)
Respiratory 57 (47)
Skin and soft tissue 24 (20)
Perianal 4(3)
Oral 3(2)
GI tract 2(2)
Multiple foci 12 (10)
Cytogenetic risk at presentation
Favorable risk 59 (49)
Intermediate risk 44 (36)
Poor risk 15 (12)
Unknown 3 (2)
Induction regimen
7+3 (cytarabine plus daunorubicin or idarubicin) 104 (86)
Daunorubicin, cladribine, and cytarabine 17 (14)
NOTE. Data presented as No. (%) unless otherwise indicated.
Abbreviations: AYA, adolescent and young adult; ECOG, Eastern Cooperative
Oncology Group.
a
Comorbidities defined as hypertension, diabetes, heart disease, or
hypothyroidism, as per standard criteria.
b
Fever is defined as a single oral temperature measurement of ≥38.3°C (101°F)
or a temperature of ≥38.0°C (100.4°F) sustained over a 1-hour period.
9
c
One patient in the data set had a duration of illness of 12 months, and another
had a duration of illness of 16 months. One patient presented with a history of
swelling over the left shoulder and fever, and the other patient presented with
generalized weakness, off and on fever, and pain in right hip (extramedullary
presentation).
Jain et al
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patients required removal. Only seven PICCs that were
removed grew a pathogen from tip culture. The median
number of days for clearance of blood cultures was 5 days
(range, 2-11 days).
Sixty-seven patients (55%) had MDR organisms in the
isolates. Thirty-four patients (28%) had extended-spectrum
β-lactamase (ESBL)–producing organisms, 14 patients
(12%) had carbepenamase-producing organisms, four
patients (3%) had methicillin-resistant Staphylococcus
aureus, two patients (2%) had vancomycin-resistant
Enterococcus, and one patient had colistin-resistant
Klebsiella.
The MDR organisms were isolated from different foci of
infection (Table 2), with Klebsiella pneumoniae being the
most common among blood culture isolates (42.9%). E coli
was most common among stool culture isolates (47.1%),
and Pseudomonas was the most common in the wound
swabs (63.6%). The numbers of patients with MDR in-
fections in different phases of therapy (after start of in-
duction and during consolidation cycles) are listed in
Table 3. Neutropenic patients with prolonged or break-
through fever were suspected of having fungal pneumonia.
Patients with fungal pneumonia were categorized as having
proven, probable, or possible invasive fungal disease.
15
In
total, 67 patients (55%) were suspected of having fungal
pneumonia during induction. Among these patients, seven
patients (5%) had probable fungal pneumonia, and the rest
had possible fungal infection.
During the course of induction, 19 patients received acy-
clovir for clinical suspicion of herpes infection. Six patients
were tested for cytomegalovirus infection based on clinical
suspicion; however, none were positive. One patient had
scabies during induction.
Induction Complications
Five patients (4%) required intensive care unit (ICU) ad-
mission, with a median ICU stay of 3 days. Six patients
required inotropic support during their course of induction.
The induction mortality rate was 7.4%, with all patients
dying from severe sepsis and three patients having a life-
threatening infection prohibiting further therapy.
Infections During Consolidation
Patients developed infections in all phases of consolidation
therapy, with predominantly GNBs, as illustrated in
Figure 2. In total, 17 patients (14%) developed probable
fungal pneumonia during the consolidation phase. In two
patients, the third HIDAC course was omitted, and the
patients proceeded directly to follow-up in view of their
complicated course.
Only two patients could proceed to an allogenic stem-cell
transplantation (ASCT) as consolidation therapy. One
patient subsequently developed corticosteroid-refractory
graft-versus-host disease after transplantation and died,
and the other patients experienced relapse and died.
Antimicrobial Use
As per departmental policy, cefoperazone-sulbactam and
amikacin were used as the first-line antibiotics for febrile
neutropenia. Most patients (104 of 121 patients) required
stronger antibiotics (carbapenems, colistin, tigecycline,
teicoplanin, or vancomycin) for control of infections, with
most antibiotics requiring courses of .10 days. Details of
antimicrobial type and duration are listed in Table 4. The
mean durations of antimicrobial use during induction are
listed in Appendix Table A1.
Efficacy Outcomes
Complete remission was attained in 84 patients (69%). Of
66 patients in whom MRD was assessed, 30 patients (45%)
attained MRD-negative status. The median follow-up time
was 53 months. Of the 108 patients who achieved re-
mission, 55 patients experienced relapse. The mean time
to relapse was 10.7 months (standard deviation, 7.9
months). Thirty-three patients were lost to follow-up. The
patient survival statistics and relapses are presented in
Figure 3.
Of the 121 patients, 75 patients (62%) experienced an
event (treatment failure, relapse, or death), leading to a
4-year EFS rate of 35.8% (95% CI, 28% to 46%) and median
EFS time of 19 months. Nine patients did not survive
Induction therapy (N = 121) patients
(deaths, n = 9; refractory disease, n = 2;
progressive disease, n = 2;
life-threatening ICU transfer, n = 3;
ileocecal intussusception, n = 1)
Consolidation cycle 1 (n = 104)
(death, n = 1; relapse, n = 1;
cardiac dysfunction, n = 1;
pyogenic meningitis, n = 1)
Consolidation cycle 2 (n = 100)
(death, n = 2; relapse, n = 1; life-threatening
infection, n = 1;prolonged cytopenia, n = 1;
follow-up,* n = 2)
Consolidation cycle 3 (n = 93)
(death, n = 1; relapse, n = 1; GVHD after ASCT, n = 1)
In follow-up (n = 92)
FIG 1. Causes for attrition. (*) Two patients were unfit for
further therapy and went on to follow-up after cycle 2
consolidation. ASCT, allogeneic stem-cell transplantation;
GVHD, graft-versus-host disease; ICU, intensive care unit.
Infection-Related Mortality in Acute Myeloid Leukemia
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induction, and remission status could not be assessed.
Twenty-nine patients died, of whom 21 died as a result of
disease relapse and eight died in remission. The 4-year OS
rate was estimated to be 41.5% (95% CI, 39.4% to 59%).
Multivariable Analysis
Patients with complete remission with MRD negativity had
a better EFS. No statistically significant correlation could be
made between disease risk status, time to induction, in-
cidence of MDR infections, or incidence of fungal infections
and EFS. Completion of treatment was found to have
a statistically significant influence on EFS (P,.001), with
a median EFS time of 30 months and 4-year EFS of
42.4% (95% CI, 33% to 54.4%; Appendix Fig A1) in pa-
tients who completed treatment. The analysis of EFS and
OS is provided in Table 5.
DISCUSSION
The key findings from our study include a higher incidence
of infections at baseline, a higher incidence of drug-
resistant infections and fungal infections, and conse-
quently a higher use of antimicrobials than reported in the
literature. The study population is different from that re-
ported in other studies but is reflective of patients with AML
in our region in terms of the younger age, male pre-
dominance, and greater prevalence of patients with good-
risk disease.
This study included patients age 15 to 57 years. The
median age of our cohort was 30 years, with only 4% of
patients older than 50 years. This reflects the younger age
of our AML population. Collective data reported on 3,848
patients from a multicenter consortium in India showed
a median age of 40 years, with only 14% of patients
.60 years old.
16
This could reflect the fact that our
population comprises a younger population and a possible
referral bias as a result of elderly patients not seeking
medical care. Only one third of the patient were female,
reflecting the overall sex disparity in seeking care in our
region. Half of our cohort had good-risk disease, unlike
other studies where ,20% of patients have good-risk
disease.
17
This could be a result of the long time to
treatment initiation (Fig 4). Good-risk patients are more
likely to survive the waiting period. This could also reflect
the preferential support given to good-risk patients by the
TABLE 2. Percentage of Cultures Isolating MDR Organisms During Induction
Culture During
Induction
No. of Cultures (%)
Total
(N =
121)
Escherichia
coli
Klebsiella
pneumoniae Pseudomonas
Enterococci/
VRE Streptococci Acinetobacter
Staphylococcus
aureus
Multiple
Organisms
PICC/blood
a
120 4 (11.4) 15 (42.9) 8 (22.9) 8 (22.9) 1 (2.9) 6 (17.1) 5 (14.3) 6
Sputum 59 1 (7.1) 7 (50) 5 (35.7) 2 (14.3) 2 (14.3) 3 (21.4) 2 (14.3) 6
Stool 90 16 (47.1) 6 (17.6) 1 (2.9) 11 (32.4) 1 (2.9) 3 (8.8) 1 (2.9) 9
Wound swab
b
14 0 (0) 6 (54.5) 7 (63.6) 0 (0) 1 (9.1) 1 (9.1) 3 (27.3) 3
Perianal 4 0 (0) 2 (66.7) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1
Abbreviations: MDR, multidrug resistant; PICC, peripherally inserted central catheter; VRE, vancomycin-resistant Enterococcus.
a
Includes both PICC line infection and blood-borne infection.
b
Includes cellulitis, hidradenitis, furuncle, abscess, otitis externa, soft tissue infections, tonsillitis, and thrombophlebitis.
TABLE 3. Patients With MDR Isolates in Different Phases of Therapy
MDR Organisms Isolated
No. of Patients (%)
Induction
HIDAC
Cycle 1
HIDAC
Cycle 2
HIDAC
Cycle 3
Total No. of patients 121 104 100 93
Escherichia coli 43 (35) 4 (4) 3 (3) 2 (2)
Klebsiella pneumoniae 20 (17) 5 (5) 4 (4) 2 (2)
Pseudomonas 13 (11) 3 (3) 1 (1) 3 (3)
Enterococci 15
a
(12) 0 0 1
b
(1)
Streptococci 4 (3) 0 0 0
Acinetobacter 6 (5) 0 1 (1) 0
Staphylococcus aureus 6
c
(5) 1 (1) 1d (1) 1d (1)
Others (rare organisms) 6 (5) 1 (1)
Abbreviations: HIDAC, high-dose cytarabine; MDR, multidrug
resistant; MRSA, methicillin-resistant Staphylococcus aureus; VRE,
vancomycin-resistant Enterococcus.
a
Ten patients had VRE.
b
VRE.
c
Four patients had MRSA.
d
MRSA.
HIDAC 1
Of 104 patients,
58 patients
developed FN,
13 positive blood
cultures (all GN
organisms),
4 patients with
probable fungal
pneumonia
HIDAC 2
Of 100
patients,
57 patients
developed FN,
10 positive blood
cultures (GN, n = 9;
GP, n = 1),
1 patient with
probable fungal
pneumonia
HIDAC 3
Of 93
patients,
59 patients
developed FN,
11 positive blood
cultures (GN, n = 9;
GP, n = 2),
5 patients with
probable fungal
pneumonia
FIG 2. Infections during consolidation. FN, febrile neutropenia; GN,
gram-negative; GP, gram-positive; HIDAC, high-dose cytarabine.
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nongovernmental funding agencies. This is a problem
because there is no universal health care system or in-
surance in our region and patients rely on support from
external agencies.
An important reason for the higher incidence of infections
at baseline (63%) is the significant delay in presentation
and treatment initiation. In the current study, patients re-
ceived induction chemotherapy an average of 3 weeks after
the registration date (Appendix Fig A1). This is similar to
reports from other centers in India. The mean duration from
onset of symptoms to initiation of treatment in a study by
Philip et al
4
was 4 weeks. Nair et al
8
described a delay in
initiation of 12 weeks in patients with infection compared
with 6 weeks in those without infection. Kumar et al
18
reported that 72% of patients had a focus of infection at
presentation, and Nair et al
8
reported that 46% of patients
had baseline infections.
In the current study, blood cultures were positive in only
22% of patients. This is similar to the Polish Adult Leukemia
Group (PALG) study, with 26% blood culture positivity,
3
but
low compared with the study by the Children’s Oncology
Group, which showed 56% blood culture positivity in
induction,
19
and a study from the Indian subcontinent,
which demonstrated 51% blood culture positivity.
18
Gram-
negative organisms were more frequent and distributed
along the treatment phases similar to other studies in the
country.
6,20,21
Gram-positive organisms were seen in 25
patients during induction, but only in three patients in
TABLE 4. Antibiotic, Antifungal, and Antiviral Use in Different Phases of Therapy
Treatment
No. of Patients
Induction
HIDAC
Cycle 1
HIDAC
Cycle 2
HIDAC
Cycle 3
Total No. of patients who received treatment 121 104 100 93
Carbapenem 99 14 19 22
Colistin 41 0 4 2
Tigecycline 23 1 1 1
Linezolid 15 1 0 1
Teicoplanin 48 8 21 10
Vancomycin 3 1 0 0
Clindamycin 33 7 7 9
Amphotericin B 19 1 0 0
Caspofungin 68 3 3 3
Voriconazole 17 0 0 0
Acyclovir 19 1 0 0
Ganciclovir 6 0 0 0
Abbreviation: HIDAC, high-dose cytarabine.
Induced
(N = 121)
• Patients with PD,
palliated (n = 2)
• Not in
remission (n = 26)
• Deaths (response
not assessed; n = 9)
Patients continued
treatment
(n = 110)
• Achieved CR after
first induction (n = 84)
• Did not attain
CR and were
reinduced (n = 26)
• Achieved CR after
reinduction (n = 24)
• Still refractory and
received BSC (n = 2)
Achieved CR
(n = 108)
• Early relapse (n = 3;
died, n = 1;
lost to FU, n = 2)
• Died during
consolidation (n = 4)
• Died due
to GVHD after
transplantation (n = 1)
• Palliated
during course of
treatment (n = 8;
lost to FU in CR, n = 3;
experienced relapse,
n = 5)
Patients in
follow-up
(n = 92)
• Maintained remission
at 2 years (42 of 92
patients)
• Lost to FU
(3 of 92 patients)
• Experienced relapse
during FU (47 of 92
patients)
Alive and in
remission at 2 years
(n = 43)
• BSC (40 of 47 patients;
dead, n = 15;
lost to FU, n = 25)
• Went for
BMT (3 of 47 patients;
all dead)
• Received salvage
chemotherapy
only (4 of 47 patients;
alive, n = 1;
dead, n = 3)
• Achieved remission
after salvage
chemotherapy (n = 1)
FIG 3. Patient survival statistics and chronology of relapse. BMT, bone marrow transplantation; BSC, best supportive care; CR, complete remission; FU,
follow-up; GVHD, graft-versus-host disease; PD, progressive disease.
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subsequent HIDAC cycles. This is different from the clinical
trial data from the AML-BFM2004, PALG, and Children’s
Oncology Group trials reported in the Western literature,
which showed predominantly gram-positive infections.
3,19,22
The probable explanation for this is a lack of fluoroquinolone
prophylaxis and low threshold for escalation to broad-
spectrum antibiotics in the current study. In addition, as
reported by Murali et al,
21
increased gut colonization with
MDR GNB (as high as 50% in surveillance cultures) could
possibly explain the increased number of patients with
GNB sepsis after the gut barrier is compromised after
anthracycline-based chemotherapy.
MDR organisms were found in the isolates of 55.3% of the
patients. ESBL production was the most frequent re-
sistance mechanism, with E coli being the most common
organism overall (35.54% of isolates). The most common
isolate in blood cultures was Klebsiella (42.9%). This was
similar to the study by Gupta et al,
6
which demonstrated
81% ESBL isolates, with Pseudomonas (37%) and Kleb-
siella (23%) being the most common organisms. With
uniform antibiotic guidelines, all patients had microbiologic
negativity by the end of treatment. Mean duration of an-
tibiotic therapy was 16 days in the study by Nair et al.
8
In the
current study, all patients required antibiotics for a mean
duration of 10 days during the course of treatment.
We report a high incidence of fungal infections possibly as
a result of ongoing construction activity and the weather.
23
In the current study, 67 patients (55%) developed fungal
pneumonia during induction (seven patients had probable
fungal pneumonia during induction). This is in contrast to
the AML-BFM2004 trial by Bochennek et al,
22
who re-
ported a 3% incidence of fungal infections. In contrast, the
PALG study by Lech-Maranda et al
3
reported a 20% rate of
proven fungal infections, and Sung et al
19
reported a fungal
pneumonia rate of 14% to 21% distributed over all phases
of treatment. Because of the limited number of patients in
this study, correlation could not be made between fungal
infection and OS and response rate, but other larger studies
have shown that fungal infections definitely affect
survival.
24
The complete remission rate of 69% in this study is
comparable to that of similar studies at centers across India
at other tertiary centers (65%-70%).
7,17
Among the 121
patients who started induction therapy, 90 patients com-
pleted therapy (three cycles of consolidation), for a treat-
ment completion rate of 74%. The advantages of a younger
cohort and overrepresentation of good-risk disease were
offset by the low transplantation rates, with just three pa-
tients undergoing ASCT. Hence, the EFS in our study must
be interpreted in that context (Table 6 and Appendix
Fig A2).
Thirteen patients (10.7%) experienced treatment-related
mortality in all phases, with induction mortality experienced
by nine patients (7.4%). This is in concordance with
Western literature.
2,3,22
Similar studies from the Indian
subcontinent have reported relatively higher induction
mortality rates, with Pandian et al
20
reporting a rate of
15.6% (Malabar Cancer Center), Philip et al
4
reporting
a rate of 24.7% (Christian Medical College Vellore), Kumar
et al
18
reporting a rate of 15.6% (Women’s Indian Asso-
ciation Cancer Institute, Chennai), and Bahl et al
7
reporting
a rate of 17.1% (All India Institute of Medical Sciences
Delhi). Collective data from 10 tertiary care cancer centers
in India reported an induction mortality rate of 18%.
16
The strengths of this study are that the patterns of infection
and infection-related outcomes are from a homogenous
cohort. These data will be useful for other centers in our
region. Because of the decent follow-up period, we are
able to understand the efficacy outcomes in a low-
transplantation setting. It is reassuring that despite the
higher rates of infection and antibiotic use, the mortality
is low.
The limitation of this study is its retrospective design. The
outcomes of patients who experienced deterioration while
waiting for induction is not known.
The focus in our setting should be to shorten the time to
treatment initiation and look at strategies such as outpatient
therapy with a 7+3 regimen in selected patients or other
agents while awaiting admission. The other area to be
addressed is the optimal use of antimicrobial prophylaxis
and antimicrobial stewardship. We need to look at non-
transplantation strategies to improve outcomes.
In conclusion, AML treatment in our setting is complicated
by drug-resistant gram-negative infections and fungal
infections. This leads to increases in morbidity, antimi-
crobial use, and use of health care resources.
TABLE 5. Analysis of EFS and OS
Survival No. of Patients
Median
(months)
95% CI
(months)
4-Year
Rate (%) 95% CI (%)
EFS 121 19 15 to 35 35.8 28 to 46
OS 121 25 16 to NR 41.5 33 to 52
Abbreviations: EFS, event-free survival; NR, not reached; OS, overall survival.
0.25
0.50
0.75
1.00
010
20 30 40 50 60 70
Time (months)
Survival Probability
OS
EFS
121 78 58 51 41 33 12 0
121 76 52 47 37 31 12 0
EFS
OS
No. at risk:
FIG 4. Overall survival (OS) and event-free survival (EFS) curves.
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TABLE 6. Comparison of Outcomes of Similar Studies
Study
Patient
Age
(years)
No. of
Patients
Risk
Strata
(%)
Treatment
Arm
Comparator
Arm
CR
Rate
(%)
Induction
Mortality
Transplantation
Rate (%) Outcomes
PALG
3
16-60 309 Not
done
DAC for 7 days DA for 7 days 84 13% v9% ——
ECOG
1
17-60 657 FR,
13.6
D
45
for 3 days + C
100
for 7 days
D
90
for 3 days +
C
100
for 7 days
FR,
81.3
D
45
, 4.5% 50.3 OS, 20.7 v
34.3 months
IR1,
41.1
IR2,
26.6
IR,
58.7
D
90
, 5.5%
AR,
18.7
AR,
51.4
JALSG
25
,65 1,064 D arm: D
50
for 3 days + C
100
for 7 days
I
12
+C
100
for
7 days
D
arm:
Early death ,60
days: 2.1% v
4.7%
12 5-year OS with D +
HIDAC, 58%
FR, 22 FR,
91
IR, 65 IR, 79
AR, 8 AR,
51
Bahl et al
7
8-60 480 FR,
21.6
D
45-90
for 3 days +
C
100
for 7 days
—FR,
84.8
18.7% 14 5-year OS, 35.5%
IR,
69.3
IR,
67.9
AR, 9.1 AR,
54.2
Kumar
et al
18
1-74 404 FR,
29.6
D
60
for 3 days + C
100
for 7 days
——15.6% ——
IR,
48.7
AR,
21.7
Philip
et al
4
Any 109 FR,
11.8
D
60
for 3 days + C
200
for 7 days
——24.7% 22 1-year OS: ,15
years, 70%
IR, 70 15-60 years,
55.6%
AR,
18.2
.60 years, 42.4%
Pandian
et al
20
.14 96 FR, 19 D
60
for 3 days + C
100
for 7 days
—74 15.6% —3-year OS, 39%
IR, 64
AR, 17
Our study .15 121 FR, 49 D
60
for 3 days or I
12
for 3 days + C
100
for
7 days
—FR,
79
7.4% 2 4-year OS, 48.2%
4-year EFS, 35.9%
IR, 61
AR,
73
IR, 36
AR, 12
NOTE. Subscript dose in mg/m
2
is followed by number of days (eg. D
60
for 3 days).
Abbreviations: AR, adverse risk; C, cytarabine; D, daunomycin; DA, daunorubicin and Ara-C; DAC, daunorubicin, Ara-C, and cladribine; ECOG, Eastern
Cooperative Oncology Group; EFS, event-free survival; FR, favorable risk; HIDAC, high-dose cytarabine; I, idarubicin; IR, intermediate risk; JALSG, Japan
Adult Leukemia Study Group; OS, overall survival; PALG, Polish Adult Leukemia Group.
Infection-Related Mortality in Acute Myeloid Leukemia
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AFFILIATIONS
1
Department of Medical Oncology, Tata Memorial Hospital, affiliated to
Homi Bhabha National Institute, Mumbai, India
2
Medical Resident, University at Buffalo School of Medicine and
Biomedical Sciences, Buffalo, NY
3
Department of Microbiology, Tata Memorial Hospital, Mumbai, India
4
Department of Hematopathology, Tata Memorial Hospital, Mumbai,
India
5
Department of Cancer Cytogenetics, Tata Memorial Hospital, Mumbai,
India
CORRESPONDING AUTHOR
Hasmukh Jain, Professor, DM, MD, Department of Medical Oncology,
Tata Memorial Hospital, Mumbai Affiliated to Homi Bhabha National
Institute 81, Ground floor, Main Building, Tata Memorial Hospital, E
Borges Rd, Mumbai 400 0112 India; Twitter: @hkJain_kmc; e-mail:
dr.hkjain@gmail.com.
AUTHOR CONTRIBUTIONS
Conception and design: Hasmukh Jain, Manju Sengar
Administrative support: Vibhor Sharma, Raajit Chanana, Karthik Rengaraj
Provision of study materials or patients: Hasmukh Jain, Manju Sengar
Collection and assembly of data: Hasmukh Jain, Manju Sengar, Vibhor
Sharma, Raajit Chanana, Jayashree Thorat, Karthik Rengaraj, Nikhil
Patkar, Papagudi Subramanian, Avinash Bonda, Lingaraj Nayak,
Prashant Tembhare, Dhanalaxmi Shetty
Data analysis and interpretation: Hasmukh Jain, Manju Sengar, Vibhor
Sharma, Raajit Chanana, Jayashree Thorat, Karthik Rengaraj, Nikhil
Patkar, Papagudi Subramanian, Avinash Bonda, Lingaraj Nayak,
Prashant Tembhare, Dhanalaxmi Shetty, Bhausaheb Bagal, Sanjay
Biswas
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS’DISCLOSURES OF POTENTIAL CONFLICTS OF
INTEREST
The following represents disclosure information provided by authors of
this manuscript. All relationships are considered compensated unless
otherwise noted. Relationships are self-held unless noted. I = Immediate
Family Member, Inst = My Institution. Relationships may not relate to the
subject matter of this manuscript. For more information about ASCO’s
conflict of interest policy, please refer to http://www.asco.org/rwc or
ascopubs.org/go/site/misc/authors.html.
Open Payments is a public database containing information reported by
companies about payments made to US-licensed physicians (Open
Payments).
No potential conflicts of interest were reported.
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nnn
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APPENDIX
P = .36
0.25
0.50
0.75
1.00
0 10203040506070
Time (months)
Survival (probability)
< 2 weeks
2-4 weeks
> 4 weeks
Time from
registration to start of induction
29 14 11 11 6 5 2 0
67 48 33 29 26 21 8 0
2514875520
> 4 weeks
2-4 weeks
< 2 weeks
No. at risk:
FIG A2. Event-free survival according to risk strata.
P < .0001
0.25
0.50
0.75
1.00
0 10203040506070
Time (months)
Survival (probability)
No
Yes
316442200
90 70 48 43 35 29 12 0Yes
No
No. at risk:
FIG A1. Event-free survival curve according to treatment
completion.
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TABLE A1. Mean Duration of Antimicrobial Usage During Induction
Antibiotic
Mean Duration
(days; SD)
Carbapenem 13 (5.9)
Colistin 9 (4.7)
Tigecycline 9 (5.3)
Linezolid 7 (3.5)
Teicoplanin 9 (4.3)
Vancomycin 10 (1.7)
Clindamycin 9 (5.3)
Amphotericin B 12 (4.9)
Caspofungin 12 (6.3)
Voriconazole 11 (7.5)
NOTE. All mean durations are provided as approximate.
Abbreviation: SD, standard deviation.
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