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Infection Prevalence in Adolescents and Adults With Acute Myeloid Leukemia Treated in an Indian Tertiary Care Center

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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 chemotherapy. 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.
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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 signicant 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 t 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
signicant 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 rst 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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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-efciency
particulate air lters. The patientsbeds 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 physicians 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 nding 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, inammation 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 rst-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 dened
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 les and
electronic medical records. Baseline details such as de-
mographic characteristics, presenting symptoms, clinical
ndings, 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 (uorescence 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 ow
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 dened as hypertension, diabetes, heart disease, or
hypothyroidism, as per standard criteria.
b
Fever is dened 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 rst-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.
Efcacy 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 unt 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 signicant 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 signicant inuence 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 ndings 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 reective 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 reects 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 reect 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,
reecting 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 reect
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 signicant 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 Childrens 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.
Infection-Related Mortality in Acute Myeloid Leukemia
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subsequent HIDAC cycles. This is different from the clinical
trial data from the AML-BFM2004, PALG, and Childrens
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 uoroquinolone
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 denitely 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% (Womens 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 efcacy 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, afliated 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 Afliated to Homi Bhabha National
Institute 81, Ground oor, 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
AUTHORSDISCLOSURES 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 ASCOs
conict 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 conicts of interest were reported.
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nnn
Infection-Related Mortality in Acute Myeloid Leukemia
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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.
Jain et al
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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.
Infection-Related Mortality in Acute Myeloid Leukemia
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... [8,9] In addition, infection caused by FN was reported in 63% of AML patients and was substantially linked with higher morbidity and mortality, despite the appropriate empirical antibiotics' treatment. [8][9][10] Several factors have been reported as predictive factors for chemotherapy-induced FN. As a result of risk factor assessment, including performance status, disease stage or disease severity, and chemotherapy regimen, it could be essential for predicting FN occurrence. ...
... [5,6] Currently, various incidences of FN and the risk of chemotherapy-induced FN have been demonstrated in several studies. [6,[9][10][11] However, many previous studies included all types of cancer, including solid tumors and hematologic malignancies. To the best of our knowledge, the incidence and risk factors associated with FN in AML in Thailand are varied. ...
... AML accounts for 70% of all acute leukemias in adults and 20% in children. In India, anecdotal reports from various cancer registries suggest that AML constitutes 1-2% of all cancer incidences [2,3]. Patients with AML present with features of bone marrow failure, typically with acute onset (<30 days), symptomatic anemia, fever, thrombocytopenic bleeding, etc. ...
... In a 121-patient study, a four-year event-free survival (EFS) rate of 35.8% (95%CI, 28-46%) and a median EFS time of 19 months were seen. Nine patients did not survive induction [3]. ...
Article
Full-text available
Background: The induction outcomes of patients with acute myeloid leukemia (AML) in India are at par with western data. But we fear that the absence of a robust defense mechanism during the COVID-19 pandemic and the resultant social, financial, political, and medical disturbance might have influenced outcomes. Hence, this study was conducted to establish relationships between the coronavirus disease 2019 (COVID-19) lockdown and induction treatment outcomes in AML patients. Objective: To determine rates of induction remission, induction failure, and induction mortalities in patients with AML treated during the COVID-19 pandemic and compare those results between lockdown and post-lockdown periods in India. Methods: This retrospective, observational study includes data from patients with AML who were started on induction therapy between May 1, 2020, and December 31, 2020. A total of 53 AML patients' data was included in this study, divided into group 1 (n = 22) and group 2 (n = 31). Based on the COVID-19 pandemic-induced lockdown period in India, patients who were given induction therapy between May 1, 2020, and August 31, 2020, were included in Group 1 (Lockdown Phase group), and patients who were given induction therapy during the post-lockdown phase, i.e., September 1, 2020, to December 31, 2020, were included in Group 2 (Post-Lockdown Phase group). Data from AML patients of both sexes and all age groups were included. Data of patients who died before starting induction chemotherapy or patients who left the hospital before the completion of induction chemotherapy were excluded. Patients on induction therapy, be it intensive chemotherapy (ICT) or low dose chemotherapy (LCT), were included. Outcomes were analyzed after the first two induction cycles or 60 days of starting induction, whichever is earlier. Results: The mean age of patients in Group 1 was 36.23±19.1 years and in Group 2 was 29±22.22 years; gender distribution was comparable in both groups. After the first induction, mortality in Group 1 was 36.36%, and in Group 2 was 45.16% (p = 0.036); partial remission in Group 1 and Group 2 was 50% and 29%, respectively (p = 0.036). Using survival analysis, death (event) after second induction was 149.77 days (111.1-188.5) in Group 1 and 137.23 (111.4-163.1) days in Group 2, which was statistically insignificant. Remission was achieved faster in Group 2, achieving complete remission in the mean of 94.96 days (74.5-115.5), while in Group 1, the mean of 147.18 days (110.9-183.5) (p = 0.034). Conclusions: There was increased induction mortality and reduced complete remission (CR) during the post-lockdown phase despite the increased use of ICT, demonstrating an improvement in supportive care (availability of medicines, blood products). This shows that the improvement in supportive care did not show any change or improvement in the outcome for the patient. The mean days for remission were lower in the post-lockdown period compared to the lockdown phase, and patients who had achieved remission had a durable response.
... Infections, especially drug resistant gram negative and invasive fungal infections continue to be the next most important contributor to treatment related mortality in AML and contributed to 30% of early deaths in our cohort. [20,22,23] Microbiologic evidence of infection was obtained in 30% of patients, with nearly half the isolates being multi drug resistant. MDR infections are increasingly being implicated as the cause of death in Indian patients with AML, at a frequency ranging from 20-40% in various studies including patients with median age ranging from 23 to 40 years. ...
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Globally, overall survival (OS) of older patients with AML continues to be suboptimal with very little data from India. In a multicenter registry analysis, we evaluated 712 patients with AML older than 55 years. Only 323 (45.3%) underwent further treatment, of which 239 (74%) received HMAs, and 60 (18%) received intensive chemotherapy (IC). CR was documented in 39% of those receiving IC and 42% after HMAs. Overall, 100 (31%) patients died within 60 days of diagnosis, most commonly due to progressive disease (47%) or infections (30%). After a median follow-up of 176 days, 228 (76%) of patients had discontinued treatment. At one year from diagnosis, 211 (65%) patients had died, and the median OS was 186 days (IQR, 137–234). Only 12 (3.7%) patients underwent stem cell transplantation. Survival was significantly lower for those older than 60 years (p < 0.001). Patients who died had a higher median age (p = .027) and baseline WBC counts (p = .006). Our data highlights suboptimal outcomes in older AML patients, which are evident from 55 years of age onwards, making it necessary to evaluate HMA and targeted agent combinations along with novel consolidation strategies to improve survival in this high-risk population.
... (19)(20)(21) Infections, especially drug resistant gram negative and invasive fungal infections continue to be the next most important contributor to treatment related mortality in AML and contributed to 30% of early deaths in our cohort. (20,22,23)Microbiologic evidence of infection was obtained in 30% of patients, with nearly half the isolates being multi drug resistant. MDR infections are increasingly being implicated as the cause of death in Indian patients with AML, at a frequency ranging from 20-40% in various studies including patients with median age ranging from 23 to 40 years. ...
Preprint
Full-text available
Globally, overall survival (OS) of older patients with AML continues to be suboptimal with very little data from India. In a multicenter registry analysis, we evaluated 712 patients with AML older than 55 years. Only 323 (45.3%) underwent further treatment, of which 239 (74%) received HMAs, and 60 (18%) received intensive chemotherapy (IC). CR was documented in 39% of those receiving IC and 42% after HMAs. Overall, 100 (31%) patients died within 60 days of diagnosis, most commonly due to progressive disease (47%) or infections (30%). After a median follow-up of 176 days, 228 (76%) of patients had discontinued treatment. At one year from diagnosis, 211 (65%) patients had died, and the median OS was 186 days (IQR, 137–234). Only 12 (3.7%) patients underwent stem cell transplantation. Survival was significantly lower for those older than 60 years (p < 0.001). Patients who died had a higher median age (p = .027) and baseline WBC counts (p = .006). Our data highlights suboptimal outcomes in older AML patients, which are evident from 55 years of age onwards, making it necessary to evaluate HMA and targeted agent combinations along with novel consolidation strategies to improve survival in this high-risk population.
... Therefore, timely diagnosis and initiation of induction chemotherapy are required for complete remission (CR). In India, AML constitutes 1-2% of all cancer incidences [3]. However, with an overall fiveyear survival (OS) of 28.3%, the prognosis of AML remains poor. ...
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Background: The aggressive, genetically diverse group of malignant illnesses known as acute myeloid leukemia (AML) is characterized by clonally related myeloblast invasion of the bone marrow, blood, and other organs. The treatment regimen plays a crucial role in the management of AML, and it is associated with poor overall survival and enhanced risk of relapse. Induction therapy with a 7+3 DA regimen (daunorubicin + ara-C) has been the treatment of choice for young and fit patients. Objective: To evaluate the effect of dose modification in young and fit patients for a modified treatment regimen. Methods: This was a retrospective, observational study of AML patients to analyze the outcomes of modified induction therapy in AML patients enrolled at Dr. B. Borooah Cancer Institute, Guwahati, Assam, India, from October 2021 to March 2022. The outcomes of modified induction therapy with intensive chemotherapy (modified 7+3 DA) and low-intensity chemotherapy decitabine (10 days) and venetoclax + azacytidine (seven days) were considered after the first two cycles or 60 days, whichever was earlier. Results: Data from 31 patients with de-novo AML was analyzed; the median age of the patients was 41 years (range: 2-71 years), and the male-to-female ratio was 1.8. There were seven patients in the pediatric age group (2-13 years), and 19%, 65%, and 13% of patients belonged to favorable, intermediate, and high-risk groups, respectively. With regards to modified induction therapy (n=31), 20 (65%) patients received modified “7+3 DA”, nine (29%) received hypomethylating agents (HMA, decitabine only), and two patients received HMA (azacitidnie) + venetoclax. Additionally, 23/31 patients completed at least two cycles of induction therapy. Overall, 60 day-induction mortality was 13%, and the complete remission (CR) and partial remission (PR) rates were 48% and 26%, respectively. In patients who received modified “7+3 DA”, the CR rate was 55%. Conclusions: The notable reduction in deaths due to infections observed in our study suggests that centers with limited resources for preventing neutropenic complications during induction therapies in AML patients could consider adopting this modified regimen.
... [6] Jain et al. reported that 63% of patients present with baseline infections and sepsis was the most common cause of induction mortality. [7] As risk of infections increase with prolonged neutropenia, despite better CR rates FLAG-IDA has not been widely adopted as the induction regimen in low-middle income countries (LMICs) like India. Therefore, 3 + 7 remains the most commonly used induction therapy for newly diagnosed AML in LMICs. ...
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Abstract: Daunorubicin and Cytarabine (DA; 3+7) has been the standard frontline Acute Myeloid Leukemia (AML) induction regimen resulting in Complete Remission (CR) rates of 50-70%. It is associated with induction mortality of 15-30%. We report a comparative analysis of DA versus fludarabine, cytarabine, G-CSF (FLAG) +/- Venetoclax in resource constrained settings. We conducted a single centre, retrospective analysis of 37 treatment naïve fit AML patients from May 2021 to December 2022 who received either standard DA regimen (Group 1) or FLAG +/- Venetoclax (Group 2). The median patient age was 36.6 years in DA arm (n=18) as compared to 40.1 years in FLAG arm (n=19). CR rates at day 28 were 55.5% in group 1 and 89.4% in group 2 (odds ratio [OR], 7.20; 95% confidence interval [CI], 1.274 -40.678; P= 0.012). Patients in FLAG based therapy arm had shorter duration of neutropenia (P=0.003), fewer episodes of grade 3 febrile neutropenia (P=0.0228), shorter duration of antibiotic therapy (P=0.03), fewer days of 3rd line antibiotic therapy (P=0.0228). Mortality rates were 16.6% (n=3) in (group 1) and 0% (n=0) in (group 2) (p=0.105). Our analysis supports that FLAG based induction regimen is an effective and well-tolerated therapy in treatment naïve fit AML patients.
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PurposeA large number of AML patients present with infection at the time of initial presentation in Indian settings. There is lack of published data on the proportion of patients with infection at initial presentation and its impact on induction mortality.MethodsA retrospective audit of patients with newly diagnosed AML more than 14 years of age, who underwent standard induction chemotherapy between the periods of January 2011 to December 2018, was done. Infection at presentation if any was documented. Induction mortality was defined as death happening within 28 days of starting induction chemotherapy.ResultsAmong a total of 315 cases of AML, 96 (30%) patients underwent induction chemotherapy with 7 + 3 regimen. Documented infection at baseline was present in 30 (31%) of patients. Another 10 patients had fever at the time of presentation but without any documented infection focus. Fifteen patients died within 4 weeks of induction amounting to induction mortality of 15.6%. Induction mortality was 28% among patients with infection at baseline compared with 7% without baseline infections (P = 0.01).Conclusion Around 40% of patients had fever at the time of presentation, and 31% had documented infections. Baseline infections led to increase in induction mortality. We would like to propose that infection at baseline is to be considered as one of the potential variables in the predictive scoring system for induction mortality in developing countries.
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Background: Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential. Methods: To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved. Results: There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses. Conclusions: These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.
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Cytogenetics is considered one of the most valuable prognostic determinants in acute myeloid leukemia (AML). However, many studies on which this assertion is based were limited by relatively small sample sizes or varying treatment approach, leading to conflicting data regarding the prognostic implications of specific cytogenetic abnormalities. The Medical Research Council (MRC) AML 10 trial, which included children and adults up to 55 years of age, not only affords the opportunity to determine the independent prognostic significance of pretreatment cytogenetics in the context of large patient groups receiving comparable therapy, but also to address their impact on the outcome of subsequent transplantation procedures performed in first complete remission (CR). On the basis of response to induction treatment, relapse risk, and overall survival, three prognostic groups could be defined by cytogenetic abnormalities detected at presentation in comparison with the outcome of patients with normal karyotype. AML associated with t(8;21), t(15;17) or inv(16) predicted a relatively favorable outcome. Whereas in patients lacking these favorable changes, the presence of a complex karyotype, −5, del(5q), −7, or abnormalities of 3q defined a group with relatively poor prognosis. The remaining group of patients including those with 11q23 abnormalities, +8, +21, +22, del(9q), del(7q) or other miscellaneous structural or numerical defects not encompassed by the favorable or adverse risk groups were found to have an intermediate prognosis. The presence of additional cytogenetic abnormalities did not modify the outcome of patients with favorable cytogenetics. Subgroup analysis demonstrated that the three cytogenetically defined prognostic groups retained their predictive value in the context of secondary as well as de novo AML, within the pediatric age group and furthermore were found to be a key determinant of outcome from autologous or allogeneic bone marrow transplantation (BMT) in first CR. This study highlights the importance of diagnostic cytogenetics as an independent prognostic factor in AML, providing the framework for a stratified treatment approach of this disease, which has been adopted in the current MRC AML 12 trial.
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Background: To evaluate infection- related mortality in patients with AML treated without preventive antibiotics and antifungals in a middle-income country. Material and methods: Infection related mortality was evaluated retrospectively in 49 pediatric patients. Results: A total of 173 chemotherapy courses were administered as first-line chemotherapy. Four patients died in the induction; one patient due to intracranial bleeding, two patients due to typhlitis and one patient due to invasive fungal infection with pulmonary vascular invasion and massive bleeding. Another two patients died with resistant disease. During consolidation there were four infection-related deaths and one death due to cardiotoxicity. In the first-line chemotherapy mortality was 22% (11/49) and 14% (7/49) was infection-related. Event- free survival and overall survival at six years were 42.9% and 61.2% (95% CI: 44-76 and 66-99 months) respectively. Conclusion: Due to considerable infection-related deaths, antibacterial and mold-active antifungal prophylaxis may be tried during neutropenic periods in pediatric AML.
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Introduction: The treatment of acute myeloid leukaemia (AML) with intensive induction regimens remains a challenge in low and middle incomes countries. Early induction related deaths particularly due to infectious complications are a major problem. This is in stark contrast to high-income countries where induction mortality has declined significantly over the last 2 decades with improved antibiotic use and supportive care. In this study we assess induction mortality (all cause and infection related) in AML patients who received intensive induction therapy in a tertiary cancer centre in India over a 10-year period (2008-2017). Methods: We included patients with newly diagnosed AML treated at Cancer Institute, Chennai in South India who received intensive induction therapy. Intensive therapy was defined as use of any anthracycline with cytarabine (3+7/ADE/others). We assessed baseline demographics including age, gender, cytogenetic risk status, and type of induction regimen used. We also assessed key clinical outcomes including patterns of antimicrobial prophylaxis and treatment, infectious complications, cause of death, ICU stay, and length of hospital stay. Induction mortality was defined as deaths occurring within 45 days of initiating treatment for AML or start of 2nd induction. Results: Between January 2008 and December 2017, 510 patients with AML were evaluated at Cancer Institute, Chennai and accepted for treatment. Excluding 51 patients with APML and 55 patients who were unfit for intensive induction, 404 patients received treatment with an intensive induction regimen. Median age was 23 years (Range: 1-74 years) and 219 (54.2%) were male patients. 165(40.8%) patients were less than 18 years of age. Among those who had cytogenetic and/ molecular data for risk stratification [N=341 (84.7%)], 101 (29.6%) were low risk, 166 (48.7%) intermediate risk and 74 (21.7%) high risk. Therapy details: 318 (78.7%) patients received daunorubicin and cytarabine ('3+7'), 52 (12.9%) received ADE, and 38 (8.4%) received other combinations ofdaunorubicin and cytarabine. 87(21.5%) of the cases had infection at the time of presentation. 389(96.8%) had an episode of febrile neutropenia with 184(45.5%) requiring management in Intensive Care Unit (ICU). Focus of infection could be identified in 294(72.7%) of the patients with 207(51.2%) having a positive culture. The overall incidence of induction mortality over the entire study period was 15.6%(n=63)and 14.8% for the most recent year included (2017). The majority of the deaths (n=53; 84.1%) were due to infectious complications (fig1). Median time to death from start of induction was 19 days. The incidence of fungal pneumonia significantly reduced since 2012 when thethe antifungal prophylaxis was switched from fluconazole to voriconazole (p=0.03). Starting in 2012, an increase in the incidence of multi-drug resistance (MDR) gram negative septicaemia and mortality (MDR: carbapenem resistant enterobacteriacea sensitive only to colistin and tigecycline) was noted. This led to proactive use of colistin in patients with febrile neutropenia and septic shock, a GI focus or baseline stool colonisation by MDR gram negative organisms.Despite this, during the last 4 years(2014-2017), there has been a significant rise in the incidence of sepsis and death due to MDR gram negative organisms (fig2). The proportion of deaths attributable to MDR sepsis is 23.8%. The early use of colistin, tigecycline and carbapenems did not significantly decrease the mortality. Conclusions: The induction mortality remains high at 15.6% and is in contrast to the declining induction mortality in high-income countries. While the morbidity and mortality due to specific infections (specifically fungal pneumonia) have changed over time, there is no signfiicant decline in infectious or all cause induction mortality over the 10 years. In the last four years, MDR gram negative sepsis has been a major cause of morbidity and mortality. The early and increased use of broad spectrum antibiotics like tigecycline, colistin and carbapenems has not led to a decrease in MDR gram negative sepsis. Overall, despite improvements in supportive care and early use of broad spectrum antimicrobial agents, infection related morbidity and mortality remains a substantial challenge in treating acute myeloid leukaemia in low- and middle-income countries. Disclosures No relevant conflicts of interest to declare.
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Multicenter large collaborative research groups have been the cornerstone for advances that have been made in multiple disciplines in medicine. These collaborative groups are specifically useful in situation where no single center based dataset is large enough to effectively address biological and clinical relevant questions that could advance the field. Most such collaborative groups exist in the developed countries and have contributed significantly to the development of the current standards of care in leukemia. The challenges in the developing countries or low middle income countries (LMIC) are distinctly different and often algorithms that have evolved in the developed world may not be applicable, relevant or accessible in the LMIC. It is imperative that these challenges be addressed through large multicenter studies that are located within the LMIC and appropriate local data driven solutions be implemented in response. The 'Hematological Cancer Consortium' is a collaborative group from India currently compromising twelve institutions spread across the country that have come together to collaborate in the field of leukemia. As an initial exercise, to establish denominators a retrospective data analysis was undertaken (Indian acute leukemia research database [INwARD]). Here we present the retrospective analysis of the acute myeloid leukemia (AML) data. Retrospective data from January 2013 to December 2017 was collected from 10 large tertiary centers from across the country (in one center data was available only from January 2017). A central online data capture and management system was in place which was independent of all the participating centers (Clinical Data Management Center [CDMC], Vellore, which is compliant with standard ICH-GCP regulations). In this initial phase some centers contributed data offline to the data management center. A total of 3848 were confirmed to have had a diagnosis of AML in this period of which it was noted that 1766 (46%) received definitive treatment (Fig 1 a). The median age of the patients was 40 years (range: 0-89) and there were 59% males. The age distribution of patients by each decade is illustrated in Fig 1b. 399 (10.4%) were ≤ 18 years). A sample for karyotyping was sent in 2609 (68%) however of these an evaluable karyotype was noted in only 1477 (57%) (Fig 1c), the reasons for lack of evaluable metaphases was not clear. A FLT3 and NPM1 mutation status was evaluated in 1338 (35%) and 1401 (36%) respectively. Of the evaluated patients 20.6% and 21.9% had FLT3-ITD and NPM1 mutated respectively (Fig 1d). Of the 1766 patients that were treated 858 (48.6%) received a conventional 7/3 induction, 170 (9.6%) received hypo-methylating agents while the rest received various abbreviated dose regimens and a small proportion (2.8%) received high dose cytosine based regimens as induction therapy. Antifungal prophylaxis was used by 82% of patients that received therapy. Of those that received induction therapy there were 18% induction deaths and 12.9% subsequently received an allogeneic SCT as part of their consolidation therapy (Fig 1a). The 5 year KM estimate for overall and event free survival for the patient that received treatment was 56.2±2.6% and 33.8±2.4% respectively. The data illustrates significant challenges and opportunities with the management of AML in India. A significant proportion of cases do not receive definitive therapy nor do they have conventional tests such as karyotyping or molecular tests done as part of the baseline diagnostic tests, various social and financial constraints could contribute to these and these need to be evaluated in more detail. Strategies to increase access to care and laboratory facilities along with an effort to reduce early induction deaths need relatively urgent attention. The relatively young age of the cohort and large number of cases would allow us to address relevant biological and clinically challenges effectively, in the future, in this cooperative setting. Disclosures No relevant conflicts of interest to declare.
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Background: Acute Myeloid Leukemia (AML) is a very aggressive cancer with difficult treatment and poor outcomes. The treatment of these patients is quite challenging due to various reasons including the need for extensive supportive care, and high cost of therapy. Reports on outcomes from India are few. Methods: We analyzed 93 adult patients (≥ 18 years) with AML who were treated with curative intent between 2007 and 2014. Patients received daunorubicin at dose of 60-90 mg/m2 and cytarabine 100 mg/m2 during induction and consolidation with 3 courses of high dose cytarabine (1.5-3 g/m2per dose for 6 doses per cycle). Only 4 patients underwent consolidation allogenic stem cell transplantation in first remission (CR1). Results: The median age was 37 (18-66) years; males: 52%. Conventional cytogenetics (N = 63) showed 23% (N = 15), 56% (N = 35), 27% (N = 13) in good, intermediate risk and poor risk category respectively. FLT3-ITD was positive in 12/33 (36%) and NPM mutation in 7/23 (30%). Daunorubicin dose was 60 mg/m2 in 75% (N = 70) and 90 mg/m2 in 25% (N = 23) patients. Induction mortality was 17% (16/93) [60 mg/m2:19% (13/70), and 90 mg/m2:13% (3/23); p = 0.39)]. Complete remission was achieved by 60% (56/93) [60 mg/m2:53% (37/70), and 90 mg/m2:83% (19/23); p = 0.09)]. The median overall survival was 9.2 months and the actuarial survival at 2 years was 30%. By univariate analysis, FLT3-ITD positivity, white cell counts higher than 100,000/mm3 at presentation, and use of lower dose of daunorubicin in induction were associated with poorer outcomes. Conclusions: Outcomes in adult AML are generally poor. Many patients with high risk disease don't receive allogenic transplantation in CR1. Increased availability of allogenic stem cell transplantation may help to improve outcomes.
Article
Mounting evidence indicates that the presence of measurable ("minimal") residual disease (MRD), defined as posttherapy persistence of leukemic cells at levels below morphologic detection, is a strong, independent prognostic marker of increased risk of relapse and shorter survival in patients with acute myeloid leukemia (AML) and can be used to refine risk-stratification and treatment response assessment. Because of the association between MRD and relapse risk, it has been postulated that testing for MRD posttreatment may help guide postremission treatment strategies by identifying high-risk patients who might benefit from preemptive treatment. This strategy, which remains to be formally tested, may be particularly attractive with availability of agents that could be used to specifically eradicate MRD. This review examines current methods of MRD detection, challenges to adopting MRD testing in routine clinical practice, and recent recommendations for MRD testing in AML issued by the European LeukemiaNet MRD Working Party. Inclusion of MRD as an end point in future randomized clinical trials will provide the data needed to move toward standardizing MRD assays and may provide a more accurate assessment of therapeutic efficacy than current morphologic measures.
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Infection, especially invasive fungal infection (IFI), is an important complication of chemotherapy and stem cell transplantation. It is also a well-known risk factor in pediatric hematologic malignancy, acute myelogenous leukemia, recurrent disease and allogeneic stem cell transplantation. We previously revealed that a diagnosis of acute myelogenous leukemia, recurrent disease and >10 years of age were risk factors for IFI in patients with pediatric hematologic malignancies. We examined and compared the incidence, risk factors and mortality rate from IFI between 276 patients from 2007 to 2016 and patients in our past report. The cumulative incidence of IFI was 10.5%; this comprised cases of probable and possible IFI at rates of 5.1% and 5.4%, respectively. Univariate analysis showed that age >9 years at admission, recurrent disease and acute myelogenous leukemia diagnosis were risk factors for IFI. Similar to the results of the previous study, multivariate analysis showed that each of these 3 variables was an independent predictor of IFI. The survival rate was lower in patients with IFI than in those without IFI (38.8% versus 69.9%; P < 0.001). However, IFI was a direct cause of death in only 2 patients. Although 11 patients received stem cell transplantation after IFI treatment, only 2 patients have survived, and the other 9 patients died of other complications.