PROGNOSTIC VALUE OF PERIPHERAL BLOOD BLAST PERCENTAGE ON DAY 8 IN LONG TERM CURE IN PATIENTS WITH ALL

www.wjpps.com Vol 3, Issue 8, 2014. 1839
Anand et al. World Journal of Pharmacy and Pharmaceutical Sciences
PROGNOSTIC VALUE OF PERIPHERAL BLOOD BLAST
PERCENTAGE ON DAY 8 IN LONG TERM CURE IN PATIENTS
WITH ALL
1
Neeti Vaghela, *Dr. I. S. Anand, 2
Dr. Deepa H. Trivedi, 3
Maulik Jani,
1
Department of Clinical Pharmacy, Shri Sarvajanik Pharmacy College,Mehsana.
*Professor and Head Department of Clinical Pharmacy and Pharmacology, Shri Sarvajanik
Pharmacy College, Mehsana.
2
Pediatric Hemato Oncologist, MD (USA), Vedanta Institute of Medical Sciences,
Hemato Oncology Clinic, Ahmedabad.
3
Department of Clinical Pharmacy, Shri Sarvajanik Pharmacy College,Mehsana.
ABSTRACT
Background and Objective: To correlate the peripheral blood blast
percentage of day1 and day 8 in patients with acute lymphoblastic
leukemia (ALL) post chemotherapy in long term cure outcome.
Settings and Design: Single centric, retrospective study. Method and
material: To determine the prognostic value of peripheral blood blast
percentage, the database of 311 ALL patients who received BFM 90
and MCP 841 treatment protocol was screened from Vedanta Institute
of medical sciences. Patients were classified into Prednisone good
Responder (blast cells<1000) and prednisone poor responder (blast
cells >1000) on the basis of their blast cell count on day 8 as well as
Blast positive (appearance of blast cell any count on day 8) and Blast
Negative (absence of blast cells on day 8) group. Patients with minimal 18 months of follow
up were included in the study. (N=47) Results: Out of 47 patients, 31 were blast negative and
16 were blast positive. The blast negative patients had 76.1% chances while blast positive
patients had 53.3% chances of 2 year event free survival. 42 patients were PGR and 5
patients were PPR. PGR had 71.42% chance of 2 year event free survival. As the sample size
of PPR is small, no statistically significant conclusion can be derived. Conclusion: The result
of our study shows that PGR have a good 2 yr EFS. Blast Negative patients fared much better
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Article Received on
17 May 2014,
Revised on 26 June
2014,
Accepted on 26 July 2014
*Correspondence for Author
Dr. I. S. Anand
Professor and Head
Department of Clinical
Pharmacy and Pharmacology,
Shri Sarvajanik, Pharmacy
College, Mehsana,

than Blast Positive patients. Thus the present study though small in sample size, indicates that
peripheral Blood Blast Percentage on day 8 have reliable prognostic value in long term cure
in children and adults with Acute Lymphoblastic Leukemia.
KEYWORDS: ALL, Prognosis, Blast cells, Prednisone Response.
INTRODUCTION
Acute lymphoblastic leukemia (ALL) is a malignant proliferation of lymphoid cells blocked
at an early stage of differentiation characterized by large amount of immature white blood
cells in the bone marrow, which develops from cells lymphoblast. Most cases of ALL occur
in children, but most deaths from ALL (about 4 out of 5) occur in adults. Children may do
better because of differences in childhood and adult ALL in the disease itself, differences in
treatment (children’s bodies can often handle aggressive treatment better than adult’s), or
some combination of these. [1]
The survival rate has improved from zero four decades ago, to
20-75 percent currently, largely due to refinement and development of new chemotherapeutic
agents, improvements in stem cell transplantation (SCT) technology and supportive care.
Five-year survival rates evaluate older, not current, treatments. New drugs, and matching
treatment to the genetic characteristics of the blast cells, may improve those rates. The
prognosis for ALL differs between individuals depending on a variety of factors such as Age,
Initial WBC, ALL subtypes, Chromosomal abnormalities and response to chemotherapy.
Presence of Blast cells in peripheral blood can be reliable prognostic predictor of treatment
failure. After 7 days of chemotherapy (single agent predinosone in most protocols and one
intrathecal chemotherapy /dose of IV vincristine), presence of the blast cells in peripheral
blood has been proven to have negative significance on treatment outcome. Prednisone
Response is the strongest predictor for treatment outcome in pediatric ALL patients.
We studied database of Vedanta Institute of Medical sciences and reviewed all the ALL
patients enrolled between 2009 and 2012. The aim of the present study was Correlation of
the peripheral blood blast percentage count of day1 and day 8 in patients with acute
lymphoblastic leukemia post chemotherapy as well as to stratify patients based on day 8
reports-if modification of treatment was done and to stratify patients into Prednisone good
and prednisone poor responders.

MATERIALS AND METHODS
The study only included patients; first seen between 2009 and 2012 at the Hemato Oncology
Clinic Vedanta Institute of Medical Science, Ahmedabad, whose follow up data of 18 months
(post treatment) was available. The diagnosis of ALL was based on examination of Bone
marrow aspiration and biopsy. Patients were analyzed for Hb concentration, platelet count,
WBC count, sex, age, lymphadenopathy, spleenomegaly, hepatomegaly, proportion of blast
cells in the peripheral blood. Patients were treated as per BFM-90 or MCP-841 protocol as
per Principle Investigator discretion. From the data Prognostic value of Peripheral blood blast
% on day 1 and day 8 were analyzed. Correlation of the peripheral blood blast percentage
count of day1 and day 8, to long term cure in patients with ALL was done. From the total
data of 311 patients treated during that period, data of 47 patients between the age of 1 to 60
yrs of age, and with at least 18 months of follow up data were included in the study. Patients
were excluded from the study if their records did not indicate the presence of blast cells at
diagnosis or if blood cell counts at Day 8 were unavailable, as well as complete therapy
protocols were not applied or replaced with different treatment, or if there was premature
withdrawal from therapy. If patients lacked essential data and Patient treated with any other
protocol than BFM 90 and MCP 841 were not included in the study. Ethical approval was
obtained from Institutional Ethics Committee.
RESULTS
Out of the total 47 patients, 38 patients (81%) were male and 9 (19%) were female.29
patients (61.70%) were below the age of 18 yrs and 18 (38.30%) were between the age of 18
to 60 yrs as shown in table 1.
Pallor (78.72%), lymphadenopathy (68.08%), hepatomegaly (57.44%) and splenomegaly
(51.05%) were the most common symptoms.Body Pain, weight loss, generalized weakness
and fever were less common symptoms as shown in table 2.
The WBC, Hb and Platelet Counts of the patients on day 1 and day 8 were noted. Patients
with ALL usually have greater than 11000 WBC counts. [2]
. In our study on day 1 (48.93%
patients had wbc >11000).Count on day 8 indicated a decrease in the WBC count due to
chemotherapy in 57.44% of patients. Most of the patients had anemia at the time of diagnosis
as well as after chemotherapy initiation. Platelet Counts were lower than the normal range at
the time of diagnosis in (80.85%) patients as shown in table 3.

After 1 week chemotherapy, out of 47 patients 16 patients had persistent presence of blast
cells on day 8. These patients were classified as Blast positive group and 31 remaining
patients in whom there was absence of blast cells were termed as Blast negative group.
All the 47 ALL patients were further classified on basis of Day 8 Prednisone Response. The
patients who had less than 1000 Blast cells on day 8 were classified as Prednisone Good
Responder (PGR) and patients with more than 1000 Blast cells on day 8 were classified as
Prednisone Poor Responders (PPR). 89.58 % patients were PGR, while 10.42% patients were
PPR as shown in table 4.
35(74.46%) patients were alive at 2 yrs after diagnosis, of whom 33 patients had survival
without events (70.21%) and 2 patients were alive with ongoing Relapse. 14(29.78%)
patients had disease Relapse, of whom 12 patients (25.53%) died and 2 were alive with
relapse.
Out of total 38 male patients, 28 males patients survived, 12 male patients had Relapse of the
disease, from whom 10 died. Among 9 female patients, 7 survived and 2 died of Relapse. In
the present study though prevalence of ALL was higher in pediatric patients, the chances of
relapse was more in the adult than in pediatric patients as shown in table 6
Prednisone Response was determined on day 8 after initiation of chemotherapy by reduction
of the Blast cells in peripheral Blood; Patients who had less than 1000 blast cells/cmm were
termed as Prednisone Good Responders (PGR) while more than 1000 blast cells/cmm were
termed as Prednisone Poor Responder (PPR). 42 patients were PGR and 5 patients were PPR.
PGR Patients had 71.42% chance of 2 year EFS. From the blast negative group of 31 patients
on day 8, 7 patients had disease relapse. Out of 16 Blast Positive patients, 7 Patients
experienced relapse. The blast negative patients had 76.1% chances while blast positive
patients had 53.3% chances of 2 year event free survival as shown in the Kaplan Meier
survival curve (figure-1).
Table 1 Demographic data of the patients
Gender Number of Patients Percentage
Male 38 81%
Female 9 19%
Age group Number of Patients Percentage
1-18 yr 29 61.70%
>18 yr 18 38.30%

Table 2 Symptoms of Acute Lymphoblastic leukemia
Table 3 WBC, Haemoglobin and WBC levels
Symptoms At the time of Diagnosis Percentage
Pallor 37 78.72
Hepatomegaly 27 57.44
Splenomegaly 24 51.06
Lymphadenopathy 32 68.08
Body pain 13 27.65
Weight loss 9 19.14
Generalized weakness 8 17.02
Fever 18 38.29
WBC count
WBC Range/cmm Day 1 (N=47) Day 8 (N=47)
<4000 9 (19.14%) 27 (57.44%)
4000-11000 15 (31.91%) 18 (38.29%)
>11000 23 (48.93%) 2 (4.25%)
Haemoglobin Levels of Children below age of 5 yrs.
Haemoglobin (g/dL) Day 1(N=15) Day 8(N=15)
<7 6 (40%) 2 (13.33%)
7.0-9.9 5 (33.33%) 12 (80%)
10-10.9 1 (6.66%) 0
>11.0 3 (20%) 1 (6.66%)
Children between age of 5-15 yrs and adult females
Haemoglobin(g/dL) Day 1(N=12) Day 8(N=12)
<8 2 (16.66%) 4 (33.33%)
8.0-10.9 8 (66.66%) 7 (58.33%)
11-11.9 0 1 (8.33%)
>12.0 2 (16.66%) 0
Males of 15 yr of age and above
Haemoglobin(g/dL) Day 1(N=20) Day 8(N=20)
<8 9 (45%) 10 (50%)
8.0-10.9 4 (20%) 6 (30%)
11-12.9 5 (25%) 4 (20%)
>13.0 5 (25%) 0
Platelet Counts
Platelets Day 1(N=47) Day 8(N=47)
<150000 38 (80.85%) 31 (65.95%)
150000-450000 7 (14.89%) 15 (31.91%)
>450000 2 (4.25%) 1 (2.12%)

Table 4 Blast cell Group
Table 5 Treatment Outcome
Table 6 Treatment Outcome and association of gender and age
Table 7 Treatment Outcome on the Basis of groups
Blast Positive/Blast Negative Patients Number Percentage
Blast Positive 16 34.05%
Blast Negative 31 65.95%
PGR/PPR Patients Number Percentage
PGR 42 89.58%
PPR 5 10.42 %
Outcome Patients Percentage
Event Free Survival 33 70.21%
Total Relapse 14 29.78%
Death with Relapse 12 25.53%
Survival After Relapse 2 4.25%
Gender Patients Event free Survival Died Due to Relapse
Male 38 26 10
Female 9 7 2
Age Group Patients Event free Survival Died Due to Relapse
1-18 yr 29 23 5
>18 yr 18 10 7
PGR/PPR Patients
Event Free
Survival
Died Due to
Relapse
PGR 42 30(71.42%) 11(26.19%)
PPR 5 3 1
Groups
Blast Positive 16 9 7
Blast Negative 31 24 7
Total 47 33 14

(Figure 1. kaplan meier curve for EFS)
(Figure shows Kaplan meier survival curve. The 2 year Event free survival for the blast
positive patients was 53.3% while that for Blast negative group was 76.1 %, indicating
that blast negative group has more chances of Event free Survival.)
DISCUSSION
Currently used methods for prognostic estimation of minimal residual disease of ALL
includes, multicolor flow cytometry, PCR Assays, detection of fusion gene transcripts or
breakpoints, Real-time quantitative PCR of clonal immunoglobulin and T-cell receptor gene
rearrangements[3,4]
All of these require sophisticated instruments and are costly as well as not widely available in
India. It has been reported that estimation of MRD by the significance of early clearance of
blast cells in peripheral blood on day 8 in ALL patient can be promising tool. Several
investigators have found the significance of peripheral blood blast percentage on day 8 for
prognostic estimation of ALL. [5,6]
The aim of the present study was to correlate the peripheral blood blast percentage count of
day1 and day 8 in patients with acute lymphoblastic leukemia post chemotherapy in long
term cure outcome of children and adults. We screened database of all the ALL patients
treated at the Vedanta Institute of Medical sciences, enrolled between 2009 and 2012. From
the data of 311 patients, data of 47 patients who met all the inclusion criteria and none of the
exclusion criteria was included in the study. Demographic data of 47 patients is described in
table 1.

In an article reviewed by Sallan et al, the prevalence of ALL is more in children than
adults.[7]
The relative frequency of the disease is markedly higher in young children. In
Present study 61.70% patients were in the age group of 1-18 yr, while 38.30% were in the age
group of more than 18 yrs.
By considering, gender wise treatment outcome. Out of total 38 male patients, 28 male
patients survived, 12 patients had Relapse of the disease of which 10 patients died. From
among 9 female patients, 7 survived and 2 died of Relapse. The development of effective
therapy for children with acute lymphoblastic leukemia (ALL) is one of the great successes of
clinical oncology, with long-term survival achieved in over 80% of patients. However, cure
rates for adults with ALL remain relatively low, with only 40% of patients cured.[7]
In present
study though prevalence of ALL was higher in pediatric patients, the chances of relapse was
more in the adult than the pediatrics. No conclusion can be derived from the results as only
25 reports were available, from the database. In two trials, the Berlin-Frankfurt-Munster
group found that circulating blast cell counts > 1000/cmm after 1 week of single agent
prednisone therapy termed as Poor prednisone responders were associated with a
significantly poorer Event Free Survival.[8]
PGR patients had 71.42% 2 year Event free
Survival. As the sample size of PPR Patient was very less, we cannot derive any conclusion
from it.
Gajjar et al ,in 1995 had concluded that the persistence of circulating leukemic blast cells
after l week of multi agent remission induction chemotherapy was an important early
predictor of treatment failure. Only 34% of patients with this feature were alive and free of
disease 5 years after diagnosis, compared with 77% of patients whose peripheral blast cells
had cleared by day 8.[9]
In our study we tried to derive the outcome on basis of blast cells on day8. From the blast
negative group of 31 patients, 7 patients had disease relapse. Out of 16 Blast Positive patients
on day 8, 7 Patients experienced relapse. The blast negative patients had 76.1% chances
while blast positive patients had 53.3% chances of 2 year event free survival. These results
indicate that blast negative group has more chances of Event free Survival.
CONCLUSION
The result of present study shows that Prednisone Good Responders have 73.80% chances of
EFS. Blast Negative patients have 76.1% chances and Blast Positive patients have 53.3%

chances of 2 year EFS which shows that blast negative group has more chances of Event free
Survival. Thus the present study though less in sample size, indicates that Peripheral Blood
Blast Percentage on day 8 have prognostic value in long term cure in children and adults with
Acute Lymphoblastic Leukemia.
REFERENCES
1. Facts 2013, Leukemia and lymphoma society August 2013.
http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/general
cancer/pdf/facts.pdf
2. “Leukemia – Acute Lymphocytic (Adults)”
http://www.cancer.org/acs/groups/cid/documents/webcontent/003109-pdf.
3. Monika B, Thorsten R and Michael Kneb, “Has MRD monitoring superseded other
prognostic factors in adult ALL?” Journal of Blood, 2012 120, 4470-4481
4. NCCN guidelines www.cancer.org
5. Rautonen J, Hovi L and MA Si, “Slow disappearance of peripheral blast cells: an
independent risk factor indicating poor prognosis in children with acute lymphoblastic
leukemia” Journal of Blood , 1988,71,989-991
6. Elaine C, Jose S, Michael L. Hancock, Bassem I, Raul C, Gaston K. “Use of peripheral
blood instead of bone marrow to monitor residual disease in children with acute
lymphoblastic leukemia” Journal of Blood, 2002 100: 2399-2402
7. Sallan E. “Acute Lymphoblastic Leukemiain Adults and Children Myths and Lessons
from the Adult/Pediatric Interface in Acute Lymphoblastic Leukemia”, American Society
of Hematology,2006.128-132
8. Reiter A, Schrappe M, Ludwig WD, Hiddemann W, Sauter S, Henze G, Zimmermann M,
Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients.
Results and conclusions of the multicenter trial ALL-BFM 86.” Journal of Blood, 1994,
84, 3122-3133.
9. Gajjar A, Raul R, Michael L. Hancock, Gaston K. Rivera, Hazern M, John T., William
M. Crist, and Ching-Hon Pui, “Persistence of Circulating Blasts After 1 Week of
Multiagent Chemotherapy Confers a Poor Prognosis in Childhood Acute Lymphoblastic
Leukemia.” Journal of Blood, 1995, 86, No 4 1292-1295.

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