Discussion:
Survival rates in children with ALL have significantly improved over the
years. The 5-year survival rate of 93.5% for St Jude’s Total Therapy 15
is an excellent example of the significant advances in
treatment.[19] Especially in High-Income Counties (HIC), risk groups
are well defined; nutritional problems are less severe, supportive care
conditions are better, hygienic conditions are more suitable, the ratio
of health care personnel per patient is high, access to drugs is faster
than Low-Income Countries (LIC) thus reducing treatment-related death
(TRD, TRM) rate to 1%. Unfortunately, survival rates from low and
middle-income countries are not as reasonable as HIC and range from 30
to 70% for various risk groups [20-22]; and TRD rate is observed at
the level of 11-21%. Poor outcomes may result from lack of adequate
supportive care, poor management of fulminant infections, elevated costs
of health care and financial problems, compliance issues, the inability
to apply current standard treatment protocols, and host factors.
Our results showed that the high remission and low relapse rates of our
patients are pretty satisfactory. All of the patients who completed
induction therapy were in remission at the remission date. Only three
patients had bone marrow relapses, and one had CNS relapse. But the high
number of patients lost due to infectious diseases caused relatively low
OS and EFS.
An overlooked point in evaluating treatment efficacy is treatment
continuity. Gupta et al., in a meta-analysis including middle-income
countries, have shown that the treatment dropout rate had a wide range
of 0-74.5%. There was not any treatment dropout in our
patients.[23]
According to 2019 data, our country is among the Upper Middle-Income
Countries (WorldBank -WB). Due to the location of our hospital, most of
our patients come from low- and middle-income segments of the Turkish
population. According to our study results, our patients’ OS, EFS, and
TRD results are seen between developing and developed countries.
According to WB 2010 data, 83% of the world’s population lives in low-
and middle-income countries. In these countries, the ratio of the child
population to the total population is also higher than in high-income
countries (Low-income 40%, Middle-income: 27%, and high-income:
17%).[24]
In most clinical studies, boys appear to have worse outcomes than girls
when given equal treatment.[25, 26] However, in our study, OS was
84.3% in boys and 73.3% in girls. (p=0.16). In our study, we found
that the biggest problem that caused the decrease in the survival of our
patients was the deaths caused by infectious diseases while the patients
were in remission.
In addition to the risk criteria that predict relapse, measurement of
early responses to therapy and the extent of MRD studies at various time
points in induction, consolidation, and continuation can significantly
improve the accuracy of risk assessment.[27] In our study, MRD
measurement was performed on days 19 and 46 of remission induction, and
on weeks 7, 17, 48, and at the end of the maintenance treatment by using
multicolor flow cytometry, and patients with positive MRD results were
referred to SCT.
Yetgin et al.[16] reported that high-dose methylprednisolone (HDMP)
has a higher cure rate, prolonged remission duration, and EFS rate, and
higher long-term effectiveness compared to the conventional dose
prednisolone administration used in ALL induction therapy. Therefore,
the St Jude Total Therapy XV protocol was used with this minor
modification.
In this study, CNS prophylactic therapy consisted of triple intrathecal
therapy without prophylactic cranial radiation in contrast to previous
Total Therapy studies. Previous study results reported that intensive
intrathecal therapy for HR groups eliminated the need for prophylactic
cranial radiation.[12] In our study, only one patient (0.87%) had
isolated CNS relapse) Furthermore, this result supports that triple
intrathecal therapy without cranial radiation is very effective as CNS
prophylaxis.
When we examined the mortality times of our patients, only three
patients (2.61%) died in the induction phase, and they died due to
infectious causes. According to literature data, mortality at the start
of treatment or induction period constitutes one-tenth of all mortality
or half of treatment-related mortality.[28] From this point of view,
it is seen that our data is compatible with the literature. Again, as an
example of lower-middle-income countries, Khan et al. from Pakistan
published a study that emphasized the induction period mortality was
20.8% in 48 newly diagnosed patients between 2014-15, and that
hemorrhage/bleeding complications were the cause of death in half of
these patients, while infection and related complications were the cause
of death in 40%.[29] This article points out how essential it is to
access blood products and the adequacy of blood centers. In our study,
no patient died due to bleeding alone. However, five patients died
(4.35% of all patients, 21.75% of all mortality) due to disseminated
intravascular coagulation (DIC) accompanied by bleeding. These findings
were valuable in showing how vital infection prevention is. Diba et al.
published their ALL study in Bangladesh (lower middle income – WB)
involving 87 children aged 1-18 years that the cumulative mortality was
found to be 29.9%, and the primary cause of death (22/26, 84.6%) was
septicemia.[30]
Infection is not just a problem of LICs. Although the mortality rate is
low when examined in HIC, infection, and septicemia are still the number
one cause among the causes of TRD. Lund et al. published a study in 2011
that reported TRD as 3.4% and 3.2% in the NOPHO ALL-92 and ALL-2000
protocols. They pointed out that the primary reason for TRD was
infection (73%).[31] Hao et al. retrospectively analyzed a total of
238 children with ALL who were followed up between 2008 and 2018 and
reported 74 deaths (cumulative mortality 31.1%). The primary reason for
this rate, which seems to be relatively high in today’s conditions, is
infection and related conditions (43.2%). Another interesting result in
the same study is that the mortality of male patients is more than twice
as high (73% vs. 27%) compared to female patients.[32] It is known
that mortality is slightly higher in males. However, such a high
difference is not reported in the literature.[2, 33-35] In our
study, cumulative mortality was 20%, and OS was higher in males,
contrary to the literature (84.3% vs. 73.3%). Another study that finds
female gender as a risk factor for TRDs is Lund et al.’s study.[31]
It is clear that with the increase in income, the conditions of care
improve, the access to supportive treatments becomes more accessible,
and the hygiene conditions are of better quality.[31] The effect of
income level on treatment is felt in different regions of the same
country. Koc et al., in the article they published in 2013, found OS
77.4% and EFS 68.9% in the Southeastern Anatolia Region of Turkey,
which has a lower income level compared to the Marmara Region, where our
patient population is located. They reported 12.3% mortality in the
remission induction phase.[36] Again, Öztürk et al. reported a 5-
and 10-year OS as 85.9% in their retrospective review of 98 patients
treated in Istanbul between 1999 and 2014. Significant causes of death
were found to be infection complications and other TRDs.[37]
Study results of various clinical trial groups are summarized in Table
5.
Physicians, the pharmaceutical industry, scientists, politicians,
international health and economic organizations should make childhood
ALL a treatable disease without morbidity. Another issue that is at
least as necessary as this should be the policy of equality in health.
It is the undisputed right of every child to have optimal health
conditions, treatment, and care services. Ensuring these conditions is
everyone’s moral responsibility. Under the leadership of international
organizations such as WHO, IMF, WB, and developed country managers, we
must fight with all our strength to provide all children of the world
with the 90-95% survival rates they deserve in ALL treatment,
regardless of their income level.