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.