Improving survival of Acute Lymphoblastic Leukemia (ALL) in adult patients has been a challenge for hematologists. Despite intensive chemotherapy, only 30 to 45% of patients maintain prolonged remission, compared to the excellent results after treatment in children.1,2,3,4 In the 21st century, intensive pediatric-inspired chemotherapy regimens demonstrated improved survival for older adolescents and young adults (AYA).3,5-7

The St. Jude Total Therapy XIIIB high-risk arm protocol is an example of an intensive chemotherapy regimen designed for pediatric patients in which post-remission therapy can be administered in an outpatient setting.6 This advantage is ideal for treating patients in our public health system, due to the scarcity of hospital beds for intensive chemotherapy management, as previously demonstrated by a Brazilian pediatric group.7

Reports on treatment results of adult ALL patients are sparse in Brazil. To our knowledge, the only available prospective cohort showed an overall survival (OS) of 41% at 5 years.8 On the other hand, a recent retrospective study of Brazilian adult ALL patients treated with a GMALL-based regimen showed a modest OS of 15.3% at 6 years.9 The main possible reasons for these results were delayed diagnosis, increased toxicity of intensive chemotherapy regimens and resources constraints in the Brazilian public health system.8,9

The survival of ALL patients at our institution until 2003 was 12 - 16% (unpublished data). Considering the best results of several pediatric-based intensive regimens to treat young adult ALL patients in the period between 2004 and 2013, our group decided to treat them with a pediatric-inspired chemotherapy or an adult-basis regimen, according to their age and risk factors. The objective of this report was to describe the results of this intensive chemotherapy treatment approach in a real-world setting for adult ALL patients diagnosed at the Hospital de Clínicas do Paraná (CHC-UFPR).

We retrospectively reviewed 72 medical records of patients diagnosed with ALL and treated at the CHC-UFPR from 2004 to 2013. These patients had not been previously treated. In this period, patients older than 14 years were assigned to either the St. Jude Total Therapy XIIIB high-risk arm6 (St. Jude) or the CALGB 881110 (CALGB) regimen (Table 1), according to age and risk factors. The following criteria were used in assigning patients to the St. Jude arm:

• 1)

  20 years old or younger;

• 2)

  Low-risk disease if older than 20 years and younger than 35 years old.

Criteria for low-risk disease were the following:

• 1)

  < 30×109/L for B-lineage ALL and < 100×109/L for T-lineage ALL;

• 2)

  Absence of central nervous system (CNS) infiltration;

• 3)

  Absence of t(9;22), t(4;11) or hypodiploidy;

• 4)

  Complete remission after induction;

• 5)

  No previous chemotherapy for any cancer treatment, nor previous use of corticosteroids for prolonged time (case-by-case decision).

Patients older than 35 years old or patients with high-risk disease and age between 20 and 35 years old were assigned to the CALGB arm and evaluated for allogeneic hematopoietic stem cell transplantation (HSCT). Eight patients with mature B ALL (Burkitt's lymphoma) and two with mixed phenotype acute leukemia were excluded from the analysis. One patient who died before starting chemotherapy and three patients who were treated with other chemotherapy regimens were also excluded.

Patients with confirmed Philadelphia ALL (Ph+ ALL) were also treated with imatinib, as neither dasatinib nor ponatinib are available in the Brazilian public health system for first-line therapy. Non-remission patients after induction were assigned to salvage therapy. Patients unfit for chemotherapy were treated with supportive care, which consisted of corticosteroids, red blood cells and platelet transfusions and antibiotics.

The leukemia morphologic and multiparameter flow cytometry (MFC) classification was based on the WHO criteria.11-13 Conventional karyotyping and molecular analysis were performed to detect chromosomal abnormalities and the BCR-ABL fusion gene, respectively. The central nervous system (CNS) infiltration criteria were defined by the presence of at least 5 cells per cubic millimeter in the cerebrospinal fluid and confirmed MFC lymphoblasts.

Complete remission required normalization of peripheral counts (hemoglobin ≥ 7.0 g/dL, granulocyte count ≥ 1×109/L and platelet count ≥ 100×109/L) and no more than 5% blast cells in the bone marrow by day 28 of induction. Quantitation of minimal residual disease (MRD) was performed by 4 colors flow cytometry.14 A bone marrow blast count threshold of < 0.01% (10−4) was established for flow cytometry MRD assessment. Although the MRD was routinely tested, it was not utilized for the purpose of treatment consolidation with HSCT. There were no robust data in that period that detectable MRD in adult patients was a solid marker of high-risk disease and best managed with HSCT.

All the information was extracted from the Hospital Information System.

Descriptive statistical analyses were performed with the Excel 2016 and EZR v1.35 programs. Survival curves were plotted with the Kaplan-Meier method and were compared with the log-rank test. Multivariable analysis with the Cox proportional hazard regression model was used for survival.

This study was approved by the CHC-UFPR Ethics Committee under the Certificate of Presentation for Ethical Consideration (CAAE) number 77963217.9.0000.0096.

Acute lymphoblastic leukemia in adults and particularly in the AYA population (15 to 39 years) remains a difficult clinical problem, especially regarding therapy selection.3,4 Data related to results of intensive pediatric regimens, compared to standard adult chemotherapy, are still growing, yet differences in disease features, response to treatment and social factors may be responsible for the worse prognosis in this group.3 On the other hand, although cytogenetic and clinical characteristics matter, response measured by the MRD and access to transplant are crucial to survival in this population.1,2

In this article, Brazilian ALL patients were evaluated retrospectively over a 10-year period and received either an intensive pediatric approach based on the St. Jude protocol or an adult-basis protocol proposed for the CALGB group, depending on their age and disease risk at diagnosis. The St. Jude treatment arm was comprised of younger patients and lower-risk disease, while the CALGB arm was the opposite. Approximately one-third of the cohort were under 20 years of age, most of them (n = 17) in the St. Jude arm.

Although there was no difference in the induction response rate between the two treatments, the St. Jude intensive post-remission chemotherapy improved survival, compared to the CALGB regimen, with a 32.6% vs. 7.4% survival rate at 10 years. However, no survival benefit was found for patients younger than 20 years old. This lack of benefit might have occurred as a combined result of mortality due to septic shock, low number of bone marrow transplants despite detectable MRD after induction and, consequently, a higher number of disease relapses. The St. Jude induction phase was highly toxic, with prolonged aplasia and some early deaths. Likewise, the unexpected DFS rate derived from the high number of non-relapse deaths.

Of note, there were two isolated CNS relapses and one CNS plus extramedullary relapse in the St. Jude arm. Although the St. Jude Total Therapy XIIIB intensive intrathecal chemotherapy markedly reduced the CNS relapse rate,5,15 very late cranial irradiation (at week 56) may be responsible for the relapses, including this cohort, especially if high-risk features at diagnosis are present.15

The multivariable analysis demonstrated that undetectable MRD and access to bone marrow transplantation favored survival, which is in accordance with the international literature,1 although this effect was not seen for the low-risk karyotype and the St. Jude regimen. However, the HSCT advantage must be interpreted with caution, as this result may be due to selection bias. The absence of karyotyping and MRD testing for some patients (including living St. Jude-treated patients) precluded better assessment of risk factors and their influence on survival. Additionally, probably related to high etoposide dose exposure, there were two secondary cases of acute myeloid leukemia in the St. Jude group, which is in accordance with long-term St. Jude Total Therapy XIIIB results.15

It must be emphasized that testing for the BCR-ABL fusion gene (p190 and p210) and high-risk karyotypes is of utmost importance, as these patients are prone to relapses and worse outcomes. Furthermore, the HSCT might overcome these adverse risk factors, as in this cohort the HSCT favored a better outcome. MRD testing is also extremely important. Currently, the MRD is a well-stablished independent risk-factor of worse prognosis, also predicting relapse and decreased survival.16,17 We acknowledge that the HSCT should have been offered to those with detectable MRD, however, robust information on the prognosis in this MRD setting was lacking in the period analyzed in this article. Other authors also published their difficulties in interpreting survival data in the absence of reports on the MRD in an analyzed period when its role was not very well defined either.18 Better assessment of survival between detectable vs. undetectable MRD may have been precluded.

The result of this study is in agreement with several others that demonstrated the same relation between intensive therapy and better survival in adult patients.3,15,19,20 In the same manner, the overall response of 22.9% was better than the previous period mentioned (12 - 16% in the early 2000´s). Conversely, the percentage of survival in those other studies is higher, when compared to the Brazilian experience.8,9 This discrepancy could be explained by the lack of resources in public hospitals for better supportive measures, such as availability of broad-spectrum antibiotics and intensive care unit beds for septic shock treatment. Complex social, economic and psychological factors may have affected therapy adherence and influenced survival as well and those are also concerns of other low-income countries, as shown by the Indian Hematology Cancer Consortium group's correspondence.21 Furthermore, we cannot know if the Philadelphia-like ALL has influenced the outcomes. This group of mutations is more frequent in Latin ethnicity and confer a poor prognosis.22,23 However, molecular tests are not widely available in Brazil for testing these mutations and consequently, not commonly reported. Finally, a retrospective analysis is the major limitation of this report, which may have led to selection bias and favored the intensive pediatric-based chemotherapy regimen.

Acute lymphoblastic leukemia is still a disease of poor prognosis for the adult population. Especially in our country, pediatric-inspired intensive chemotherapy and wide population access to bone marrow transplantation are still challenges for the Brazilian public health system. The joint effort of several centers to standardize treatment and seek solutions is the way to start improving this scenario.