Retrospective study of Dana Farber Consortium Protocol in newly diagnosed Egyptian adolescents and young adults with acute lymphoblastic leukemia: Tanta experience

Intensive acute lymphoblastic leukemia (ALL) regimens in children improve the 5-year event-free survival (EFS) to reach ~ 90%. Adolescents and young adults (AYA) have EFS (30% to 45%). Young AYA ALL patients treated with pediatric chemotherapy protocols such as Dana Farber Consortium Protocol (DFCP) experience a better prognosis. This study aimed to assess the efficacy [EFS and overall survival (OS)] and the toxicity of DFCP in the treatment of Egyptian AYA with newly diagnosed ALL. A retrospective study was performed on 41 patients with newly diagnosed ALL (15 and 39 years) who were treated with DFCP. EFS and OS were estimated using the Kaplan-Meier method. Thirty-eight patients (92.68%) achieved complete remission (CR). Eleven patients (26.83%) relapsed. Ten (24.39%) patients died. One, two, and three years of EFS were 75.61%, 72.91%, and 67.51% respectively. One, two, and three years OS were 85.3%, 77.26%, and 74.39% respectively. Neutropenia was the most common adverse event observed in 100% of patients. DFCP can be considered as an effective ALL protocol for the AYA group of patients with good CR, EFS, and OS rates. DFCP seemed to be feasible in AYA despite the toxicities experienced.


Background
Acute lymphoblastic leukemia (ALL) is a heterogeneous lymphoid neoplasm characterized by a malignant transformation and proliferation of lymphoid precursors in the bone marrow, blood, and many other organs [1]. ALL is the most common pediatric malignancy represents about 75% of acute leukemia among this age group; while in adults; ALL represents about 20% of all leukemia [2].
The survival rates for ALL patients have improved significantly due to advanced diagnostics especially for minimal residual disease, new targeted therapy, and the use of allogeneic bone marrow transplantation (BMT) [3].
So, this study aimed to assess the efficacy [Event free survival (EFS) and overall survival (OS)] and the toxicity of the DFCP in the treatment of Egyptian adolescents and young adults with newly diagnosed acute lymphoblastic leukemia.

Patients
This was a retrospective study performed on 41 patients with newly diagnosed ALL who were treated with DFCP selected consecutively and diagnosed between January 2014 and December 2017 at Tanta Cancer Center (acute leukemia unit) and Hematology Unit, Internal Medicine Department, Faculty of Medicine, Tanta University.
The diagnosis of ALL was based on the characteristic presence of 20% or more lymphoblast in bone marrow (BM) examination and was confirmed by immunophenotyping and cytogenetic and /or molecular studies [10].

Eligibility criteria
The patients included in this study were newly diagnosed ALL with no prior chemotherapy, aged between 15 and 39 years.
ALL patients with performance status Eastern Cooperative Oncology Group (ECOG) (3 or more) and patients with chronic renal, hepatic, or uncontrolled severe cardiovascular disease and pregnant women were excluded. Patients with an uncontrolled active infection, human immunodeficiency virus, active psychiatric illness, cerebrovascular accident or hemorrhage, or prior history of pancreatitis were also excluded.
Treatment protocol: (Table 1) All patients received DFCP with supportive therapy [11]. Imatinib or dasatinib was added to the protocol in the case of Philadelphia positive [12].

Data collection
Data were collected by reviewing patients' records. Records with incomplete data (four patients) were omitted from the study. Every patient has a file with a private code number to ensure the privacy of our patients. All patients' data were handled according to ethical standards in accordance with the Declaration of Helsinki. Signed informed consents from all alive and still followed up included patients were taken before the starting of data collection. Data that were collected included age, sex, history, physical examination, and initial laboratory investigations including complete blood count (CBC), BM aspiration, immunophenotyping, cytogenetics study, and BCR-ABL1 test.

Follow-up
While patients on therapy complete blood counts and BM aspirations with other routine investigations were done for assessing the patient's response. The patients were followed up weekly by complete blood counts for 33 weeks during phase II induction, central nervous system (CNS) prophylaxis, and phase III intensifications therapy. After the completion, patients were followed up by the complete physical examination, blood cell counts, and routine chemistry; every month during the first year. Thereafter, every 3 months in the 2 nd year then half-yearly from the 3 rd year. BM aspiration was done every 6 months or as needed clinical for 5 years. BCR-ABL1 was done periodically every 3 months for Philadelphia positive patients [8].
Minimal residual disease (MRD) was evaluated postinduction and those who achieved more than 0.1% were referred for allogeneic BMT with Philadelphia positive and relapsed patients [8].
Response to treatment [8] Complete remission Less than 5% blasts in BM, no peripheral blood blasts, absolute neutrophil count at least 1 × 10 9 /L, platelet counts of at least 100 × 10 9 /L, and no extramedullary disease, if only platelets count and/or absolute neutrophil count not reach to the target complete remission (CR) with incomplete blood count recovery.

Refractory disease
Failure to achieve CR at the end of induction.

Relapsed disease
The reappearance of blasts in the blood or bone marrow (> 5%) or any extra-medullary site after CR.

Outcomes
Event-free survival (EFS) was calculated from the date of ALL diagnosis till the date of treatment failure, ALL relapse, last follow-up, or death. Overall survival (OS) was calculated from the date of ALL diagnosis to the date of last follow-up or death.

Statistical analysis
The collected data were analyzed using SPSS version 23 software (SPSS Inc, Chicago, ILL Company). Non-parametric distributed quantitative data are expressed as median and range. Categorical variables are expressed as numbers and percentages. Cumulative Incidence of EFS and OS were estimated using the Kaplan-Meier method. P value ≤ 0.05 was considered statistically significant.

Results
Patients' characteristics: (Table 2) Forty-one patients with newly diagnosed ALL were included in our study with a median age of the patients was 28 years (range 18-39 years). Male was the predominant Table 1 Dana Farber Consortium Protocol used in the study [11,12]  Outcome results: (Table 3) Thirty-eight patients (92.68%) achieved complete remission (CR), only 3 (7.32%) were refractory. Eleven patients (26.83%) relapsed (seven in the 1 st year, three in the 2 nd year, and one after that). Two patients out of the eleven relapsed patients had CNS relapse manifested by facial palsy and persistent headache with severe vomiting. Ten (24.39%) patients died (three just after induction after they became refractory and seven of them died after relapse). The median follow-up period was 42 months (95% CI, 27.981-38.068). One-, two-, and three-year event-free survivals (EFS) were 75.61%, 72.91%, and 67.51% respectively ( Fig. 1). One-, two-, and three-year overall survivals (OS) were 85.3%, 77.26%, and 74.39% respectively (Fig. 2).
Toxicity: (Table 4) All the patients (100%) had DFCP side effects; some patients had more than one side effect. No major side effects were observed that necessitated treatment discontinuation. Neutropenia was the most common adverse event observed in 41 patients (100%). Many other adverse events were also developed in patients under DFCP in the form of thrombocytopenia, febrile neutropenia, infections, hyperglycemia, mucositis, venous thromboembolism, neuropathy, hepatotoxicity, pancreatitis, and avascular necrosis. No other long-term side effects were developed during the follow-up period. No patient developed an allergy.
Raw data of all patients of the study were mentioned in (Table 5).

Discussion
Adolescent and young adult (AYA) ALL patients represent a special patient group, as they may receive chemotherapy based on either pediatric or adult chemotherapy protocol [13]. The favorable outcomes found in children, coupled with unfavorable outcomes noticed in AYA, generated the idea for practical use of pediatric protocols among AYA. Also, many novel drugs such as Blinatumomab, inotuzomab, and chimeric antigen receptor T cell have been established to improve outcomes in poorly responding, relapsed, or refractory B cell ALL [14].
In ALL, AYA patients have poorer EFS and OS compared to children, because AYA tends to have unfavorable characteristics, such as T cell phenotype, more incidence of Philadelphia chromosome (9;22), and less occurrence of favorable chromosomal abnormalities such as hyperdiploidy [15]. In our study, immunophenotyping study revealed 26.83% of our patients were T-ALL, and 19.51% were Philadelphia chromosome-positive. These results coincide to a great extent with literatures, as in adults, T-ALL accounts for about 25% of cases, also Philadelphia chromosome in adults ALL can range from 15 to 50% increasing with age [16].
Several retrospective studies have shown that AYA patients who received pediatric protocols have better outcomes (CR 90-99% and EFS 63-80%) when compared with AYA patients who received adult protocols (CR 80-94% and EFS 34-71%) [17]. Although, one study by Usvasalo et al. [17] showed no superiority of both pediatric and adult protocols regarding CR and EFS.  Several factors may clarify better outcomes in pediatric protocols. Firstly, pediatric protocols have more non-myelosuppressive drugs with more activity on leukemic cells particularly during the BM suppression phase induced by anti-metabolites and anthracyclines. Moreover, in pediatric protocols, CNS prophylaxis as intrathecal methotrexate was administered earlier, more frequently, and for a longer time as CNS is the shelter for blast cells. Also, the maintenance therapy period is shorter in adult protocols [18,19].
In our study, forty-one patients received the pediatric protocol DFCP, Thirty-eight patients (92.68%) achieved complete CR, eleven patients (26.83%) relapsed, and ten (24.39%) patients died. One-, two-, and three-year EFS were 75.61%, 72.91%, and 67.51% respectively. One-,  These results coincide to a great extent with some differences reported in many studies. DeAngelo et al. [20] used DFCP for the treatment of 74 adult patients (18-50 years) with ALL. Eighty-four percent of the patients achieved CR, with 2-year EFS and OS of 72.5% and 77.1%, respectively.
As ALL therapies have more intensified, more toxicities have been increased especially in AYA patients. The toxicities of intensified protocols increase in both incidence and severity due to hormonal changes, body weight changes, and different chemotherapy metabolism [25]. Researchers are focused on decreasing early and late toxicities by good use of supportive care to improve OS [26].
Pancreatitis and venous thromboembolism are usually linked with L-asparaginase use in DFCP but may be related to increased steroid dose and the use of dexamethasone [27,28]. Avascular necrosis incidence was more experienced in DFCP trials using dexamethasone [29]. Hyperglycemia risk is more likely in the AYA patients of ALL due to adult hormonal changes, and is usually associated with immune suppression and the risk for infections [30].
These results match with a great extent with some differences that were reported in many studies. DeAngelo et al. [20] shown in their study that the incidence of venous thromboembolism (19%) and pancreatitis (13%) but this drug-related toxicity was controllable.
The discrepancy between results of our study and other previous studies could be explained by variations in number and age of patients, follow-up time, ALL phenotype (B or T), Philadelphia chromosome incidence, the occurrence of favorable, and unfavorable chromosomal abnormalities, ethnic differences, and regimens of chemotherapy used as DFCP has many modifications. To our knowledge, this is the first study to collect data from Egyptian ALL patients. The present study had some limitations such as a small number of patients and a short time of followup. Also, our study was retrospective; therefore, unrecognized biases might be considered. To    Table 5 Raw data of all patients of the study overcome these limitations, further larger, longer, prospective, and multicenter studies are necessary.

Conclusion
DFCP can be considered as an effective ALL protocol for the AYA group of patients with a good complete remission, event-free survival, and overall survival rates. DFCP seemed to be feasible in AYA despite the toxicities experienced which overcame by good supportive care and temporary cessation of some drugs.