|Ahead of print publication
Outcome of adult acute lymphoblastic leukemia, a single-center experience
Hawar Ghareb Khudhur1, Kawa Muhamadamin Hasan2, Ranan Kardagh Polus3, Ahmed Khudair Yassin2, Nawsherwan Sadiq Mohammad4, Saya Salahaldeen Najmaldeen1
1 Clinical Hematology, Nanakali Hospital, Erbil, Kurdistan Region, Iraq
2 Department of Medicine, College of Medicine, Hawler Medical University, Erbil, Kurdistan Region, Iraq
3 Department of Pathology and Medicine, College of Medicine, Hawler Medical University, Erbil, Kurdistan Region, Iraq
4 Laboratory Hematopathologist, Nanakali Hospital, Erbil, Kurdistan Region, Iraq
|Date of Submission||28-Jul-2022|
|Date of Acceptance||11-Aug-2022|
|Date of Web Publication||05-Dec-2022|
Hawar Ghareb Khudhur,
Clinical Hematology, Nanakali Hospital, Erbil, Kurdistan Region
Source of Support: None, Conflict of Interest: None
BACKGROUND: Adult acute lymphoblastic leukemia (ALL) has a dismal outcome within the optimal situations as the 5-year overall survival (OS) is not reaching 40%.
OBJECTIVE: The objective of this study was to evaluate the outcome of adult ALL in Erbil, Iraq, and to see the factors predicting better survival among them.
PATIENTS AND METHODS: We analyzed data from 71 adult ALL patients aged 14–81 years (mean age: 28.6 years). Diagnosis is based on the peripheral blood film, bone marrow examination, and flow cytometry.
RESULTS: The median OS was 21 months and the median relapse-free survival (RFS) was 13 months. The 3-year OS and the 3-year RFS were 49.3% and 40.8%, respectively, while the 5-year OS and the 5-year RFS were 37.5% and 32.5%, respectively.
CONCLUSION: Factors predicting better survival included in the study; age at diagnosis, remission achievement at first induction, risk assessment, and allogeneic stem cell transplantation optimal response.
Keywords: Adult acute lymphoblastic leukemia, overall survival, Philadelphia chromosome
|How to cite this URL:|
Khudhur HG, Hasan KM, Polus RK, Yassin AK, Mohammad NS, Najmaldeen SS. Outcome of adult acute lymphoblastic leukemia, a single-center experience. Iraqi J Hematol [Epub ahead of print] [cited 2023 Mar 22]. Available from: https://www.ijhonline.org/preprintarticle.asp?id=362631
| Introduction|| |
Acute lymphoblastic leukemia (ALL) is an aggressive malignancy of precursor T and B lymphoid cells. Age has a major influence on the incidence and outcome of ALL. While it is one of the common malignancies in the pediatric age group,,, ALL is rare in adults. It has a bimodal distribution, having the first peak in 4–5 years and the second peak after 50 years of age. Overall, the age-adjusted incidence is 1 per 100,000 population.
ALL has a very disappointing outcome in adults with a 5-year overall survival (OS) not reaching 40%, unlike its outcome in pediatrics which has a 5-year (OS) exceeding 80%. These are due to the increasing incidence of adverse prognostic factors, having more comorbidities, and dose reductions that are needed for increasing age.,,,,
While most of these data come from the developed countries where ALL has been extensively studied, there is little information and study in the developing and undeveloped countries regarding the characteristics and outcome of this serious disease.
This study is an attempt to understand the outcome of adult ALL in a single-center hospital in Iraq, to know whether its outcome is comparable with the rest of the world or not, as sometimes the diagnostic and therapeutic approaches are strict within the standard guidelines due to many regional-related factors.
| Patients and Methods|| |
In this retrospective cohort study, 71 diagnosed ALL cases are included aged 14–81 years (mean age: 28.6 years), from January 2012 to November 2018 in Nanakali hospital for hematologic disorders and cancer in Erbil–Iraq with the past follow-up dated December 31, 2021. Any of the following features if present, the patient would be excluded from the study; ALL younger than 14 years, ALL transformed from chronic myeloid leukemia or other myeloproliferative neoplasms, ALL cases who received chemotherapy previously for any cancer, lymphoblastic lymphoma (LL), Burkitt's leukemia/lymphoma (ALL-L3).
Diagnosis is made by detection of 20% lymphoblast in the peripheral blood and/or bone marrow, confirmed by flow cytometry on the peripheral blood or bone marrow aspirate sample. The assessment of the central nervous system (CNS) involvement was done by examining cerebrospinal fluid (CSF).
Patients were grouped as standard risk if they have none of the following and high risk for having any of the following: Age 35 years and older, white blood cell (WBC) >30 10⁹/l for B lineage or >100 × 10⁹/l for T lineage, presence of BCR-ABL rearrangement, CNS involvement at presentation, and failure of complete remission after 4 weeks of induction therapy.
Three chemotherapy protocols and best supportive care are used for treatment, including the medical research council United Kingdom ALL (UKALL XII) protocol, Hyper-CVAD, and Dana–Farber protocol. Patients who were positive for BCR-ABL, a tyrosine kinase inhibitor (TKI) were added for their treatment. Allogeneic stem cell transplant (ASCT) is suggested for candidate high-risk patients.
For induction response evaluation, bone marrow aspirate was examined at the end of induction. Hematologic complete remission was defined as undetected blast in the peripheral blood, cerebrospinal fluid, and <5% blasts in the bone marrow with no leukemic infiltration of other organs.,
The appearance of blast in peripheral blood, CSF, or anywhere or increased marrow blast after achieving remission was defined as relapse., The time from the diagnosis of ALL to the date of death or last follow-up was determined as OS. Relapse-free survival (RFS) was defined as the time from remission to relapse or nonrelapse death.
Data analysis was done using Statistical Package for the Social Statistical Package for the Social Sciences (SPSS, version26, IBM, NY, United States of America). Qualitative data are expressed as frequency and percentage and quantitative data as mean and median. For the identification of an association between different parameters, Chi-square and t-test were used. Survival rates were analyzed using Kaplan–Meier method. P ≤ 0.05 were considered statistically significant.
The ethics committee of the Kurdistan Higher Council for Medical Specialties approved this article. Informed consent was taken from patients and Nanakali Hospital for blood disorders and cancer.
| Results|| |
In this study, 71 patients were included. The median age was 21 years (range: 14–81 years). Among them, 18 (25.4%) patients were ≥35 years, 37 (52.1%) patients were males and 34 (47.9%) patients were females. The male-to-female ratio is 1.08:1.
Blood indices include a median hemoglobin of 9 g/dl (range: 5.0–13.0 g/dl), median platelet count 43 × 10⁹/l (range: 2–258 × 10⁹/l), median leukocyte 26.0 × 10⁹/l (range: undetected –546 × 10⁹/l), and median peripheral blast of 66% (range: 0%–98%).
By using flow cytometry, 20 (28.2%) patients were T-lineage ALL and 51 (71.8%) patients were B-lineage ALL. Out of the 53 patients who were <35 years, 16 (30.2) patients are T-lineage and 37 patients (69.7%) are B-lineage, while among 18 patients who were ≥35 years, four of them (22.2%) were T-lineage and 14 (77.8%) were B-lineage (P = 0.516).
Among the B-ALL patients, 21 (41.2%) patients had WBC >30 × 10⁹/l (P = 0.383) and only 10 of them (19.6%) had WBC >100 × 10⁹/l, whereas among T-ALL patients, 6 (30%) patients had WBC >100 × 10⁹/l (P = 0.346).
According to age, 10 (18.9%) patients out of the 53 who were <35 years had WBC >100 × 10⁹/l opposite to the 6 (33.3%) patients out of the 18 who were ≥35 years (P = 0.204).
Significant lymphadenopathy was found in 18 (25.4%) patients and the most common site was cervical lymphadenopathy either alone or with other sites.
Splenomegaly was found in 32 (45.1%) patients, among them, 7 (9.9%) patients had huge spleen (range: 19–20 cm). Regarding hepatomegaly, it is found only in 14 (19.7%) patients.
Philadelphia (PH) chromosome was found only in 10 (14.1%) patients. Its incidence was (27.8%) among those aged ≥35 years opposite to (9.4%) among the younger patients (P = 0.009).
Among the 16 patients who have WBC >100 × 10⁹/l, PH chromosome was found in 9 (56.3%) patients opposite to the 1 (1.8%) patient in the group with lower WBC (P = 0.0001).
CSF study at presentation showed that only 1 (1.4%) patient had CNS disease for having blasts in the CSF.
There were two patients with a history of hypertension and two patients with Down syndrome making comorbidities to be (5.6%) in this study.
Overall, 34 (47.9) patients were grouped as having standard risk disease and the remaining 37 (52.1%) patients had high-risk diseases. [Table 1] shows patients' characteristics.
Induction chemotherapy was given with curative intent to 67 (94.4%) patients, the remaining 4 (5.6%) patients were treated with supportive therapy for having poor performance status and old age.
Among the treatment protocols, UKALL XII was the most commonly used treatment plan by the physicians' decision, used for 37 (52.1%) patients, while 28 (39.4%) patients were treated with Hyper-CVAD and Dana–Farber protocol used just for 2 (2.8%) patients.
Assessment of remission induction showed that 63 (88.7%) patients got remission after induction, 4 (5.6%) patients were found to have persistent disease after first induction with the remaining 4 (5.6%) patients who were treated just with supportive care. Remission rates were (92.5%) and (77.8%) for <35 years and ≥35 years of the age groups, respectively (P = 0.089).
Among the patients who received UKALL XII, remission was found in 35 (94.6%) patients comparing to the Hyper-CVAD which was found to have induced remission in 26 (92.9%) out of the 28 patients. Moreover, both of the patients who received the Dana–Farber protocol were achieved remission.
Regarding the PH chromosome, it was found that all patients got remission with the first induction.
Three patients were died due to neutropenic sepsis after the induction, among them, two received Hyper-CVAD and one received UKALL.
The OS in this study is 39.4% with median OS of 21 months and the median RFS of 13 months [Figure 1].
There is no statistical significance in OS for both sexes, OS was (37.8%) and (41.2%) for males and females, respectively (P = 0.998) [Figure 2]a, whereas age has its own effect on OS, the OS was (49.1%) for <35 years and (11.1%) for ≥35 years of age (P = 0.00011) [Figure 2]b. OS was (25.9%) for patients with initial high WBC and (47.7%) for those who had no high WBC initially (P = 0.160) [Figure 2]c.
|Figure 2: Kaplan–Mayer survival curve of overall survival. Comparison between (a) Male and female. (b) <35 years and >35 years. (c) High WBC and low WBC. (d) Philadelphian positive and negative. (e) High risk and low risk. (f) Remission and resistance to induction. WBC: White blood cell|
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PH chromosome-positive patients had an OS of (30%) opposite to the (44.4%) for PH-negative patients (P = 0.195) [Figure 2]d. Meanwhile, the OS was 61.8% and 18.9% for standard risk and high-risk patients, respectively (P = 0.00010) [Figure 2]e.
Regarding the effect of remission to induction on OS, the OS was zero for those who did not get remission to initial induction and 44.4% for those who had remission to initial induction (P = 0.00010) [Figure 2]f.
The 3-year OS was 49.3% and the 3-year RFS was 40.8% while the 5-year OS and the 5-year DFS were 37.5% and 32.5%, respectively.
Regarding the impact of age, the current study showed that the 3-year OS was (60.4%) and (16.7%) for <35 years and ≥35 years of age, respectively (32 patients out of 53 patients who were younger than 35 years are alive after 3 years of diagnosis, while three patients out of the 18 patients who were ≥35 years old are alive) (P = 0.001), and the 3-year RFS was (50.9%) and (11.1%) (P = 0.003) for each group, respectively (27 patients out of the 53 patients who were <35 years had 3-year RFS while two out of the 18 patients who were ≥35 years had 3-year RFS).
Meanwhile, the 5-years OS was (42.4%) and (14.3%) for <35 years and ≥35 years of age, respectively (out of 33 patients who were <35 years, 14 of them were alive after 5 years from their initial diagnosis while only one out of the seven patients who were ≥35 years old was alive after 5 years from the initial diagnosis) (P = 0.162), whereas the 5-year RFS was (36.4%) and (14.3%) for the aforementioned, respectively (P = 0.257). [Table 2] shows 5-year OS and 3-year OS according to different parameters with their P value.
|Table 2: Five years overall survival and 3 years overall survival according to different parameters with their P value|
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Relapse and death
In this study population, 26 (36%) patients were relapsed, most of the relapses occurred within the first 3 years from the diagnosis (22 patients, 84.6%).
In correlation with other risk factors, relapse rates were 39.6% and 27.8% for <35 years and ≥35 years of age, respectively (P = 0.367), whereas its 31.4% and 50.0% for B-cell and T-cell, respectively (P = 0.143), and its 40% for both PH-positive and -negative patients (P = 0.548).
Regarding the relapse risk with the use of different chemotherapy protocols, its 37.8% and 39.3% for UKALL XII and Hyper-CVAD, respectively (P = 0.462).
On the other hand, relapse rates were 32.8% for transplanted patients who got relapsed after allogeneic stem cell transplantation (allo-SCT) and 60% for nontransplanted patients (P = 0.098).
Among the 43 death events, 19 (44.2%) patients died due to relapsed resistant disease and 17 (39.5%) patients are dead due to neutropenia-related events during the induction or later during the course of treatment. Other death causes include sudden death, CNS disease, and unknown which no available data were present.
Among the 21 patients who received UKALL XII protocol and are dead, 12 of them died due to relapsed resistant disease and only five due to febrile neutropenia, whereas for the 18 dead patients treated with Hyper-CVAD protocol, seven patients died of relapsed resistant disease and eight patients due to febrile neutropenia.
| Discussion|| |
In this study, the outcome of 71 newly diagnosed ALL patients in a single tertiary center was analyzed, in an attempt to understand more about the outcome of adult ALL in developing countries.
The 5-year OS of 37.8% in this study is quite comparable to most of the studies in the USA, Italy, Germany, Spain, and France.,,,, It is expected also to see a high remission rate after the first induction, as well as a very poor outcome for the primary resistant diseases.,,
Age at diagnosis remains one of the dominant prognostic markers.,,,, There were significant differences in remission induction, OS, and RFS between younger and older participants. The survival declines rapidly with increasing age, especially after 35 years. These are supported by the higher incidence of poor prognostic markers with increasing age. These differences in outcome were not seen between both genders in our study, as is seen in some literature such as in Sweden, putting the male sex in the list of poor prognostic markers.
Regarding the role of initial WBC count, the current study shows inferior outcomes for those presenting initially with high WBC count but this was statistically not significant. This is partly contributing to inferior outcomes with increasing age as the incidence of initial high WBC count is more with older patients.,,,
The frequency of PH chromosome among the study patients is lower than most published literatures such as in Italy and the USA,, could be due to the lack of data for a significant number of our patients. However, higher rates were observed among older patients as reported by most working groups on adult ALL.,, In comparison between positive and negative participants for PH chromosome, the remission rate is higher in the positive group that could be explained by the role of TKI, that was included in the treatment plan for them, but OS and RFS were lower with the positive group.,,,, though statistically it is not significant.
Nearly, one-third of the patients are T-lineage ALL. Historically, T-ALL has inferior outcomes compared to B-ALL due to many reasons including patients with T-ALL are generally older, have higher WBC count, are more resistant to chemotherapy, and more extramedullary relapses are seen among them. On the other hand, higher favorable genetic subtypes are observed among B-ALL., These differences in outcome are not seen in this study as there are no statistically significant differences in OS and RFS at 3 and 5 years between the two groups.
Overall, the general risk assessment is well known to have a major influence on survival. This study confirms high-risk patients have inferior 5-year OS, 5-year RFS, 3-year OS, and 3-year RFS.
Different chemotherapy protocols had been used, mainly UKALL XII and Hyper-CVAD, which showed no difference in remission induction; however, OS was superior with UKALL XII, although not reached a statistically significant level. As known in other studies, Hyper-CVAD protocol may lead to more death incidence and this is mainly a consequence of neutropenic sepsis caused by severe marrow suppression in patients treated with Hyper-CVAD.,
Transplantation has it is own survival impact as seen in our study showing survival advantage for the group that underwent transplantation.,, Although more than half of the patients in this study were high-risk patients, only 10 of them received allo-SCT as consolidation, mostly due to the lack of transplant center in this hospital and difficulties in access to it with economic and other factors related to this part of the world. Survival is expected to be higher if this were done for all the indicated patients.
Conventionally, late relapses are uncommon among adults suffering from ALL.,, Relapses are seen in more than one-third of our patients, most of them occurring within the first 3 years of diagnosis. This confirms early relapses are more common than late relapses among adult ALL patients as reported in other literatures.
| Conclusion|| |
Significant factors contributing to survival outcomes include age, risk assessment, remission induction, and transplantation. Survival can be improved by better supportive care for preventing and controlling neutropenic sepsis and consolidating candidate patients with allo-SCT.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]