Abstract
Background
Despite the increased lymphoma burden in the Kingdom of Saudi Arabia (KSA) and poor prognostic factors in patients from KSA, limited data exist regarding the characteristics and outcomes of peripheral T-cell lymphoma (PTCL) patients. The present retrospective analysis evaluated the characteristics, treatment patterns, and survival outcomes of patients with PTCL in KSA.
Methods
The present retrospective chart review retrieved the data of patients with PTCL (aged ≥ 14 years) from two KSA centers. Data on clinical characteristics, treatment modalities, tumor response, and survival outcomes were obtained.
Results
Ninety-nine patients were enrolled, with a mean age of 50.68 ± 1.62. The two most prevalent histological subtypes were peripheral PTCL-not otherwise specified (NOS; 38.4%) and ALK-negative anaplastic large cell lymphoma (ALK-ALCL; 26.3%). The majority of individuals (60.6%) were diagnosed with Ann Arbor Stage IV disease. Approximately 54% of individuals had an IPI ≥ 3 at the time of diagnosis. Combination chemotherapy was used as the first-line treatment in 32.3% of cases. Only 14.1% and 13.1% of the patients underwent ASCT and radiation therapy as first-line treatments, respectively. The five-year progression-free survival (PFS) and overall survival (OS) rates were 23.6% and 44%, respectively. A significant difference was observed in the 5-year PFS (p = 0.048) and OS rates (p = 0.017) between treatment regimens. Older age (Hazard ratio [HR] = 1.03, 95% confidence interval 1.00-1.05, p = 0.01) was an independent predictor of PFS. Likewise, B-symptoms and extranodal involvement were independent predictors of OS.
Conclusion
Patients with PTCL in KSA tend to present at a younger age and at more advanced disease stages compared to patients from Western and other Asian countries. The survival of patients with PTCL remains poor in the Kingdom, highlighting the need for standardized protocols for early diagnosis, prompt referral, and treatment.
Keywords: T-cell lymphoma, Survival, Treatment, Saudi arabia
Introduction
T-cell lymphomas (TCL) are diverse group of non-Hodgkin lymphomas (NHL) that develop from T lymphocytes and natural killer (NK) cells [1]. They account for approximately 5–10% of all lymphomas, with a reported greater incidence in some Asian nations (almost 15–20% of NHLs) [2, 3]. TCL pathophysiological mechanisms are defined by the malignant transformation of T-lymphocytes, which results in a wide range of clinical phenotypes, from cutaneous presentations in cutaneous T-cell lymphomas (CTCL) to systemic disease in peripheral TCL (PTCL) [4]. PTCLs are a heterogeneous group of aggressive non-Hodgkin lymphomas with overlapping clinical and histopathological features. Subtype-specific immunohistochemistry (IHC) markers include CD30 for anaplastic large cell lymphoma (ALCL), CD56 for extranodal NK/T-cell lymphoma, and CXCL13, PD-1, and ICOS for angioimmunoblastic T-cell lymphoma (AITL). Additionally, TIA-1, granzyme B, and perforin help characterize cytotoxic T-cell lymphomas [5]. Few identified risk factors for TCL have been reported, including exposure to certain chemicals and toxins, history of immunosuppression, and human T-lymphotropic virus 1 (HTLV-1) infection [6].
Despite its rarity, the management of PTCL is challenging in clinical practice. Current evidence indicates that patients with PTCL typically exhibit poor survival outcomes (5-year progression-free survival [PFS] = 18%, and 5-year overall survival [OS] = 39.02%) [2, 7]. The grave PTCL prognosis is usually attributed to aggressive PTCL histological subtypes, late diagnosis, and lack of well-established treatment protocols for many subtypes of PTCL [1]. For many PTCL subtypes, first-line therapy often comprises combination chemotherapy regimens, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOEP (CHOP plus etoposide). These regimens, which are more effective for B-cell lymphomas, often lead to unsatisfactory survival outcomes in PTCL [8]. Novel targeted therapies, such as brentuximab vedotin and pralatrexate, and advances in allogeneic stem cell transplantation (ASCT) have shown promise. For instance, compared to CHOP, first-line brentuximab vedotin was associated with superior 5-year PFS (51.4% vs. 43%) and OS (70.1% vs. 61%) [9]. First-line ASCT also led 4-year OS of 59%, and a 4-year relapse rate of 28% [10]. However, the accessibility of targeted therapies and ASCT-related complications remains a major concern [11].
The incidence of hematological malignancies has increased notably in the Kingdom of Saudi Arabia (KSA), which can be attributed to a combination of factors, including aging population and improved healthcare infrastructure and advancements in medical diagnostics [12, 13]. Previous epidemiological studies reported that lymphoma cases accounted for nearly 10.5% of all new cancer cases in 2015, with NHL being the fourth most common cancer type in KSA [14]. A more recent report demonstrated an increasing trend in lymphoma incidence, approaching 11% of all new cancer cases; nearly 3% of lymphoma cases were PTCL [15]. Notably, lymphoma cases from KSA typically present with advanced-stage disease and are younger than those from Western countries [15, 16]. Despite the increasing lymphoma burden in Saudi Arabia and the poor prognosis of patients from Saudi Arabia, there is inadequate data on the features and outcomes of patients with PTCL. This highlights the importance of further understanding the treatment paths and survival outcomes of patients with PTCL in the Kingdom of Saudi Arabia, which may have unique demographic and clinical features. The current retrospective investigation assessed the characteristics, treatment methods, and survival outcomes of patients with PTCL in Saudi Arabia.
Materials and methods
The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Institutional Review Board (IRB) of King Abdullah International Medical Research Center (KAIMRC), King Abdulaziz Medical City (KAMC) (IRB/1662/23: NRJ23J-028-01; Dated 20th July, 2023). The data collection of this study was for the period of 2010 to 2022.
Data source and population:
We included data for all consecutive ninety-nine patients, aged ≥ 14 years diagnosed with PTCL between the period stipulated by the IRB approval. Patient selection was based on a confirmed diagnosis of PTCL in accordance with the 2008 and 2016 World Health Organization (WHO) classifications of hematological malignancies [17, 18]. Data was obtained from two oncology centers - Princess Noora Oncology Centre at KAMC, Jeddah and Oncology Centre at KAMC, Makkah. Inclusion criteria encompassed patients with a histologically confirmed diagnosis of PTCL subtypes as per the WHO classification, availability of complete medical records, and adequate follow-up data for treatment and survival analysis. There were no restrictions on the PTCL subtypes or treatment modalities. patients with other concurrent malignancies and those who had received treatment at another institution were excluded from the study.
Data collection:
The following data were extracted from the medical records using a standardized data extraction form: demographics (such as age and sex), clinical presentation (including B cell symptoms, Ann Arbor stage at diagnosis, international prognostic index [IPI], and histological subtype of PTCL), treatment modalities at each line of treatment, treatment response according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and survival outcomes (OS and PFS). The follow-up duration was calculated from the date of diagnosis to the date of death or loss to follow-up. Patients who were alive, did not progress, or were lost to follow-up at the time of analysis, had their data censored at the date of the last tumor evaluation.
Statistical analysis
Statistical analysis was conducted using Statistical Package for Social Sciences version 24 (SPSS-24) for Windows. Descriptive analysis was performed according to the data type and normality distribution. The Kaplan-Meier method was used to estimate the OS and PFS for the overall cohort which was also stratified according to histological subtype and treatment modality. The Log-rank test compared survival distributions among different histological subtypes and treatment modalities. Unadjusted Cox proportional hazards regression analysis evaluated the association between individual covariates and survival outcomes (OS and PFS). Adjusted Cox regression analysis, was performed to evaluate the independent predictors of survival outcomes for the same patients. The outcomes of Cox regression analysis were presented as hazard ratios (HRs) with 95% confidence intervals (CIs). A p-value of less than 0.05 was deemed statistically significant.
Results
The study included 99 patients with PTCL, with an average age of 50.68 ± 1.62 years at diagnosis. The three most common histological subtypes were PTCL-not otherwise specified (NOS; 38.4%), ALK-ALCL (26.3%), and ALK + ALCL (8.1%). The majority of individuals (60.6%) were classified as Ann Arbour Stage IV, with 29.3% having an IPI of 2. Approximately 54% of individuals had IPI ≥ 3 at diagnosis. B symptoms were present in 51.5% of patients at diagnosis, and extranodal involvement was seen in 62.6%, including 14.1% with bone marrow involvement. The median duration of follow-up after diagnosis was one year (range: 0–12). At the end of the follow-up period, 48.5% of the 99 participants had died (Table 1).
Table 1.
Demographics and Clinical Characteristics
| Characteristic | Total (n =99) | ≤40 years | 41 – 65 years | > 65 years |
|---|---|---|---|---|
| Age (mean ± SD) | 50.68 ± 1.62 | --- | ---- | ---- |
| Gender, n (%) | ||||
| Male | 32 (32.3) | 8 (29.6) | 18 (31.6) | 6 (40.0) |
| Histological Subtype, n (%) | ||||
| Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) | 38 (38.4) | 9 (33.3) | 25 (43.9) | 4 (26.7) |
| Angioimmunoblastic T-cell lymphoma (AITL) | 7 (7.1) | 1 (3.7) | 4 (7.0) | 2 (13.3) |
| Anaplastic large cell lymphoma, ALK-positive (ALK+ ALCL) | 8 (8.1) | 4 (14.8) | 2 (3.5) | 2 (13.3) |
| Anaplastic large cell lymphoma, ALK-negative (ALK− ALCL) | 26 (26.3) | 6 (22.2) | 16 (28.1) | 4 (26.7) |
| Adult T-cell leukemia/lymphoma (ATLL) | 2 (2.0) | 0 (0.0) | 1 (1.8) | 1 (6.7) |
| Extranodal NK/T-cell lymphoma (ENKTL) | 14 (14.1) | 7 (25.9) | 6 (10.5) | 1 (6.7) |
| Enteropathy-associated T-cell lymphoma (EATL) | 1 (1.0) | 0 (0.0) | 1 (1.8) | 0 (0.0) |
| Others | 3 (3.0) | 0 (0.0) | 2 (3.5) | 1 (6.7) |
| Ann Arbor Stage at Diagnosis, n (%) (n =93) | ||||
| I | 6 (6.5) | 0 (0.0) | 6 (6.5) | 0 (0.0) |
| II | 11 (11.8) | 4 (4.3) | 7 (7.5) | 0 (0.0) |
| III | 16 (17.2) | 9 (9.7) | 5 (5.4) | 2 (2.2) |
| IV | 60 (64.5) | 12 (12.9) | 36 (38.7) | 12 (12.9) |
| International Prognostic Index (IPI) at Diagnosis, n (%) | ||||
| 0 | 3 (7.3) | 0 (0.0) | 3 (12.5) | 0 (0.0) |
| 1 | 4 (9.8) | 3 (33.3) | 1 (4.2) | 0 (0.0) |
| 2 | 12 (29.3) | 4 (44.4) | 8 (33.3) | 0 (0.0) |
| 3 | 8 (19.5) | 1 (11.1) | 5 (20.8) | 2 (25.0) |
| 4 | 9 (22.0) | 1 (11.1) | 4 (16.7) | 4 (50.0) |
| 5 | 5 (12.2) | 0 (0.0) | 3 (12.5) | 2 (25.0) |
| B Symptoms at Diagnosis, n (%) (n =80) | ||||
| Yes | 51 (63.7) | 11 (13.8) | 29 (36.2) | 11 (13.8) |
| No | 29 (36.2) | 8 (10.0) | 18 (22.5) | 3 (3.8) |
| Extranodal Site Involvement, n (%) (n =87) | ||||
| Yes | 62 (71.3) | 12 (13.8) | 37 (42.5) | 13 (14.9) |
| No | 25 (28.7) | 10 (11.5) | 14 (16.1) | 1 (1.1) |
| Bone Marrow Involvement, n (%) (n = 78) | ||||
| Yes | 14 (17.9) | 2 (2.6) | 10 (12.8) | 2 (2.6) |
| No | 64 (82.1) | 16 (20.5) | 41 (52.6) | 7 (9.0) |
| Time to Follow-up Since Diagnosis (Months), Median (IQR) | 70 (53.25–86.74) | |||
| Current Status, n (%) | ||||
| Alive | 28 (28.3) | 9 (33.3) | 18 (31.6) | 1 (6.7) |
| Dead | 48 (48.5) | 10 (37.0) | 26 (45.6) | 12 (80.0) |
| Lost to follow-up | 23 (23.2) | 8 (29.6) | 11 (22.8) | 2 (13.3) |
PTCL-Nos Peripheral T-cell lymphoma - not otherwise specified, AITC Allyl isothiocyanate, ALK-ALCL ALK-negative anaplastic large cell lymphoma, ATLL Adult T cell leukaemia/lymphoma, ENKTL Extranodal natural killer (NK)/T cell lymphoma, EATL Enteropathy-associated T-cell lymphoma, IPI International Prognostic Index, PIT Prognostic index for T-cell lymphoma
Table 2 shows the treatment patterns of the patients included. CHOP, CHOEP, and CHP + Brentuximab were the first-line systemic regimens in 36.4%, 16.2%, and 7.1% of patients, respectively; 32.3% of the cohort received combination chemotherapy as the first-line treatment. Only 14.1% and 13.1% of patients underwent ASCT and radiation therapy as first-line treatments, respectively. On first-line systemic regimens, 28.3% and 26.3% of patients achieved complete response (CR) and partial response (PR), respectively. In the second-line context, combined chemotherapy was given to 8.1% of patients. The second-line treatment had CR and PR rates of 4% and 2%, respectively. During the second-line treatment phase, just one patient underwent radiation therapy, whereas 2% received ASCT.
Table 2.
Treatment characteristics
| Treatment Characteristic, n (%) | Total (n = 99) | < 40 years | 41–65 years | > 65 years |
|---|---|---|---|---|
| Initial First Systemic Treatment (n = 71) | ||||
| CHOP | 36 (50.7) | 8 (11.3) | 23 (32.4) | 5 (7.0) |
| CHOEP | 16 (22.5) | 6 (8.5) | 10 (14.1) | 0 (0.0) |
| CHP + Brentuximab | 7 (9.9) | 2 (2.8) | 3 (4.2) | 2 (2.8) |
| Alemtuzumab | 1 (1.4) | 0 (0.0) | 1 (1.4) | 0 (0.0) |
| Others | 21 (29.6) | 6 (8.5) | 13 (18.3) | 2 (2.8) |
| Response to First Treatment (n = 70) | ||||
| Complete response (CR) | 28 (40.0) | 12 (17.1) | 15 (21.4) | 1 (1.4) |
| Partial response (PR) | 26 (37.1) | 6 (8.6) | 18 (25.7) | 2 (2.9) |
| Stable disease (SD) | 1 (1.4) | 0 (0.0) | 0 (0.0) | 1 (1.4) |
| Progressive disease (PD) | 15 (21.4) | 3 (4.3) | 10 (14.3) | 2 (2.9) |
| Autologous or Allogeneic Transplant at First Treatment (n = 71) | ||||
| Yes | 14 (19.7) | 7 (9.9) | 7 (9.9) | 0 (0.0) |
| No | 57 (80.3) | 13 (18.3) | 39 (54.9) | 5 (7.0) |
| Radiation at First Treatment (n = 63) | ||||
| Yes | 13 (20.6) | 5 (7.9) | 7 (11.1) | 1 (1.6) |
| No | 50 (79.4) | 14 (22.2) | 32 (50.8) | 4 (6.3) |
| Response to Second Retreatment (n = 11) | ||||
| Complete response (CR) | 4 (36.4) | 1 (9.1) | 3 (27.3) | 0 (0.0) |
| Partial response (PR) | 2 (18.2) | 0 (0.0) | 2 (18.2) | 0 (0.0) |
| Progressive disease (PD) | 5 (45.5) | 0 (0.0) | 3 (27.3) | 2 (18.2) |
| Autologous or Allogeneic Transplant as Second Treatment (n = 14) | ||||
| Yes | 2 (14.3) | 0 (0.0) | 2 (14.3) | 0 (0.0) |
| No | 12 (85.7) | 2 (14.3) | 8 (57.1) | 2 (14.3) |
| Radiation at Second Retreatment (n = 11) | ||||
| Yes | 1 (9.1) | 1 (9.1) | 0 (0.0) | 0 (0.0) |
| No | 10 (90.9) | 0 (0.0) | 8 (72.7) | 2 (18.2) |
CR Complete Response, PR Partial Response, PD Progressive Disease
The median OS for the entire cohort was 24 months, with a 5-year OS rate of 44%. Likewise, the median PFS was 9 months, with a 5-year PFS rate of 23.6% (Fig. 1). The subgroup analysis revealed no significant correlation between PFS and histological subtypes (p = 0.26). The 5-year PFS rates were: 18.8% for ALK + ALCL, 30.3% for ALK-ALCL, 30.9% for PTCL-NOS, 17.9% for AITC, and 8.2% for ENKTL. There was no significant correlation between OS and histological subtypes (p = 0.06). However, the 5-year OS rates were significantly varied amongst subtypes: 50%, 42%, 54%, 18%, and 17% for PTCL-NOS, ALK + ALCL, ALK-ALCL, ENKTL, and AITC, respectively.
Fig. 1.
Kaplan-Meier curves of the PFS (a) and OS (b) of the overall cohort
We also compared the survival outcomes according to treatment regimens. A significant difference was observed in the median PFS among the different treatment regimens (p = 0.048). Specifically, the 5-year PFS rates were 40.9% for CHOEP, 11.6% for CHOP, and 14.3% for CHP + Brentuximab. The median PFS duration was 8 months for CHOEP, followed by 7 months for CHOP, 11 months for CHP + brentuximab, and one month for alemtuzumab (Fig. 2a). Similarly, the 5-year OS rates varied significantly among the treatment regimens (p = 0.017). The 5-year OS rates were 40.9% for CHOEP and 38.2% for CHOP, and 14.3% for CHP + brentuximab. The median OS duration was the longest for CHOEP at 79 months, followed by 51.4 months for CHOP, 11 months for CHP + brentuximab, and 1.5 months for alemtuzumab (Fig. 2b).
Fig. 2.
Kaplan-Meier curves of the PFS (a) and OS (b) according to the individual treatment regimens
Patients aged ≤ 40 years at diagnosis had significantly longer median PFS (13 months) compared to those aged 41–65 years (9 months) and > 65 years (3 months; p = 0.023; Fig. 3a). On the other hand, the median OS was significantly longer on those aged ≤ 40 years (not reached) and 41–65 years at diagnosis (35 months) compared to those aged > 65 years (6 months; p = 0.002; Fig. 3b).
Fig. 3.
Kaplan-Meier curves of the PFS (a) and OS (b) according to age
Univariate Cox regression analysis revealed that age significantly decreased OS (HR = 1.03, 95% CI: 1.01–1.04, p < 0.001). B symptoms (HR = 2.56, 95% CI: 1.21–5.41, p = 0.01), Ann Arbor stage III-IV (HR = 3.3, 95% CI: 1.19–9.3, p = 0.022), and extranodal site involvement (HR = 5.72, 95% CI: 2.24–14.59, p < 0.001), and bone marrow involvement (HR = 2.27, 95% CI: 1.07–4.080, p = 0.03) also adversely impacted OS. The initial treatment regimen with CHOP (HR = 0.37, 95% CI: 0.18–0.75, p = 0.01) significantly increased OS. However, in the multivariate Cox proportional regression, CHOEP (HR = 0.29, 95% CI: 0.09–0.93, p = 0.038), B-symptoms (HR = 3.2, 95% CI: 1.01–10.06, p = 0.049), and extranodal involvement (HR = 63.9, 95% CI: 5.1–800.1, p = 0.001) were independent predictors of OS (Table 3).
Table 3.
Cox proportional hazards regression for OS
| Variables | No. | Univariate analysis | Adjusted Model | ||
|---|---|---|---|---|---|
| HR (95.0% CI) | p-value | HR (95.0% CI) | p-value | ||
| Age at diagnosis | 99 | 1.03 (1.01–1.04) | 0.001* | ||
| Age (Ref: <40 years old) | |||||
| <40 years old | 27 | Ref | Ref | ||
| 41–65 years | 57 | 1.12 (0.55–2.28) | 0.748 | 2.59 (0.48–14.1) | 0.269 |
| > 65 years | 15 | 3.37 (1.47–7.73) | 0.004* | 0.278 (0.33–23.1) | 0.345 |
| Initial treatment (Ref: other treatment) | |||||
| Other treatments | 47 | Ref | Ref | ||
| CHOEP | 16 | 0.67 (0.30–1.49) | 0.33 | 0.29 (0.09–0.93) | 0.038* |
| CHOP | 36 | 0.37 (0.18–0.75) | 0.01* | 0.32 (0.09–1.16) | 0.083 |
| B-symptoms (Ref: No) | |||||
| No | 19 | Ref | Ref | ||
| Yes | 80 | 2.56 (1.21–5.41) | 0.01* | 3.2 (1.01–10.06) | 0.049* |
| Extranodal involvement | |||||
| No | 12 | Ref | Ref | ||
| Yes | 87 | 5.72 (2.24–14.59) | < 0.001* | 63.9 (5.1 −800.1) | 0.001* |
| Bone marrow involvement | |||||
| No | 21 | Ref | Ref | ||
| Yes | 78 | 2.27 (1.07–4.08) | 0.03* | 1.41 (0.42–4.78) | 0.58 |
| Ann Arbor Stage at diagnosis | |||||
| I-II | 13 | Ref | Ref | ||
| III-IV | 61 | 3.3 (1.19–9.3) | 0.022* | 0.97 (0.30–3.13) | 0.955 |
IPI International Prognostic Index
aOther chemotherapy regimens were excluded from the multivariate model due to heterogeneity and small sample sizes. The final multivariate model included 52 patients who received either CHOP or CHOEP with complete data
Regarding PFS, the univariate Cox regression analysis identified age as a significant predictor with an HR of 1.02 (95% CI: 1.00-1.04, p = 0.01). Extranodal site involvement significantly decreased PFS (HR = 2.91, 95% CI: 1.44–5.89, p = 0.003), as did bone involvement (HR = 2.12, 95% CI: 1.01–4.44, p = 0.04). Initial first treatment also significantly affected PFS (HR = 1.40, 95% CI: 1.08–1.82, p = 0.01). Multivariate Cox proportional regression revealed that older age (HR = 1.03, 95% CI: 1.00-1.05, p = 0.01) was an independent predictor of PFS (Table 4).
Table 4.
Cox proportional hazards regression for PFS
| Variable | No. | Univariate analysis | Adjusted Modela | ||
|---|---|---|---|---|---|
| HR (95.0% CI) | p-value | HR (95.0% CI) | p-value | ||
| Age at diagnosis | 99 | 1.02 (1.00–1.04) | 0.01* | 1.03 (1.00–1.05) | 0.01* |
| Age (Ref: <40 years old) | |||||
| <40 years old | 27 | Ref | Ref | ||
| 41–65 years | 57 | 1.19 (0.75–1.91) | 0.44 | 1.48 (0.57–3.82) | 0.416 |
| > 65 years | 15 | 2.02 (1.06–3.86) | 0.033* | 2.4 (0.68–8.64) | 0.169 |
| Initial first systemic treatment | |||||
| Other Treatments | 47 | Ref | Ref | ||
| CHOEP | 16 | 0.38 (0.15–0.94) | 0.03* | 0.75 (0.34–1.67) | 0.489 |
| CHOP | 36 | 0.39 (0.21–0.74) | 0.004* | 0.82 (0.3–2.25) | 0.706 |
| Extranodal involvement | |||||
| No | 12 | Ref | Ref | ||
| Yes | 87 | 2.91 (1.44–5.89) | 0.003 | 1.66 (0.74–3.71) | 0.223 |
| Bone marrow involvement | |||||
| No | 21 | Ref | Ref | ||
| Yes | 78 | 2.12 (1.01–4.44) | 0.04* | 1.63 (0.72–3.69) | 0.173 |
| B-symptoms (Ref: No) | |||||
| No | 51 | Ref | |||
| Yes | 29 | 1.49 (0.94–2.36) | 0.094 | ||
| Ann Arbor Stage at diagnosis | |||||
| I-II | 17 | Ref | |||
| III-IV | 76 | 1.15 (0.68–1.96) | 0.606 | ||
aOther chemotherapy regimens were excluded from the multivariate model due to heterogeneity and small sample sizes. The final multivariate model included 52 patients who received either CHOP or CHOEP with complete data
Discussion
The current retrospective analysis sheds new light on the clinical features, treatment procedures, and real-world survival rates of patients with PTCL in Saudi Arabia. Demographic factors and clinical stage at presentation significantly influence PTCL presentation and outcomes. The age at diagnosis has shown notable geographic and ethnic variations [19, 20]. Current data suggest that a significant number of patients with lymphoma in KSA are diagnosed at a younger age, which has been attributed to genetic, environmental, or healthcare system-related risk factors [15]. In the present study, the mean age of patients with PTCL at diagnosis was 51 years old, indicating that PTCL is diagnosed at a younger age in Saudi Arabia than in Western and other Asian nations. For example, population-based studies from the United States (US) revealed that the median age at diagnosis varied between racial groups, ranging from 54 to 71 years old [17, 18]. Similarly, data from Japan revealed an average age of 57.1 years at the time of PTCL diagnosis [19]. In a population-based study conducted in Beijing, China, patients with PTCL had a median age of onset of 59–61 years [2]. More research is needed to understand why PTCL is diagnosed at a younger age in Saudi Arabia, which will help inform healthcare policy and attempts to detect and treat the disease earlier.
Advanced stages at diagnosis, alongside B symptoms and extranodal involvement, indicate a more aggressive disease course and poor prognosis of patients with PTCL [21]. For instance, B symptoms were found to significantly impact the patient’s quality of life and were associated with more aggressive treatment regimens [22]. In our cohort, approximately two-thirds of the patients presented with Ann Arbour stage IV at diagnosis with extranodal involvement. Additionally, more than half of the patients had IPI ≥ 3 and B symptoms, indicating a more severe disease with potentially poor consequences. These findings are consistent with previous research, which showed that lymphomas are often identified in advanced stages in Saudi Arabia. Altowairqi et al. found that 61% of patients with lymphoma from KSA exhibited B symptoms and that 72% of them were in advanced stages [15]. Comparatively, European registries showed that nearly 65% of the patients with PTCL presented with stage III-IV, and 43.4–59% had B symptoms; however, fewer patients (11-19.9%) had extranodal involvement [21, 23]. Our findings emphasize the need for more effective diagnostic strategies to ensure early PTCL diagnosis and improve prognosis.
Likewise, we noted a high percentage of patients (54%) presenting with an IPI score of ≥ 3 at diagnosis, reflecting a poor prognosis tendency in TLC cases in Saudi Arabia. This trend confirms the observation that patients with PTCL from Saudi Arabia have advanced disease at presentation, which may be due to delayed diagnosis, under-recognition of early disease symptoms, or limited access to comprehensive healthcare resources and specialized hematological care [15, 24]. Such a pattern emphasizes the need for a proactive, multidisciplinary approach to improve early detection and management strategies of PTCL in Saudi Arabia.
The prognosis and survival rates of PTCL are generally poor due to aggressive tumor behavior, advanced stage at diagnosis, and the lack of effective first-line options [1]. The 5-year OS and PFS rates in the current trial were 44% and 23.6%, respectively. These numbers were consistent with prior data showing a 5-year survival rate of fewer than 50% in patients with PTCL. In a 2014 Swedish study, the 5-year OS and PFS of patients with PTCL were found to be 34.1% and 25.7%, respectively [21]. Data from China showed a 5-year OS rate of 39.02% [2]. A recent prospective study from the US showed that the median OS of patients with PTCL was 43 months [25]. In relapsed/refractory PTCL, the median OS was reported to be 29.1–38 months [26, 27]. It is worth noting that the survival outcomes of patients with PTCL in KSA, as demonstrated by our study, appear to be less favorable than other lymphoma subtypes [15], which confirms the aggressive nature of PTCL and the urgent need for improved diagnostic and therapeutic strategies.
The use of targeted therapy, such as Brentuximab Vedotin combined with CHP, was evaluated in the landmark ECHELON-2 trial, which demonstrated a significant improvement in both OS and PFS compared to the standard CHOP regimen for CD30-positive PTCL. Specifically, the median PFS reported in the ECHELON-2 trial was 62.3 months at 5-year follow-up [9]. Patients were considered eligible for this treatment if they exhibited a 10% or greater expression of CD30 on malignant cells and were deemed fit to receive this intensive therapeutic protocol. For patients who are CD30-negative or who do not meet the eligibility criteria for Brentuximab + CHP, alternative regimens such as CHOP or CHEOP are utilized as standard treatment options in our center. Despite this promising result, our study found that the median PFS for patients on CHP + brentuximab was only 11 months. This runs in line with previous real-world studies showing a median PFS of 5.2–26.5 months for patients receiving brentuximab vedotin in combination with chemotherapy for relapsed/refractory PTCL [28, 29]. This highlights the potential differences in real-world outcomes versus controlled clinical trial settings due to factors such as patient heterogeneity, variations in comorbidities, and adherence to treatment protocols that may contribute to this discrepancy.
On the other hand, we found that the 5-year PFS rates were 11.6% for CHOP and 40.9% for CHOEP. Such findings align with previous studies exploring combination chemotherapy in the frontline setting for patients with PTCL. For example, traditional CHOP therapy has shown a 5-year PFS ranging from 20 to 63% in patients with peripheral PTCL [21]. Similarly, for the CHEOP regimen, studies indicate a 5-year PFS of 75.4% in patients with PTCL [23].
Despite the superior benefits of targeted therapies and ASCT in Saudi Arabia, their availability and accessibility play a critical role in shaping treatment outcomes. Brentuximab vedotin is primarily indicated for CD30-positive PTCL cases in Saudi Arabia; however, its incorporation into routine clinical practice is often delayed due to reimbursement challenges and limited access in non-tertiary centers. Additionally, disparities in healthcare infrastructure across different regions may result in variability in the use of targeted therapies, thereby influencing treatment outcomes. Likewise, the practical application of ASCT in Saudi Arabia remains challenging due to limited donor registries, financial constraints, and logistical barriers related to transplant centers. Moreover, infrastructure limitations in transplant facilities and the availability of post-transplant supportive care, including graft-versus-host disease (GVHD) management, further restrict the widespread use of ASCT.
The current study is one of the few published reports on the features and survival outcomes of PTCL in the Middle East region; nonetheless, we recognize several limitations. Primarily, the retrospective approach introduces the potential of selection and information bias due to dependence on prior medical records, which may have resulted in errors in data collection and coding. The sample size was small, and data were collected from only two center restricting the generalizability of our findings to the PTCL population in KSA. The follow-up duration may not have been adequate to reliably predict long-term survival results. PTCL’s histological heterogeneity may have resulted in variability in treatment responses and survival outcomes, with subgroup studies likely limited because of the diverse histological subtypes and small sample sizes. Also, the retrospective nature of the study posed its own set of challenges, including the reliance on existing medical records, which may have been subject to incomplete data and variable documentation quality over the 12-year period. Additionally, our database was limited in providing a comprehensive analysis of prognostic factors.
Another key limitation is the small sample size of certain treatment groups, particularly CHP + brentuximab and alemtuzumab, which had fewer than ten events in the Cox regression analysis. Given the potential for overfitting and unreliable hazard ratio estimates in models with sparse data, we have excluded these variables from the analysis to ensure statistical robustness. Additionally, we have updated Tables 3 and 4 to explicitly specify the total sample size (n = XX) for each treatment group, enhancing clarity in patient numbers and improving the transparency of our findings.
Regarding the observed survival benefit of single-agent therapy (SA) compared to combination chemotherapy, we recognize that the small sample size (n = 9 for SA) necessitates cautious interpretation. Although our findings indicate a notably longer median survival time of 76 months versus 28 months for combination therapy, these results should be interpreted carefully due to potential selection bias, limited statistical power, and unmeasured confounding factors. Additionally, we acknowledge a 23.2% total loss to follow-up at a median of 70 months, which may impact the accuracy of survival estimates and introduce potential attrition bias.
We recognize that there may be additional variables influencing prognosis, such as genetic mutations, molecular subtypes, and immune microenvironment characteristics, that were not captured within the scope of our study. Finally, our adjusted regression analysis could have been influenced by unmeasured or uncontrolled confounding factors such as patients’ comorbidities, socioeconomic status, or medication adherence. Future research that addresses these limitations, particularly through prospective study designs with larger and more diverse cohorts, can make a significant contribution to a better understanding of PTCL treatment and survival outcomes in Saudi Arabia and abroad. Thus, we recommended further investigations to elucidate additional prognostic markers for patients with PTCL-NOS.
In conclusion, patients with PTCL in KSA tend to present at a younger age and more advanced disease stages compared to patients from Western and other Asian countries. The survival of PTCL remains poor in the Kingdom, and there is a notable disparity in survival outcomes across different histologic subtypes and treatment modalities. Our analysis identified several independent predictors impacting the survival rates of patients with PTCL, including age, extranodal site involvement, B symptoms, disease stage, treatment response, and subsequent treatment lines. These findings underscored the need for standardized care protocols to ensure early diagnosis, timely referral, and consistent management of patients with PTCL. Developing and implementing evidence-based treatment protocols would be crucial to enhancing survival rates and improving the overall prognosis of patients with PTCL in Saudi Arabia. Additionally, establishing multidisciplinary tumor boards and improving awareness campaigns could further facilitate early detection and more effective treatment interventions.
Acknowledgements
Not Applicable.
Authors’ contributions
All authors have critically reviewed and approved the final draft and are responsible for the content and similarity index of the manuscript. MM conceptualized & designed the study and wrote the initial draft of manuscript.HAA, DES, ESA, AMA, MOB, MAA contributed in the data collection and writing of manuscript.SSA wrote the initial draft of manuscript, edited and revised the manuscript in the final form.
Funding
Not Applicable.
Data availability
Access to the raw data is available on request from the corresponding authors.
Declarations
Ethics approval and consent to participate
The study protocol was approved by the was approved by the Institutional Review Board (IRB) of Institutional Review Board (IRB) of King Abdullah International Medical Research Center (KAIMRC), King Abdulaziz Medical City (KAMC), Jeddah (IRB/1662/23: NRJ23J-028-01; Dated 20th July 2023).
Consent for publication
As this is a retrospective study of the data collection from the medical records, which was covered by the IRB provided by the KAIMRC. The study, however, followed the principles of Helsinki in letter and spirit, during the data collection.
Conflict of interest
No conflict of interest between authors occurs.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
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Data Availability Statement
Access to the raw data is available on request from the corresponding authors.