INTRODUCTION

Anaplastic Large T-Cell Lymphoma (ALCL), initially described in 1985¹, belongs to the T-cell family and is a unique type of lymphoma strongly expressing the CD30 antigen. This neoplasm is relatively infrequent, found in around 2 to 8% of all non-Hodgkin's lymphomas, between 10% to 20% of high-grade lymphomas, and 16% of T-lymphomas².

According to the World Health Organization (WHO)³, the expression of Anaplastic Lymphoma Kinase 1 (ALK1) determines the presence of two different entities: ALCL ALK positive (+), which represents 70%, it is more common in children and adolescents, males with a less aggressive course and better prognosis; and ALCL ALK negative (-), considered a provisional entity, more common in adults, without gender predominance, low incidence of systemic symptoms and worse prognosis^4,5. Both entities share similar characteristics, especially the morphological ones and the overexpression of CD30, which allows them to be differentiated from the rest of the peripheral T-cell lymphomas.

The International Prognostic Index (IPI) is a tool used as a predictive index for the survival of patients with non-Hodgkin's lymphoma. In recent years, a prognostic index for T-cell lymphoma (PIT) has been introduced, which includes the compromise of bone marrow, which is rare in ALCL, both indices are similar in this pathology⁶, so it has not yet been fully approved for ALCL.

Treatment continues to be combined chemotherapy associated with anthracyclines⁷, which reaches up to 80% complete response, with relapse rates of approximately 25%; in patients with residual disease (especially in mediastinal lymphomas) radiotherapy is indicated.

The present study seeks to determine the epidemiological, clinical-pathological, and prognostic characteristics of patients older than 14 years with ALCL, diagnosed at the National Institute of Neoplastic Diseases (INEN) in Lima, Peru 2006 and 2016. This will allow to know the form of presentation in our population and thus be able to take the best management and monitoring option. In addition, it will serve as the basis for future analyzes and improvements in treatment.

METHODS

RESULTS

The characteristics of the patients are detailed inTable 1. There were 86 patients in the study with a mean age of 43 years (range, 15 to 88 years), of whom 49 (57.0%) were men and 37 (43.0%) were men. .0%) women. More than 50% of patients had a good ECOG 1 performance status. According to DHL levels, 48 (55.8%) patients had elevated status. According to ALK expression, 18 (20.9%) patients were positive, 53 (61.6%) were negative, and 15 (17.4%) did not have this result. According to the stage, 19 (22.1%) were stage I, 29 (33.7%) were stage II, 12 (14.0%) were stage III, and 24 (27.9%) were stage IV, in 2 ( 2.3%) patients, the stage is not specified. According to the international prognostic index, 34 (39.5%) were low risk (BR), 23 (26.7%) low intermediate (IB), 20 (23.3%) high intermediate (IA), and 6 (7 .0%) high risk (AR), in 3 (3.5%) patients the index is not specified because they do not have the complete data recorded in the history. 67 patients (79.6%) received chemotherapy, 3 (3.4%) radiotherapy, and 16 (17%) did not receive treatment; the causes were sepsis (5 patients), no desire for therapy (4 patients), and transfers to another institution ( 6 patients). Of the patients who received chemotherapy, 24 (35.8%) achieved complete response (CR), 10 (14.9%) partial response (PR) and 33 (49.3%) no response and/or disease progression.

Regarding the distribution of ALK+ and ALK- cases by age groups, the T-test for independent samples shows that the average age for ALK + patients was significantly lower than that of ALK - patients (27.9 years vs. 47.4 years p<0.05). In the group of ALK+ patients, 25% were under 17 years of age, 50% were under 22.5 years of age, and 25% over 34 years of age. 01 distant value to the rest (atypical case) of a 58-year-old patient was identified. In the ALK- group, 25% were under 30 years old, 50% were under 50 years old, and 25% were over 62 years old; no atypical cases were found.

The five year progression-free survival (PFS) ranges for ALCL ALK+ and ALK- patients were 62.2% and 20.7%, respectively (HR: 4.52; 95% CI, 1.6-12.74). ; p=0.004). The International Prognostic Index (IPI) (Figure 1) identified different risk groups across the entire cohort. 5-year PFS was 56.8% for low IPI, 18.4% for low-intermediate, 20.9 % for intermediate IPI, and 0% for high risk; something similar occurred with the PIT, which also showed a high risk of mortality in the high and intermediate-high group compared to the low and intermediate-low group (HR: 6.25; 95% CI, 2.96-12.79; p= 0.05).

Figure 1 Estimated progression-free survival curves by International Prognostic Index (IPI). 

When performing multivariate analysis, including ALK characteristics, DHL, stage and IPI, and choosing the most influential characteristics, it turned out that an ALK negative has approximately 6 times more risk of progression compared to an ALK positive, and that the low intermediate IPI, high and high intermediate have 3, 6 and 6 times more risk of progression compared to a low IPI, respectively (Table 2).

Regarding overall survival, the median follow-up time was 72 months. Estimated overall survival at 1, 3, and 5 years was 61.4%, 46.8%, and 40.8%, respectively. In the group of patients with ALK+, overall survival at 1, 3, and 5 years was estimated at 85.6%, 77%, and 67.4%, respectively; and in the group with ALK- it was estimated at 54.1%, 36.3% and 30.2% at 1, 3 and 5 years, respectively. A significant difference was found between both groups. In the group of patients with normal LDH, overall survival at 1, 3, and 5 years was estimated at 89.1%, 70%, and 61%, respectively. In the group with high LDH it was estimated at 41.5%, 28.9% and 25.3% at 1, 3, and 5 years, respectively, a significant difference was found between both groups.

In the group of patients with stage I, overall survival at 1, 3, and 5 years was estimated at 73.3%, 66.7%, and 66.7%, respectively; in the group, with stage II it was estimated at 71.2%, 53.3% and 42.6% at 1, 3 and 5 years, respectively; in the group of patients with stage III, overall survival at 1, 3, and 5 years was estimated at 75%, 45%, and 22.5%, respectively. In the group with stage IV it was estimated at 36.7%, 24.4% and 24.4% at 1, 3 and 5 years, respectively. A significant difference was found between the groups. In the group of patients with IPI BR, overall survival at 1, 3, and 5 years was estimated at 85.2%, 70.4%, and 65.7%, respectively; in the group with IPI IB it was estimated at 66.9%, 46.3% and 30.9% at 1, 3 and 5 years, respectively; in the group of patients with IPI IA, overall survival at 1, 3, and 5 years was estimated at 31.4%, 15.7%, and 15.7%, respectively; and in the IPI AR group, it was estimated at 0.0% at 9 months. A significant difference was found between the groups (Figure 2).

Figure 2:  The estimated curve of overall survival (2A), estimated curves of overall survival by ALK expression (2B), by clinical stage (2C), and by IPI (2D). 

In the multivariate analysis, including the ALK characteristics, DHL, stage and IPI, it was found that ALK-negative has a 5-fold higher risk of death compared to ALK-positive and that the low intermediate, high intermediate and high IPI have 3, 10, and 9 times higher risk of death compared to a low IPI (Table 3).

DISCUSSION

ALCL is a lymphoma with an aggressive and heterogeneous clinical course, with a higher prevalence in children and young adults. Most studies report a better response to treatment in young patients, reaching a response range between 60%-90%. Sibón et al. reported in patients under 40 years of age, survival regardless of ALK status^14,15. Recent analyzes promote high-dose chemotherapy followed by Stem Cell Transplantation to prolong survival time; e there, the importance of the search and identification of prognostic factors for selecting the most aggressive population to offer them more intense and optimal therapy regimens.

In our study, we analyzed the epidemiological, clinicopathological, and prognostic characteristics of patients with ALCL. The median age of 40 years was found, regardless of ALK status, which is somewhat higher compared to other series where the median age was less than 35 years^16,17, the range of men/women was 1, 3:1, similar to other published series with a range of 1.6-1.8:1. Patients with ALK expression were more frequent in the first and second decades of life, with a median age of 22 years, which is lower compared to other publications such as that of Ferrari et al. 2012¹⁸where they present median age of 34 years. Other studies, such as the one by Savage et al.², found that ALCL ALK positives compromise skin, subcutaneous cellular tissue, and bone marrow. We found 3 patients with visceral, hepatic, and splenic compromise and only 2 patients with the compromise of bone marrow.

Various studies consider ALCL a chemosensitive disease, in some cases even comparable to Diffuse Large B-Cell Lymphoma, to treatment with the indication of starting first-line chemotherapy based on anthracyclines¹²the standard scheme is CHOP, and in cases of relapses with schemes based on platinum. Studies show an overall response between 70% and 80%¹⁹, higher than that found in our study, where it reached 50.7% after the first line of treatment.

In our analysis, it was shown that the complete response achieved after the first line of chemotherapy has a better prognosis and a longer overall survival time compared to patients who only achieved a partial response. The literature indicates that the partial or complete response after the administration of chemotherapy, based on the CHOP or CHOP like scheme, can reach up to 65%; in our study said the response to the first line of treatment reached up to 50.7%.

The 5-year survival for ALK+ patients was 62.5%, similar to the 60% reported by Savage et al; for ALK - patients it was 29.6% lower than the 36% reported in the same study, evidencing, also described in other studies, that ALCL ALK + is an important favorable factor in survival². It has been shown that ALK plays an important lymphomatogenesis⁵, strongly suggesting that its inhibition would be sufficient to attenuate the growth and survival of ALCL ALK+ cells, considering it as a potential molecular target in the therapy of this disease and in others where its presence has been demonstrated, such as lung cancer and inflammatory myofibroblastic tumor^20,21. A study showed that the better evolution of patients with ALCL ALK+ may also be associated with higher levels of apoptosis due to chemotherapeutic agents than ALK- cells²², which would increase the greater responses and better prognosis in these patients.

Other factors that could be considered prognostic factors were also identified: lactic dehydrogenase above the normal value, the International Prognostic Index, and the clinical stage⁶, all with statistical significance, while other works do not consider that these are independent factors²³. We found positivity for ALK as a prognostic factor and an international prognostic index with a significant statistical difference.

The limitations of the study have been that it is a retrospective study and that 17% of the population did not receive cancer treatment.

CONCLUSIONS

ALCL is an aggressive disease with a heterogeneous distribution for age and slightly more frequent in males, where ALK expression can be considered a prognostic factor (where its expression determines the existence of two different entities due to the age of presentation and aggressiveness) and the International Prognostic Index. Treatment based on anthracyclines allows obtaining an overall response greater than 50% with overall survival of 38.5% at 5 years.