Non-anaplastic Peripheral T-cell Lymphoma Research Articles

Hematopoietic stem cell transplantation for pediatric patients with non-anaplastic peripheral T-cell lymphoma. An EBMT pediatric diseases working party study

Peripheral T-cell lymphomas (PTCL) other than anaplastic large-cell lymphoma are rare in children, and the role of hematopoietic stem cell transplantation (HSCT) has not been clarified yet. In a retrospective analysis of registry-data of the European Society for Blood and Marrow Transplantation we analyzed 55 patients aged < 18 years who received allogeneic (N = 46) or autologous (N = 9) HSCT for PTCL. Median age at HSCT was 13.9 years; 33 patients (60%) were in first remission, and 6 (19%) in progression at HSCT. Conditioning was myeloablative in 87% of the allogeneic HSCTs and in 27 (58.7%) based on total body irradiation. After allogeneic HSCT the 5-year overall- and progression-free survival was 58.9% (95% CI 42.7–71.9) and 52.6% (95% CI 36.8–66.1), respectively. 5-year relapse incidence was 27.6% (95% CI 15.1–41.6), the non-relapse mortality rate was 19.8% (95% CI 9.7–32.6). Five of the six patients with progression at HSCT died. Seven of nine patients after autologous HSCT were alive and disease-free at last follow-up. Our data suggest a role of allogeneic HSCT in consolidation-treatment of patients with high-risk disease, who reach at least partial remission after primary- or relapse-therapy, whereas patients with therapy-refractory or progressive disease prior to transplantation do not profit from HSCT.

Molecular features of non-anaplastic peripheral T-cell lymphoma in children and adolescents.

Non-anaplasticperipheral T-cell lymphomas (PTCL) are rare tumors in children, adolescents, and young adults (CAYA) with poor prognosis and scarce genetic data. We analyzed lymphoma tissue from 36 patients up to 18years old with PTCL, not otherwise specified (PTCL-NOS), hepatosplenic T-cell lymphoma, Epstein-Barr virus (EBV)-positive T-lymphoproliferative diseases, subcutaneous panniculitis-like T-cell lymphoma, and other PTCL types. Twenty-three patients (64%) had at least one genetic variant detectable, including TET2, KMT2C, PIK3D, and DMNT3A. TP53 and RHOA variants, commonly found in adults, were not identified. Eight of 20 (40%) CAYA PTCL-NOS had no detectable mutations. The genetic findings suggest that CAYA PTCL differ from adult cases.

Prognostic Significance of T-Cell Phenotype in Aggressive Non-Hodgkin's Lymphomas

Peripheral T-cell lymphomas (PTCL) have been generally reported to have a worse prognosis than B-cell lymphomas (BCL). Because of their heterogeneity and scarcity, the outcomes of the different histological subtypes have not been compared. From October 1987 to March 1993, 1,883 patients with diffuse aggressive non-Hodgkin's lymphomas (NHL) included in the LNH87 protocol could be assessed for both morphology and immunophenotyping. Among them, 288 (15%) had PTCL and 1,595 (85%) had BCL. According to the Kiel classification, most PTCL were classified as angioimmunoblastic (AIL; 23%), pleomorphic medium and large T-cell (PML; 49%), or anaplastic large cell (ALCL; 20%) lymphomas. Comparing PTCL with BCL patients, the former had more disseminated disease (78% v 58%), B symptoms (57% v 40%), bone marrow involvement (31% v 17%), skin involvement (21% v 4%), and increased beta2-microglobulin (50% v 34%), whereas BCL patients had more bulky disease (41% v 26%). According to the International Prognostic Index (IPI), PTCL and BCL scores were, respectively: 0 factors, 13% and 15%; 1 factor, 17% and 22%; 2 factors, 24% and 25%; >/=3 factors, 45% and 37% (P = .09). For BCL and PTCL, respectively, complete remission rates were 63% and 54% (P = .004); the 5-year overall survival (OS) rates were 53% and 41% (P = .0004) and event-free survival (EFS) rates were 42% and 33% (P < . 0001). Comparison of the different histological subtypes of lymphoma showed that the 5-year OS rate for T-ALCL (64%) was superior to those of other PTCL (35%) as well as diffuse large B-cell (53%) NHL. When multivariate analysis was applied using the IPI score as one factor, nonanaplastic PTCL remained an independent parameter (P = . 0004). Although the poor prognosis of non-ALCL PTCL could be due in part to the presence of adverse prognostic factors at diagnosis, this study shows that the T-cell phenotype is an independent significant factor, which should be incorporated into the definition of prognostic groups.

Stem Cell Transplantation for Pediatric Patients with Non-Anaplastic Peripheral T-Cell Lymphoma on Behalf of the EBMT-Pediatric Diseases Working Party

Peripheral T-cell lymphomas (PTCL) other than anaplastic large cell lymphoma are rare in children, and data about outcome and treatment results especially regarding the role of stem cell transplantation (SCT) are scarce. Here we present the results of a retrospective study of SCT for pediatric patients with PTCL within the European Group of Bone marrow transplantation (EBMT). Out of 125 patients aged <18 years with PTCL diagnosed between 1995 and 2015 who were registered to the EBMT database, reports about the primary therapy and data about the course of SCT were sufficient for analysis in 55 patients. 37 (69%) had PTCL not otherwise specified (NOS), 7 (13%) hepato-splenic T-cell lymphoma, 4 (7%) angioimmunoblastic T-cell lymphoma, 3 (6%) NK/T-cell lymphoma, 2 (4%) subcutaneous panniculitis-like T-cell lymphoma, and 1 systemic EBV-lymphoproliferative syndrome. Median age at PTCL-diagnosis was 13.0 years (range: 0.7-17.6), and was 13.9 years (range: 2.5-17.9) at SCT, respectively. 35 (65%) of the patients were male. 43 (81%) of the patients had received T-NHL/ lymphoblastic lymphoma-type therapy; radiotherapy (RT) was given to 7 patients (16%) prior to SCT. 45 (83%) patients underwent allogeneic SCT (16 from related and 29 from unrelated donor), and 9 (17%) patients received autologous SCT (ASCT). Myeloablative conditioning (MAC) was used in 44 (88%) patients, 6 (12%) patients received reduced-intensity conditioning (RIC). Total body irradiation (TBI) was part of the conditioning regimen in 26 patients (48%).After SCT the 5-year overall survival (OS) and lymphoma-free survival (LFS) probability was 57% (95% CI 44.5-72.5) and 56% (95% CI 43.4-71.2), respectively. Relapse incidence was 25% (95% CI 14.1-37.9), whereas the non-relapse mortality (NRM) rate was 18% (95% CI 9.4-29.7).Patients with younger age (0-9 years, vs. 10-18 years) at diagnosis of PTCL had a tendency for better outcome (OS 80% vs. 50%, respectively p=0.069), whereas age at SCT and gender had no influence on outcome (p=0.2 and p=0.6, respectively). Year of SCT (1995-2007 vs. 2008-2015) was of no significance for the outcome (p=0.31).A tendency for better outcome (OS/LFS) was observed in patients who received RT in the pre-transplant treatment, and for patients who achieved first/second complete remission (CR1/CR2) before SCT, as compared to those with later/ without CR prior to SCT (OS 72% vs 46%, p=0.1). Patients receiving MAC conditioning had a better OS compared to patients receiving RIC (66% vs. 33%, p=0.07). LFS was inferior after ASCT compared to allogeneic SCT, resulting in non-significant difference in OS .Acute Graft-versus host disease (aGvHD) grade III/IV was seen in 6 (14.6%) patients. 6 patients suffered from chronic GvHD, 2 of them from the extensive form.In conclusion, SCT for pediatric patients with PTCL in CR1/CR2 is a valid option of treatment. MAC may currently be chosen for conditioning in order to possibly prevent relapses. DisclosuresBader:Neovii: Research Funding; Cellgene: Consultancy; Riemser: Research Funding; Novartis: Consultancy, Speakers Bureau; Medac: Patents & Royalties, Research Funding.

Final Analysis of the Front-Line Phase III Randomized ACT-1 Trial in Younger Patients with Systemic Peripheral T-Cell Lymphoma Treated with CHOP Chemotherapy with or without Alemtuzumab and Consolidated By Autologous Hematopoietic Stem Cell Transplant

Final Analysis of the Front-Line Phase III Randomized ACT-1 Trial in Younger Patients with Systemic Peripheral T-Cell Lymphoma Treated with CHOP Chemotherapy with or without Alemtuzumab and Consolidated By Autologous Hematopoietic Stem Cell Transplant

Non-anaplastic peripheral T cell lymphoma in children and adolescents—an international review of 143 cases

Peripheral T cell lymphomas (PTCL) are rare in children and adolescents, and data about outcome and treatment results are scarce. The present study is a joint, international, retrospective analysis of 143 reported cases of non-anaplastic PTCL in patients <19years of age, with a focus on treatment and outcome features. One hundred forty-three patients, between 0.3 and 18.7years old, diagnosed between 2000 and 2015 were included in the study. PTCL not otherwise specified was the largest subgroup, followed by extranodal NK/T cell lymphoma, hepatosplenic T cell lymphoma (HS TCL), and subcutaneous panniculitis-like T cell lymphoma (SP TCL). Probability of overall survival (pOS) at 5years for the whole group was 0.56±0.05, and probability of event-free survival was (pEFS) 0.45±0.05. Patients with SP TCL had a good outcome with 5-year pOS of 0.78±0.1 while patients with HS TCL were reported with 5-year pOS of only 0.13±0.12. Twenty-five percent of the patients were reported to have a pre-existing condition, and this group had a dismal outcome with 5-year pOS of 0.29±0.09. The distribution of non-anaplastic PTCL subtypes in pediatric and adolescent patients differs from what is reported in adult patients. Overall outcome depends on the subtype with some doing better than others. Pre-existing conditions are frequent and associated with poor outcomes. There is a clear need for subtype-based treatment recommendations for children and adolescents with PTCL.

Clinical Characteristics and Treatment Outcomes of Non-anaplastic Peripheral T-Cell Lymphoma in Children and Adolescents: A Single-center Experience

Results: According to the World Health Organization (WHO) classifications for PTCL, 11 patients had PTCL, not otherwise specified (PTCL-NOS), 6 patients had extranodal natural killer/T-cell lymphoma, nasal type (ENKL), and 1 patient had subcutaneous panniculitis-like T-cell lymphoma. Patients were treated with various chemotherapeutic regimens. Of these 18 patients, 5 (27.7%) relapsed and 7 (38.9%) died from disease progression. Two relapsed patients received high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HDCT-ASCT). The 5-year event-free and overall survival rates were 43.2% and 66.7% in all cases, 45.5% and 54.5% in PTCL-NOS, and, 25.0% and 83.3% in ENKL, respectively.

Immunohistochemistry as a valuable tool to assess CD30 expression in peripheral T-cell lymphomas: high correlation with mRNA levels

AbstractThe extended use of brentuximab-vedotin was reported for CD30+ nonanaplastic peripheral T-cell lymphomas (PTCLs) with promising efficacy. CD30 status assessment is thus a critical factor for therapeutic decision, but the reliability of immunohistochemistry (IHC) in evaluating its expression remains to be defined. This prompted us to investigate the correlation between semiquantitative CD30 protein assessment by IHC and messenger RNA (mRNA) assessment by microarrays in a cohort of 376 noncutaneous PTCLs representative of the main entities. By IHC, CD30 expression was heterogeneous across and within entities and significantly associated with large tumor cell size. In addition to 100% anaplastic large-cell lymphomas, 57% of other PTCL entities were CD30-positive at a 5% threshold. CD30 protein expression was highly correlated to mRNA levels. mRNA levels were bimodal, separating high from low CD30-expressing PTCL cases. We conclude that IHC is a valuable tool in clinical practice to assess CD30 expression in PTCLs.

Stem cell transplantation for paediatric patients with non‐anaplastic peripheral T‐cell lymphoma in Japan

Reports of non-anaplastic peripheral T-cell lymphoma (PTCL) in paediatric patients, especially results of stem cell transplantation (SCT), are relatively rare. We herein report the results of SCT using the Transplant Registry Unified Management Program system of the Japanese Society of Stem Cell Transplantation in paediatric patients with non-anaplastic PTCL. We analysed 26 patients (13 females and 13 males) aged ≤18years with non-anaplastic PTCL who underwent a total of 28 SCT. Median age at transplantation was 13·5years (range: 0-18years). PTCL not otherwise specified was diagnosed in 17 patients; extranodal Natural Killer (NK)/T cell lymphoma, nasal type in nine; and subcutaneous panniculitis-like T-cell lymphoma in two. Transplantation was with syngeneic donor in one, related donor in 10; unrelated donor in 10; and auto transplantation in 7. Five-year overall survival rate and event-free survival rate was 62·96% and 55·56%, respectively. Male gender, chronic graft-versus-host disease (GVHD), and reduced intensity conditioning were good prognostic factors in all patients. In 20 patients with refractory or relapsed disease, male gender and chronic GVHD were also good prognostic factors. This study is the first report concerning transplantation in children with non-anaplastic PTCL, although the number of patients was small. Larger studies are needed to confirm these findings.

Retrospective analysis of non‐anaplastic peripheral T‐cell lymphoma in pediatric patients in Japan

Reports of non-anaplastic peripheral T-cell lymphoma (PTCL) in pediatric patients are relatively rare. We performed a retrospective analysis in patients with PTCL over an 18-year period (1991-2008). We could analyze clinical data in 21 patients with non-anaplastic PTCL; 10 were female and 10 male. Median age of onset was 11 years (range: 1-21 years). There were nine patients with PTCL, not otherwise specified (PTCL-NOS); ten with extranodal NK/T-cell lymphoma, nasal type; one with angioimmunoblastic T-cell lymphoma; and one with subcutaneous panniculitis-like T-cell lymphoma. Initial lesions involved cervical lymph nodes in five patients, and the skin in five patients. In five patients, hemophagocytic syndrome (HPS) was the initial clinical feature. There were 12 patients with advanced stage disease (stages III and IV). Chemotherapy and radiation was administered in 18 and 2 patients, respectively. Among the two patients who did not receive chemotherapy and radiation, one patient died while being treated for HPS but another improved spontaneously. Although 5 patients relapsed, 18 of 21 patients remained alive without disease at last follow-up. Five-year overall survival rate was 85.2%. Generally, the outcome results of conventional chemotherapy for high-risk PTCL are poor in adult patients. However, the excellent results in our study suggest that PTCL of childhood is quite different from that of adulthood. Although this study is first report about PTCL of Asian children, the number of patients was small in this study. Larger studies are needed to confirm these findings.

Prognostic value of T-cell receptor γ rearrangement in peripheral blood or bone marrow of patients with peripheral T-cell lymphomas

Peripheral T-cell lymphomas (PTCL) have a variable outcome. We have investigated the prognostic value of molecular staging in non-anaplastic PTCL. T-cell receptor γ rearrangements were routinely determined in peripheral blood (n = 40) and bone marrow (n = 38) of patients with PTCL (75% unspecified) by conventional PCR at diagnosis. Tissue controls for PCR included 24 tumour biopsies. Twenty-four patients (60%) had a PCR-detectable clonal TCRγ rearrangement in PB or BM. These TCRγ PCR positive patients had significantly more stage IV disease (14 patients of 15 patients; P = 0.001), elevated LDH (14 of 18 patients; P = 0.04), higher IPI (16 of 21 patients; P = 0.03), more anemia (15 of 19 patients; P = 0.02) and lower platelet counts (seven of seven patients; P = 0.02). Clinical outcome of this clonal group was characterised by lower complete remission rates (37.5% vs. 62.5%), and overall response rates (58.3% vs. 87.5%; P < 0.05) as well as a significantly shorter median overall survival (12.8 vs. 30.0 months; P = 0.006). Patients with clinical stages I – III but molecular stage IV had an equally poor overall survival when compared with patients with clinical stage IV (15.8 vs. 13.9 months). In contrast, patients with CS I – III in the absence of a TCRγ rearrangement in PB or BM had a favourable outcome with an estimated overall survival of 70% at 3 and 5 years. Molecular staging in PB and BM by TCRγ PCR at diagnosis may serve as a useful prognostic tool in PTCL.

Secondary Neoplasms Subsequent to Berlin-Frankfurt-Muenster (BFM) Therapy of Non-Hodgkin Lymphoma of Childhood: Significantly Higher Risk for Patients with Lymphoblastic Lymphoma Compared to Other NHL-Subtypes.

We evaluated the rate and type of second malignant neoplasms (SMN) after BFM treatment of children with Non-Hodgkin lymphoma (NHL). Between January 1981 and February 2003 2451 patients (pts) <15 years (y) of age at diagnosis were enrolled into the subsequent trials NHL-BFM 81, 83, 86, 90, and 95. Pts with lymphoblastic lymphoma (LBL) (n=547) or non-anaplastic peripheral T-cell lymphoma (n=97) received acute lymphoblastic leukemia (ALL)-type therapy including cumulative doses of cyclophosphamide (max. 3g/m2), daunorubicine/doxorubicin (max. 280mg/m2), but, except few pts, no etoposide. Prophylactic cranial radiotherapy (CRT) was given in stage III/IV (omitted in NHL-BFM95). Pts with mature B-cell neoplasms (n=1597), or anaplastic large cell lymphoma (n=210) received B-type therapy, consisting of 2–8, 5-day courses including cumulative doses of cyclophosphamide (max. 7g/m2), ifosfamide (max. 8g/m2), doxorubicine max. 150mg/m2 (in trial 81 max. 200mg/m2), and etoposide (max. 1.4g/m2). CRT was omitted since trial NHL-BFM86. With a median follow-up of 6.9 (range 0.2–22.6) years the probability of survival at 15 y was 83+1%. By June 2005, 47 SMN were documented, including 16 acute myeloid leukemias/myelodysplastic syndromes (AML/MDS), 11 NHL, 2 ALL, 1 Hodgkin's lymphoma, 7 brain tumors, and 10 other SMN. All SMN occurred in first remission after a median time of 2.9 (range: 0.4–12.3) years from diagnosis of NHL. The cumulative incidence of SMN at 15 y was 4.0% (95% confidence interval [CI]: 1.9%–6.1%) for the total group. The cumulative incidence of SMN was significantly higher among pts with LBL receiving ALL-type therapy (6.3% at 15 y [95%CI: 2.4%–10.3%] (13 AML/MDS, 2 NHL, 3 brain tumors, and 3 other SMN), as compared to pts with other NHL-entities receiving B-type therapy (3.4% at 15 y [95% CI: 0.5–6.4%] (3 AML/MDS, 9 NHL, 2 ALL, 1 Hodgkin's lymphoma, 4 brain tumors, and 7 other SMN), p=0.002. There was no significant difference of cumulative incidence of SMN in pts who received CRT compared to pts not receiving CRT. However, 5 of 7 pts, who developed brain tumor, received CRT of 12–24 Gy. Also, there was no significant correlation between the incidence of SMN and the cumulative doses of drugs, except for anthracyclines. For pts receiving a cumulative dose of anthracyclines of >160mg/m2 (almost exclusively pts with LBL receiving ALL-type therapy) the cumulative risk for SMN at 15 y was 6.5% (95% CI: 1.5-11.5%), as compared to 2.0% (95% CI: 1.1–2.9%) for pts with lower doses, p=0.007. Exposure to etoposide was not a risk factor for secondary AML/MDS (11 of 16 pts with sec. AML/MDS did not receive etoposide). In a Cox regression analysis only diagnosis of LBL remained a significant risk factor for SMN (RR 2.5, 95% CI 1.4–4.4). Our analysis revealed a cumulative risk for SMN of 4% at 15 y after successful treatment of childhood NHL. The cumulative incidence of SMN was significantly higher in LBL-pts than in other pts. AML/MDS were the most frequent SMN following LBL while second lymphoid malignancies were the most frequent SMN following non-LBL.

Anaplastic large cell lymphomas lack the expression of T-cell receptor molecules or molecules of proximal T-cell receptor signaling

AbstractAnaplastic large cell lymphoma (ALCL) designates a heterogeneous group of CD30+ (systemic or primary cutaneous) peripheral T-cell lymphomas (PTCLs). A subgroup of systemic ALCL is transformed by anaplastic lymphoma kinase (ALK). We compared 24 ALK+, 15 ALK- systemic, and 7 cutaneous ALCLs with 29 nonanaplastic PTCLs in terms of T-cell receptor (TCR) rearrangements, expression of TCRs and TCR-associated molecules (CD3, ZAP-70 [zeta-associated protein 70]). Despite their frequent clonal rearrangement for TCRβ, only 2 (4%) of 47 ALCLs expressed TCRβ protein, whereas TCRs were detected on 27 of 29 nonanaplastic PTCLs. Moreover, both TCRβ+ ALCLs lacked CD3 and ZAP-70 (ie, molecules indispensable for the transduction of cognate TCR signals). Defective expression of TCRs is a common characteristic of all types of ALCL, which may contribute to the dysregulation of intracellular signaling pathways controlling T-cell activation and survival. This molecular hallmark of ALCL is analogous to defective immunoglobulin expression distinguishing Hodgkin lymphoma from other B-cell lymphomas. (Blood. 2004; 104:3358-3360)

T-cell receptor Vbeta repertoire in nodal non-anaplastic peripheral T-cell lymphomas.

The aim of this study was to evaluate the T-cell receptor (TCR) Vbeta repertoire in the two main histological subtypes of nodal non-anaplastic peripheral T-cell lymphoma: Not Otherwise Specified (NOS) and angioimmunoblastic lymphoma (AIL). Frozen lymph node tissues of eight NOS and six AIL were analyzed. A reverse transcriptase polymerase chain reaction (RT-PCR) was carried out to assess the expression of the 24 Vbeta gene families. Our study showed a broad TCR Vbeta repertoire in AIL and NOS, with a slight increase in the number of Vbeta families in AIL (16 vs 10 on agarose gels). Nevertheless, there was a clear difference in four cases. A predominant Vbeta family was observed in two NOS, whereas no predominant Vbeta family was observed in the AIL. Two AIL showed the whole Vbeta repertoire, whereas it was never observed in NOS. This pattern may help to categorize these histopathological entities and further suggests a differential T-cell response. These results show that numerous reactive T-cells are present both in AIL and NOS. Possibly, they play a role in the growth of these lymphomas.