Favorable Outcome in a Large Cohort of Prospectively Treated Adult Patients with T-Lymphoblastic Lymphoma (T-LBL) Despite Slowly Evolving Complete Remission Assessed By Conventional Radiography

Abstract

LBL is a rare subtype of NHL and mostly displays a T-cell phenotype. The WHO classification combines acute lymphoblastic leukemia (ALL) and LBL; pts with ≥ 25% bone marrow (BM) infiltration are considered as ALL. LBL pts are usually treated according to ALL protocols and sometimes reported within ALL trials. There are however specific clinical and management questions, such as role of mediastinal irradiation (MedRad), optimal remission evaluation or risk stratification and there is a lack of prospective trials in LBL. The German Multicenter Study Group for Adult (GMALL) has reported results on 45 T-LBL pts (Hoelzer et al, Blood 2002). Based on this experience a prospective T-LBL trial was activated (cohort I) followed by a prospective registry with documentation of pts treated according to an GMALL expert recommendation (cohort II). Therapy was based on the GMALL trial for ALL (07/2003) with a prephase (Dexa, Cyclo), induction I (Dexa, VCR, Dauno, PEG-Asparaginase) and induction II (Cyclo, ARAC, Mercaptopurine) together with CNS irradiation and i.th. prophylaxis. MedRad (36 Gy) was scheduled after induction and followed by consolidation (cons) I (VCR, Dexa, VP16, HDMTX, HDARAC), cons II, III, VI (HDMTX/PEG-ASP), reinduction, cons IV (HDARAC) and V (CYCLO/ARAC). Salvage therapy was recommended in pts without CR/CRu after cons I. Essential time-points (TP) for remission evaluation were after induction II (TP1), after MedRad (TP2 in cohort I only) and after cons I (TP3). For cohort II MedRad was omitted and PET analysis was recommended in CRu or PR at TP3. 149 pts (cohort I:101; cohort II: 48) from 64 hospitals were included between 9/04 and 1/13. The median age was 31 (17-62) yrs. 73% were male. 93% had mediastinal involvement, 61% pleural and 34% pericardial effusion, 18% BM and 2% CNS involvement. 59% had stage III-IV disease. 63% had a thymic subtype (N=66) and 37% had an early or mature T phenotype (N=39). Results of response evaluation according to standard procedures (excluding PET) are given in table 1. CR/CRu rates increased from 34% to 59% and 76% through TP1-3. 96% had CR,CRu or PR as best response at TP1-3. Positive PET results at TP3 were detected in 0/21 pts with CRu and 10/22 (45%) pts with PR (p=0.001). Overall survival (OS) was 65% at 5 yrs. 3 yr OS appeared superior in cohort II vs cohort I (76% vs 67%; p>0.05), due to a lower relapse rate (15% vs 31%;p=0.07) but at shorter median follow-up (1.9 vs 5.6 yrs). 2% died in CR. No difference was observed in terms of 5y OS for pts with CR, CRu or PR, 71%, 82% and 75% resp (p>0.05). In the majority of PR pts therapy was continued per protocol. 5y OS was slightly superior for pts with thymic (N=66; 78%) vs early/mature (N=39; 58%) subtype (p>0.05). Pts <> 25 yrs had 5 yr OS rates of 75% vs 60% resp. (p=.09); stage , BM involvement and aaIPI had no significant impact on OS. Pts with early achievement of CR/CRu (TP1) had a slightly better OS (N=49; 69%) compared to those with PR/Failure (N=95; 65%) (p=.09). Overall 26% of the pts relapsed (42% BM±other, 11% CNS+other, 8% CNS only, 40% lymph node or extramedullary only). The proportion of mediastinal relapses did not increase in cohort II vs cohort I (24% vs 17%). This is the largest so far reported cohort of prospectively treated adult patients with T-LBL. The response rate including PR was high (96%). Response evaluation was challenging since many patients showed persistent residual mediastinal tumors (CRu/PR) and responses formally evolved slowly. Conventional remission evaluation had limited clinical relevance as indicated by similar OS of CR, CRu and PR pts. PET evaluation yielded positive results in 45% of the PR pts and may be helpful for decision making on salvage therapies. The omission of MedRad did not impact relapse risk and may have contributed to better feasibility of dose intense chemotherapy. Whereas pts with early/mature phenotype and older pts had a trend towards poorer OS other factors did not significantly influence outcome. In the future additional prognostic factors like minimal residual disease evaluation may help to identify patients with potential benefit from salvage therapy and/or stem cell transplantation (supported by the Jose Carreras Foundation; Grant: Ho9/01f) Table 1: Results of Remission Induction TP1 (after induction) TP2*(after irradiation) TP3 (after consolidation) Best response Evaluable 148 86 138 149 CR 22% 33% 63% 60% CRu 12% 26% 13% 13% PR 62% 35% 15% 23% Failure 3% 2% 6% 1% Early death 3% 5% 3% 3% * Cohort 1 only Disclosures No relevant conflicts of interest to declare.

Lymphoblastic lymphoma: an updated review on biology, diagnosis, and treatment

“…This question was addressed with better methodology by two recent studies. In the GMALL trial postinduction, PET results were significantly associated with the response obtained after consolidation I (PET+: 0/21 CRu vs. 10/22 PR [partial remission], P = 0.001), suggesting an equivalence between CR and PET‐negative CRu, which may be informative eliminating the need for intensification of chemotherapy or mediastinal irradiation . In the GRAALL‐Lysa study, PET results did not predict long‐term outcome ; however, end of induction and CT results correlated significantly with PET data.…”

“…LBL occurs more commonly in children and male patients, and although T‐ and B‐cell LBL are morphologically indistinguishable, the clinical presentation can suggest a different disease biology. The most frequent sites of involvement observed in adults and children are summarized in Tables and .…”

“…However, in most childhood series, no prognostic factor was identified following the introduction of highly effective ALL‐type chemotherapy. In adult LBL (Table ) (), the favorable prognostic factors were young age (<40 yrs) , female gender , low international prognostic index (IPI) score , B‐cell phenotype, and lack of BM or CNS involvement . Regarding response to ALL‐type chemotherapy, some underlined the importance of an early CR , while others did not, including two recent large series from GMALL and GRAALL‐Lysa .…”

Hyper‐CVAD plus nelarabine in newly diagnosed adult T‐cell acute lymphoblastic leukemia and T‐lymphoblastic lymphoma

“…As previously reported, patients with T‐LBL had better outcomes compared to T‐ALL . The role of SCT in adult T‐ALL remains unclear; with some authors recommending SCT in all patients in CR1 and others restricting SCT to higher‐risk patients.…”

NHL in adolescents and young adults: A unique population

“…92,93,[102][103][104][105] Outcomes appear to be superior in AYAs with the use of pediatric designed treatment protocols, particularly with the current practice of utilizing ALL-type regimens, which has resulted in improved disease-free survival of over 70% in recent studies (Table 1). 106,107 An additional approach for advanced LL in the AYA group has been the use of high-dose therapy and autologous or alloSCT. Bouabdallah et al reported the results of alloSCT (n = 12; 11 underwent the procedure in first complete remission [CR1]) and autologous stem cell transplantation (n = 18; 16 = CR1) in patients aged >14 years with a mean age of 35 with advanced LL.…”