Hematopoietic SCT for peripheral T-cell lymphoma

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1 (2008), 1 9 & 2008 Macmillan Publishers Limited All rights reserved /08 $ REVIEW Hematopoietic SCT for peripheral T-cell lymphoma A Gutiérrez 1, MD Caballero 2,GPérez-Manga 3 and J Rodriguez 3 1 Department of Haematology, University Hospital Son Dureta, Palma de Mallorca, Spain; 2 Department of Haematology, Clinic Hospital of Salamanca, Salamanca, Spain and 3 Department of Oncology, Gregorio Marañon Hospital, Madrid, Spain Results of conventional chemotherapy for high-risk peripheral T-cell lymphoma () are poor compared with those for their aggressive B-cell counterparts. We aim to review the current data on the use of hematopoietic SCT in these patients in both frontline and salvage settings. With respect to autologous SCT (ASCT), conclusions from retrospective studies are that ASCT in the salvage setting is as useful in as in aggressive B-cell lymphomas and also that consolidation in first complete response of high-risk patients has very good results when compared with conventional chemotherapy (with long-term PFS higher than 50%). From first frontline prospective clinical trials, it appears that ASCT is feasible and has a low TRM (o5%); consolidation in first complete response is associated with a very good outcome; around 25% of patients do not undergo ASCT due mainly to disease progression; new approaches aimed at increasing the number of chemosensitive patients should be found. Furthermore, 25 30% of patients deemed complete responders post transplant still relapse afterward. For all these mainly chemoresistant patients, there is preliminary evidence that allogeneic SCT (Allo-SCT) may produce a plateau in survival curves (with long-term PFS around 50%), which indicates a graft-versus- effect. For this reason, Allo-SCT procedures are the object of ongoing clinical trials. advance online publication, 20 October 2008; doi: /bmt Keywords: peripheral T-cell lymphoma; autologous SCT; allogeneic SCT Introduction Correspondence: Dr J Rodriguez, Department of Oncology, Gregorio Maran on General University Hospital, C/Doctor Esquerdo, 46, Madrid 28007, Spain. joseguez89@hotmail.com Received 8 July 2008; revised 21 August 2008; accepted 21 August 2008 Malignancies originated in mature T cells or NK cells constitute a heterogeneous group, with a complex diagnosis 1 and a relatively reduced incidence (between 10 and 15% of non-hodgkin s lymphomas in Western countries). 2,3 Table 1 shows the current World Health Organization (WHO) classification for T/NK neoplasms, considering its predominant nodal, extranodal or leukemic expression. The subjects of this review are nodal or non-cutaneous extranodal T or NK cell malignancies. These diseases can be clinically subdivided into three main categories according to current data on response and outcome: anaplastic lymphoma kinase-positive (ALK þ ), anaplastic large cell lymphoma (ALCL) with a good prognosis, nodal peripheral T-cell lymphoma () (including ALK ALCL, angioimmunoblastic T-cell lymphoma (AIL), and not otherwise specified (-NOS) and extranodal with a poor and a very poor prognosis), respectively (Table 2). Peripheral T-cell lymphomas have been treated with anthracycline-based polychemotherapy schemes used for aggressive B-cell lymphomas with generally poor results according to the lower number of complete response (CR) and higher degree of early relapses. 4,5 This makes standard CHOP-like schemes for aggressive B-cell lymphomas a good alternative for good prognosis, but insufficient for higher risk ones. 6,7 In fact, overall survival (OS) at 5 years in these lymphomas is not higher than 25 30% with the exception of ALK þ ALCL cases. 8 Several strategies have been proposed to improve these results: induction regimens with higher CY or doxorubicin doses (non-myeloablative dose intensity), 9 adding new drugs to the regimens or dose-density schemes with variable results but overall discouraging data. In addition, their heterogeneity and low incidence make finding adequate treatment for these diseases more difficult. However, the most attractive and solid data presented until now are with the use of hematopoietic SCT (HSCT), both as high-dose chemotherapy followed by autologous SCT (ASCT) or seeking for a graft-versus-lymphoma immunotherapy (allogeneic-hsct (Allo-HSCT)). Here, we will review current data on the use of. Retrospective studies of ASCT for Autologous SCT is the standard consolidation treatment after salvage chemotherapy in a relapsed aggressive B-cell lymphoma, provided the lymphoma has been chemosensitive to the conventional salvage chemotherapy regimen.

2 2 Table 1 WHOclassification of T/NK neoplasms Nodal, unspecified Anaplastic large-cell lymphoma Angioimmunoblastic T-cell lymphoma Cutaneous Mycosis fungoides/se zary s syndrome Primary cutaneous CD30-positive T-cell lymphoproliferative disorders Primary cutaneous anaplastic large cell lymphoma Lymphomatoid papulosis Borderline lesions Other extranodal Extranodal T/NK cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Leukemic/disseminated T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Aggressive NK cell leukemia Adult T-cell leukemia/lymphoma Abbreviations: ¼ peripheral T-cell lymphoma; T/NK ¼ T and natural killer cells; WHO ¼ World Health Organization. However, the role of ASCT in the corresponding aggressive T-cell lymphomas has only recently been clarified. Although most information comes from retrospective studies, it seems that, in the salvage setting with this strategy, results are similar to those obtained in aggressive B-cell lymphomas, ALK þ ALCL patients having better prognosis than the other s. 8 Table 3 shows the results from the main retrospective series. In these series, it is interesting to note that TRM was around 10%, and as in the case of aggressive B-cell lymphomas, chemoresistance at transplant was a major predictor of failure. In the largest published series, reported by the Spanish Group for Lymphoma and ASCT (GEL/TAMO) from 2003 to 2007, 14,20 we presented similar results provided patients were chemosensitive to the salvage regimen. We also found that two prognostic adverse factors (adjustedinternational prognostic index (a-ipi) 2 3 and elevated b-2- microglobulin) may define a prognostic index, which is able to predict the outcome and survival of patients receiving ASCT in the salvage setting (Figure 1). The value of this index is in identifying a subset of patients with the two adverse prognostic factors that, together with Table 2 Clinical classification of nodal or non-cutaneous extranodal T/NK neoplasms Good prognosis Bad prognosis Very bad prognosis ALK+ ALCL (2%) -NOS (3.7%) Extranodal T/NK cell lymphoma, nasal type (1.4%) ALK ALCL (0.4%) Enteropathy-type T-cell lymphoma (o1%) AIL (1.2%) Hepatosplenic T-cell lymphoma (o1%) Subcutaneous panniculitis-like T-cell lymphoma (o1%) Abbreviations: AIL ¼ angioimmunoblastic lymphoma; ALCL ¼ anaplastic large cell lymphoma; ALK ¼ anaplastic lymphoma kinase; -NOS ¼ peripheral T-cell lymphoma not otherwise specified; T/NK ¼ T and natural killer cells. Percentages of non-hodgkin s lymphoma cases. Table 3 Main retrospective series on the use of ASCT in Study Cases ALCL (%) Clinical setting Survival TRM (%) Comment Rodriguez et al NA Salvage 3-year OS: 36% 10 Results similar to DLCL 3-year PFS: 28% Blystad et al Frontline first CR 3-year OS: 58% 7.5 Good results if chemosensitive Salvage 3-year PFS: 48% Song et al Salvage 3-year OS: 48% 17 Results similar to DLCL 3-year PFS: 37% Jantunen et al Frontline first CR 5-year OS: 45% 11 Better results in ALCL Salvage 5-year PFS: 28% Kewalramani et al Salvage 5-year OS: 33% NA Results similar to DLCL 5-year PFS: 24% Smith et al Salvage 5-year OS: 34% 3 Results worst than in DLCL 5-year DFS: 18% Feyler et al Salvage 2-year OS: 49% 3 Good results if chemosensitive 2-year PFS: 49% Rodriguez et al Frontline first CR 5-year OS: 68% 4 Very good results in first CR 5-year PFS: 63% Worst if PIT42 Rodriguez et al Salvage 5-year OS: 45% 5 Results similar to DLCL 5-year PFS: 34% Worst if a-ipi41 and m B2M Abbreviations: m ¼ elevated; a-ipi ¼ adjusted International Prognostic Index; ALCL ¼ anaplastic large-cell lymphoma; ASCT ¼ autologous SCT; B2M, b-2-microglobulin; CR ¼ complete response; DLCL ¼ diffuse large-cell lymphoma; NA ¼ not available; OS ¼ overall survival; PIT ¼ prognostic index for peripheral T-cell lymphoma.

3 P < potential selection bias. To clarify this problem, several prospective clinical trials have been presented or are ongoing. 3 % surviving % freedom from progression adverse factor OS 28% (10 45) (n=34) 2 adverse factors OS 0% (n=8) 0 adverse factors OS 60% (44 76) (n=46) Months from transplant 2 adverse factors PFS 0% (n=7) 0 adverse factors PFS 43% (27 58) (n=46) 1 adverse factor PFS 24% (8 40) (n=31) Months from transplant P < Figure 1 Pretransplant value of a-ipi and b-2-microglobulin for peripheral T-cell lymphoma () in the salvage setting. a-ipi, adjustedinternational prognostic index; OS, overall survival. truly chemoresistant cases, do not benefit from ASCT consolidation and where new therapeutic strategies should also be tested, including Allo-HSCT. Another controversial point is the value of ASCT in the consolidation of the first CR. The largest retrospective series was reported by the GEL/TAMOgroup describing the outcome of 74 patients. 19,21 This study, which had a long follow-up, shows an OS and PFS of 68 and 63%, respectively. The only independent prognostic index able to identify a subset of patients who do not benefit from ASCT as frontline consolidation of first CR was the presence of more than two adverse factors of the prognostic index for described by Gallamini et al. 22 Thus, as in the case of treated with conventional chemotherapy, this index is also useful for predicting outcome after ASCT as frontline consolidation. It can be noted that we could not find the IPI associated with the prognosis in this setting. Several retrospective works focusing on particular subsets of, such as AIL, have also found a place for ASCT, both in the salvage and in the frontline setting, 23,24 with similar results to the bigger -NOS group. Of course all this information, although encouraging, has to be taken with caution as it is based on retrospective studies, sometimes from cooperative groups, subjected to Prospective studies of ASCT for At present we have preliminary information of several prospective studies concerning the use of ASCT as frontline consolidation for high-risk (Table 4). Although all these studies analyze the role of ASCT in high-risk, there are important differences in the general therapeutic approaches and outcomes that need to be addressed in order to evaluate the data provided by these studies. The first was presented by Reimer et al. 26,30,31 and last updated in the 2008 Annual Meeting of the American Society of Clinical Oncology. They finally included 83 patients with high-risk with better preliminary results for AIL, and with a lower percentage of -NOS patients arriving at transplant. Three-year OS and disease-free survival were 53 and 36%, respectively. Although these results are better than expected with conventional regimens, they should be interpreted with caution as several aspects could be reducing the potential beneficial value of ASCT. In fact, the therapeutic approach consisted in a CHOP induction followed by a DexaBEAM or E-SHAP (etoposide, cisplatin, cytarabine, prednisone) consolidation and a frontline ASCT conditioned with radiochemotherapy (TBI and high-dose CY (60 mg per kg body weight)). The role of TBI in has not been defined and further analysis is needed. Moreover, from our own experience, we have reported several studies showing TBI as an independent adverse prognostic factor in aggressive B- and T-cell lymphomas as well as in Hodgkin s lymphoma. 11,32 In any case, this is an important issue that needs to be specifically addressed. Corradini et al. 25 reported the outcome of 62 patients with a long follow-up (76 months) with a 5-year OS and PFS of around 54 and 40%, respectively. The authors concluded that only durable remissions could be obtained in the ALK þ group, and that the CR during induction treatment was significantly associated with survival. Recently, the GEL/TAMOgroup reported a prospective trial where patients were induced with three cycles of Mega- CHOP (2 g/m 2 CY, 90 mg/m 2 doxorubicin, vincristine 1.4 g/m 2, prednisone 60 mg/m 2 and mesna). In this study, to achieve a greater number of chemosensitive patients prepared to undergo the procedure, we introduced two different concepts with respect to earlier published series: the concept of early evaluation after three cycles of MegaCHOP chemotherapy with computerized tomography and gallium scan, and early rescue with ifosfamide and etoposide in non-cr patients. In our series, direct or rescued chemosensitive patients finally received a frontline ASCT with BEAM conditioning. OS and PFS at 3 years were 72 and 53%, respectively, in 24 patients. There were no differences in whether chemosensitivity was achieved directly (MegaCHOP) or with the early rescue approach. 28 Interestingly, in spite of early rescue, 23% of the patients still did not undergo transplantation because they did not

4 4 Table 4 Prospective series on the use of frontline ASCT in high-risk Corradini et al. 25 Reimer et al. 26 D Amore et al. 27 Rodriguez et al. 28 Mercadal et al. 29 n 62 (19 ALK+) 65 (No ALK+) 121 (No ALK+) 26 (No ALK+) 41 (No ALK+) Median age (years) Regimen (1) 2 APO42 DHAP 4HD MTX/Mel (2) MACOP-B4HD 4 6 CHOP+ DexaBEAM4HD Cy+TBI 6 CHOEP- 144BEAM MegaCHOP/ IFE4BEAM 3 MegaCHOP+3 E-SHAP BEAM or BEAC AraC/Mito/Mel ASCT (%) CR/PR 56/16 47/26 50/35 61/16 49/10 pretransplant (%) TRM (%) OS (%) 34 (12 years) 50 (3 years) 67 (3 years) 75 (3 years) 39 (4 years) PFS (%) 30 (12 years) NA NA 53 (3 years) 30 (4 years) Follow-up post transplant post transplant 47 (months) Risk status of patients AA stages II IV AA stages II IV Excluding ALK+ AA stages II IV Excluding ALK+ a-ipi 2 or 3 a-ipi 1 and m B2M Excluding ALK+ AA stages II IV Excluding ALK+ Abbreviations: m ¼ elevated; AA ¼ Ann Arbor; a-ipi ¼ adjusted-international Prognostic Index; ALK ¼ anaplastic lymphoma kinase; APO ¼ vincristine, doxorubicin and prednisone; B2M ¼ b-2-microglobulin; BEAC ¼ BCNU, etoposide, cytarabine, CY; BEAM ¼ BCNU, etoposide, cytarabine, melphalan; CR ¼ complete response; DexaBEAM ¼ dexamethasone, BCNU, etoposide, cytarabine, melphalan; DHAP ¼ cisplatin, cytarabine, dexamethasone; E-SHAP ¼ etoposide, cisplatin, cytarabine, prednisone; HD AraC/Mito/Mel ¼ high-dose cytarabine, mitoxantrone, melphalan; HD Cy+TBI ¼ high-dose Cy+TBI; CHOEP-14 ¼ CY, vincristine, doxorubicin, etoposide and prednisone; HD MTX/Mel ¼ high-dose MTX and melphalan; IFE ¼ iphosphamide, etoposide; MACOP-B¼ methotrexate, leucovorin, doxorubicin, CY, vincristine, bleomycin, prednisone; MegaCHOP ¼ CY, vincristine, doxorubicin, etoposide and dexamethasone; OS ¼ overall survival; PR ¼ partial response. achieve the chemosensitive condition necessary by the protocol to undergo the transplant. The last published study was presented by Mercadal et al. 29,33 from the GELCAB Spanish group. In this series, only 17 out of 41 patients (41%) were finally transplanted. Between patients chemosensitive to induction treatment, those patients transplanted showed an important reduction (2.5-fold) in the rate of relapses (23% for transplanted vs 57% in the chemosensitive non-transplanted patients) and a 2-fold increase in 4-year PFS, that is, 59% for the transplanted group vs a 29% in the chemosensitive nontransplanted group. 33 d Amore et al. 27,34 from the Nordic Lymphoma Group reported the biggest series on 99 treated frontline patients with CHOEP14 (dose-dense cyclophosphamide, vincristine, doxarubicin, etoposide and prednisone) consolidated with ASCT if at least a partial response was achieved. Furthermore with a short follow-up, they presented a 3-year OS of 67% with around a quarter of patients relapsing after transplant. A common problem in all the series is the high number of patients who do not achieve ASCT mainly because of disease progression (from 23 to 59%) with the lower rate in the early rescue group. This suggests that the introduction of an early non-cross-resistant salvage regimen may reduce the number of non-chemosensitive patients. Therefore, we need strategies aimed at improving the number of responses and thereby increasing the number of chemosensitive patients at transplant, with the addition of new drugs. In fact, this group of roughly 30% of patients who progress (or are chemoresistant) should be the focus of future trials. At the same time, the procedure appears feasible and with a reduced TRM. In summary, frontline ASCT appears to be the most effective approach for the consolidation of response in high-risk, although only a randomized clinical trial can definitively confirm this. Allo- As in the case of aggressive B-cell lymphomas, allo-hsct has no clearly defined role in, although cumulative evidence of a graft-versus effect has been recently reported, most of them performed over heavily pretreated patients. 15,35,36 Similarly, Corradini et al. 35 reported 17 patients with relapsed or refractory disease who underwent a reduced intensity allogeneic procedure. The authors found an impressive OS of 80% and PFS of 60% at 3 years. In this initial series, 15 out of 17 patients were chemosensitive before transplant. Interestingly, the nonrelapse mortality was only 6% at 2 years. Recently, these investigators have updated their experience in 35 patients with a median follow-up of 44 months. The PFS of this series is now 49% and the OS 54%. Moreover, CR patients after transplant had a 72% PFS versus only 25% in those in chemorefractory status at transplant. Table 5 depicts series with 10 or more patients who underwent allo-hsct both at reduced and full-intensity regimens. As shown, PFS and OS are encouraging with PFS ranging from between 31 and 64% at 2 5 years of median follow-up, with a corresponding OS ranging from between 35 and 88%, respectively. If we take into account the population targeted by the procedure, mainly patients relapsing or refractory, with some patients (one-third in some series) having failed earlier an ASCT, then the results are quite good. The European Group for Blood and Marrow Transplantation experience is also very illustrative of the presence of a graft-versus- effect (manuscript in preparation). Retrospective experience comprising 8 years of registered data in this group has recently been reported in both AIL and -NOS, respectively (Table 5). Interestingly, the refractory group of AIL at transplant had a 36% PFS,

5 Table 5 Series of allogeneic-hsct in 5 Author N Modality Donor PFS (%) OS (%) NRM (%) Corradini et al RIC 16 MRD 1 MUD Wulf et al RIC 40% MRD 60% MUD Le Gouill et al FC 60 MRD 10 MUD 7 MMUD 49 (5 years) 54 (5 years) (1 year) 70 (1 year) 53 (5 years) 57 (5 years) 33 Tanosaki et al % FC/83% RIC NA 47 (2 years) 60 (2 years) Zain et al FC/RIC NA 53 (5 years) 36 O Leary et al % FC/10% RIC 80% MRD 10% MUD 10% MMUD 49 (2 years) 77 (2 years) 19 Gu nther et al FC 70% MUD 20% MRD 10% other 60 (2 years) 60 (2 years) 10 Hamadani et al RIC NA 31 (3 years) 35 (3 years) 57 EBMT() 91 RIC NA 39 (5 years) 43 (5 years) 29 EBMT (AIL) 45 53% FC/47% RIC NA 57 (5 years) 64 (5 years) 25 Abbreviations: AIL ¼ angioimmunoblastic T-cell lymphoma; EMBT ¼ European Group for Blood and Marrow Transplantation; FC ¼ full-conditioned; MMUD ¼ mismatched unrelated donor; MRD ¼ matched related donor; MUD ¼ matched unrelated donor; NA ¼ not available; NRM ¼ non-relapse mortality; OS ¼ overall survival; RIC ¼ reduced-intensity conditioning. suggesting that some of these patients who are uncurable under any other treatment, can still benefit from this procedure. The experience in corresponds to 91 patients registered in the European Group for Blood and Marrow Transplantation. With a prolonged follow-up of 50 months, the PFS at 4 years was 39% and the OS 43%. Similar to other series, a plateau in the PFS and OS curve is shown since 2 years after the transplant. Recently, Le Gouill et al. 36 and other French investigators have reported their retrospective experience in 77 patients with several subtypes of who underwent Allo-HSCT. In this series, most patients underwent a full myeloablative procedure and again the results were encouraging with a 57% 5-year OS and a corresponding 53% EFS. These results are similar to the ones reported by the European Group for Blood and Marrow Transplantation with basically no differences between patients receiving a full versus a reduced intensity procedure. However, in this French series, the non-relapse mortality was 33%. Predictors of poor outcome in this series were refractory disease at transplant for PFS and this condition plus the appearance of acute GVHD grades III IV by multivariate analysis. As with the other series, several interesting points need to be highlighted. First, the presence of a plateau after 18 months in the Kaplan Meier plots is observed. Second, a graft-versus-lymphoma effect is shown, as two patients relapsing after the transplant entered into a new remission with donor lymphocyte infusion. Third, although the patients chemorefractory to the transplant fare worse than the corresponding chemosensitive cases, around 30% of these patients, which is similar to the other series, still benefit from the procedure. Fourth, even though there are some differences in the results among the distinct subtypes of, again they are not significant, as is the case in the other large series reported. Fifth, the subtype that emerges as particularly benefiting from this therapeutic modality seems to be the hepatosplenic lymphoma, especially because this disease portends a dismal prognosis. There are therefore common points from these major series. For instance, most patients are in CR at transplant and the disease status pretransplant is a major predictor of the outcome. However, interestingly in this series, preliminary experience suggests that around one-third of refractory patients at transplant respond to this procedure and might be potentially cured of their disease. Meanwhile, 70% of CR patients can be cured of their disease according to data from these three largest series. On the basis of this encouraging experience, two large European groups, Italian and German, are launching randomized studies comparing both autologous and allogeneic myeloablative procedures in patients with this group of lymphoma as the consolidation of frontline therapy. Conclusions and future considerations With the current data, there is a clearer role of ASCT in relapsed or high-risk. Overall, conclusions from retrospective studies are that ASCT in is as useful as in aggressive B-cell lymphomas in the salvage setting and also that consolidation in first CR of high-risk patients provide very good OS, relapse rate and PFS when compared with retrospective studies with conventional chemotherapy. Lessons from the first prospective clinical trials about the use of frontline ASCT are as follows: first, the procedure is feasible and with a low TRM; second, as observed in retrospective studies, ASCT consolidation in first CR of high-risk is associated with a very good outcome; third, around a quarter of patients do not

6 6 diagnosis and risk assessment AA stage I II AA stage III IV Low / lowintermediate risk a-ipi 0-1 PIT 0-2 High-intermediate / high-risk a-ipi 2-3 PIT 3-4 Clinical trial (preferred) or multiagent chemotherapy DLCLtype (i.e.: CHOP-like) ± locorregional radiotherapy Clinical trial (preferred) or multiagent chemotherapy DLCLtype (i.e.: CHOP-like) ± locorregional radiotherapy Response assessment with PET Response assessment with PET CR PR or <PR PR or <PR CR Follow-up Salvage treatment <PR PR or CR ASCT If very high-risk features, good ECOG PS and available matched donor consider RIC Alo-HSCT New drugs / experimental approaches Figure 2 Treatment algorithm for (excluding ALK þ cases). AA, Ann Arbor; a-ipi, adjusted International Prognostic Index; Allo-HSCT, allogeneic hematopoietic SCT; ALK þ, anaplastic lymphoma kinase-positive; ASCT, autologous SCT; CR, complete response; DLCL, diffuse large-cell lymphoma; ECOG PS, Eastern Cooperative Oncology Group Performance Status; PET, positron emission tomography; PIT, Prognostic Index for Peripheral T-cell Lymphoma; PR, partial response;, peripheral T-cell lymphoma. undergo ASCT mainly because of disease progression, and new approaches aimed at increasing the number of chemosensitive patients should be found. In this line, new nucleoside analogs such as gemcitabine or nelarabine have shown good results alone or combined; recently encouraging results have been reported with the novel antimetabolite pralatrexate. Furthermore, exploring new molecular targets drugs such as bortezomib and mtor inhibitors (temsirolimus) or using positron emission tomographybased response-adapted strategies are warranted. 28,43 45 Fourth, 25 30% of patients deemed CR post transplant still relapse afterward. Thus, nowadays defining this population clinically and biologically is a must. In this vein, a maintenance concept might be tested, especially now when new drugs with relatively low toxicity and proven efficacy are becoming known (histone deacetylase

7 inhibitors; immunomodulatory drugs such as lenalidomide or MoAbs such as alemtuzumab, Ontak, anti-cd30 and others). 46,47 At the same time, there is preliminary evidence that allo- HSCT may produce a plateau in both PFS and OS curves, which may indicate that this procedure, if feasible, may in fact cure a fraction of these patients, remarkably including chemorefractory cases. In this way, conventional or reduced intensity conditioning procedures are the object of ongoing clinical trials. Chemoresistant patients are optimal candidates for these trials. Similarly, high-risk patients who do not benefit from frontline or salvage ASCT according to prognostic factors (that is, a-ipi 41 and elevated b-2-microglobin) 14 should also be considered for reduced intensity conditioning allo-hsct trials. Figure 2 shows a standard treatment algorithm including all these 7 diagnosis and risk assessment Low-risk profile a-ipi 0 or a-ipi 1 & normal B2M High-risk profile a-ipi 2-3 or a-ipi 1 & B2M Multiagent chemotherapy DLCLtype (i.e.: CHOP-like) ± locorregional radiotherapy MegaCHOPx3 ± locorregional radiotherapy Response assessment with PET Early response assessment with PET CR PR or <PR PR or <PR CR Follow-up Salvage treatment (IFE 2) Two additional cycles of MegaCHOP <PR PR or CR ASCT a-ipi 2-3 & B2M Good ECOG PS available matched donor RIC Alo-HSCT New drugs / experimental approaches Figure 3 Suggested experimental algorithm sustained on a PET-based response-adapted strategy (GEL/TAMOapproach). m, Elevated; a-ipi, adjusted International Prognostic Index; Alo-HSCT, allogeneic hematopoietic SCT; ASCT, autologous SCT; B2M, beta-2-microglobulin; CR, complete response; DLCL, diffuse large-cell lymphoma; ECOG PS, Eastern Cooperative Oncology Group Performance Status; IFE, ifosfamide and etoposide; MegaCHOP (2 g/m 2 CY, 90 mg/m 2 doxorubicin, vincristine 1.4 g/m 2, prednisone 60 mg/m 2 and mesna); PET, positron emission tomography; PR, partial response;, peripheral T-cell lymphoma; RIC, reduced intensity conditioning.

8 8 considerations and Figure 3 shows a suggested experimental approach on the basis of a positron emission tomography-based response-adapted strategy (GEL/ TAMOapproach). According to most recent clinical research, it seems that the dismal prognosis for is going to change in a few years. Therefore, it is essential to enroll patients with these rare diseases into clinical trials in order to make this progress. References 1 Chan JK. Peripheral T-cell and NK-cell neoplasms: an integrated approach to diagnosis. Mod Pathol 1999; 12: A clinical evaluation of the International Lymphoma Study Group classification of non-hodgkin s lymphoma. The Non- Hodgkin s Lymphoma Classification Project. Blood 1997; 89: Melnyk A, Rodriguez A, Pugh WC, Cabannillas F. Evaluation of the Revised European-American Lymphoma classification confirms the clinical relevance of immunophenotype in 560 cases of aggressive non-hodgkin s lymphoma. 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