Common origin of sequential cutaneous CD30+ lymphoproliferations with nodal involvement evidenced by genome-wide clonal evolution.

AIMS: This study sought to clarify the molecular pathways underlying the putative evolution from lymphomatoid papulosis (LyP) to cutaneous anaplastic large-cell lymphoma (c-ALCL) and lymph node invasion (LNI). METHODS AND RESULTS: We analysed nine sequential tumours from the same patient presenting with parallel evolution of LyP (n = 3) and c-ALCL (n = 1) with LNI (n = 1), combined with systemic diffuse large B-cell lymphoma (DLBCL) (n = 4). Clonality analysis showed a common clonal T-cell origin in the five CD30+ lesions, and a common clonal B-cell origin in the four DLBCL relapses. Array-comparative genomic hybridisation and targeted next-generation sequencing analysis demonstrated relative genomic stability of LyP lesions as compared with clonally related anaplastic large-cell lymphoma (ALCL) tumours, which showed 4q and 22q13 deletions involving the PRDM8 and TIMP3 tumour suppressor genes, respectively. The three analysed CD30+ lesions showed mostly private (specific to each sample) genetic alterations, suggesting early divergence from a common precursor. In contrast, DLBCL tumours showed progressive accumulation of private alterations, indicating late divergence. CONCLUSIONS: Sequential cutaneous and nodal CD30+ tumours were clonally related. This suggests that LyP, c-ALCL and LNI represent a continuous spectrum of clonal evolution emerging from a common precursor of cutaneous CD30+ lymphoproliferations. Therefore, nodal ALCL tumours in the context of LyP should be considered as a form of transformation rather than composite lymphoma.

Bendamustine-based conditioning prior to autologous stem cell transplantation (ASCT): Results of a French multicenter study of 474 patients from LYmphoma Study Association (LYSA) centers.

Carmustine shortage has led to an increase use of alternative conditioning regimens prior to autologous stem cell transplantation for the treatment of lymphoma, including Bendamustine-based (BeEAM). The aim of this study was to evaluate the safety of the BeEAM regimen in a large cohort of patients. A total of 474 patients with a median age of 56 years were analyzed. The majority of patients had diffuse large B-cell lymphoma (43.5%). Bendamustine was administered at a median dose of 197 mg/m2 /day (50-250) on days-7 and -6. The observed grade 1-4 toxicities included mucositis (83.5%), gastroenteritis (53%), skin toxicity (34%), colitis (29%), liver toxicity (19%), pneumonitis (5%), and cardiac rhythm disorders (4%). Nonrelapse mortality (NRM) was reported in 3.3% of patients. Acute renal failure (ARF) was reported in 132 cases (27.9%) (G ≥2; 12.3%). Organ toxicities and death were more frequent in patients with post conditioning renal failure. In a multivariate analysis, pretransplant chronic renal failure, bendamustine dose >160 mg/m2 and age were independent prognostic factors for ARF. Pretransplant chronic renal failure, hyperhydration volume, duration of hyperhydration, and etoposide dose were predictive factors of NRM. A simple, four-point scoring system can stratify patients by levels of risk for ARF and may allow for a reduction in the bendamustine dose to avoid toxicity. Drugs shortage may have dangerous consequences. Prospective, comparative studies are needed to confirm the toxicity/efficacy extents from this conditioning regimen compared to other types of high dose therapy.

Concomitant systemic and central nervous system non-Hodgkin lymphoma: the role of consolidation in terms of high dose therapy and autologous stem cell transplantation. A 60-case retrospective study from LYSA and the LOC network.

The purpose of our study is to determine the outcome of patients with systemic non-Hodgkin lymphoma presenting with neurologic localization at diagnosis, as well as the impact of consolidation in terms of high-dose therapy followed by autologous stem cell transplantation. Newly diagnosed non-Hodgkin lymphoma patients with concomitant systemic and neurological involvement at diagnosis were included in this study. Sixty patients (37 males; 25 females) were included. Median age was 61 years (23-85 years). Histological subtype was mainly diffuse large B-cell lymphoma (n = 54; 90%). The International prognostic index was over 2 in 41 (72%) patients. Median number of extranodal sites was 2 (range: 1-5). Central nervous system involvement alone was documented in 48 patients. Paravertebral involvement with epidural mass and cord compression and positive cerebrospinal fluid were present in 7 patients. Five patients had both central nervous system and epidural involvement. First-line chemotherapy was mainly anthracycline-based (88%) plus high-dose methotrexate (74%) with or without cytarabine. Consolidation with high-dose therapy followed by autologous stem cell transplantation was performed in 19 patients. For the whole population, overall response rate after induction chemotherapy was 76%. Three-year progression-free survival and overall survival were 42 ± 7% and 44 ± 7%, respectively. For patients under 66 years of age, consolidation strategy using high-dose therapy followed by autologous stem cell transplantation positively impacted 3-year overall survival and progression free survival (P = 0.008) and (P = 0.003), respectively. In multivariate analysis, high-dose therapy had a positive impact on 3-year overall survival and progression-free survival for the whole population as well as for patients under 66 years old in CR after induction therapy (OS [HR=0.22 (0.07-0.67)] and progression-free survival [HR = 0.17 (0.05-0.54)]). In conclusion, non-Hodgkin lymphoma prognosis with concomitant systemic and neurological involvement at diagnosis is poor with a high risk of relapse when treated with conventional chemotherapies alone. This retrospective study supports the feasibility and the potential benefit of a consolidative strategy with high-dose therapy followed by autologous stem cell transplantation in this subset of patients. This strategy and the best intensive chemotherapy regimen remain to be validated in prospective trials.

FDG-PET/CT is a pivotal imaging modality to diagnose rare intravascular large B-cell lymphoma: case report and review of literature.

Intravascular large B-cell lymphoma (IVLBCL) remains a diagnostic challenge, because of non-specific findings on clinical, laboratory, and imaging studies. We present a case in which 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography was particularly useful to suspect the diagnosis, to detect unexpected locations, to guide contributive biopsy, and to assess the response to treatment. In case of initial negative results, FDG-PET should be repeated in the course of clinical evolution. In the presence of neurological or hormonal symptoms without brain magnetic resonance imaging abnormality, FDG-PET brain slices could depict additional pituitary and/or brain hypermetabolisms. We discuss the potential interests of FDG-PET in IVLBCL by a literature review.

Brentuximab vedotin followed by allogeneic transplantation as salvage regimen in patients with relapsed and/or refractory Hodgkin's lymphoma.

Patients with relapsed or refractory Hodgkin lymphoma (RR-HL) have poor outcomes. Brentuximab vedotin (BV), an antibody-drug conjugate comprising an anti-CD30 antibody conjugated to the potent anti-microtubule agent, monomethyl auristatin E, induces high tumour responses with moderate adverse effects. In a retrospective study, we describe objective response rates and subsequent allogeneic stem cell transplantation (allo-SCT) in patients with RR-HL treated by BV in a named patient program in two French institutions. Twenty-four adult patients with histologically proven CD30(+) RR-HL treated with BV were included from July 2009 to November 2012. Response to BV treatment was evaluated after four cycles. Eleven patients were in complete response (45.8%), while five patients were in partial response (20.8%), with an overall response rate of 66.6%. Eight patients failed to respond to BV (33.3%). All of the responding patients could receive consolidation treatment after BV: three patients underwent autologous stem cell transplantation (auto-SCT), three patients received a tandem auto-SCT/allo-SCT, nine patients received allo-SCT and one patient was treated with donor lymphocyte infusion. We found no treatment-related mortality at day 100 among the 12 patients who underwent BV following by allogeneic transplantation. With a median follow-up of 20 months (range 10.5-43.2), none of them relapsed or died. BV followed by allo-SCT represents an effective salvage regimen in patients with RR-HL.

A conditioning platform based on fludarabine, busulfan, and 2 days of rabbit antithymocyte globulin results in promising results in patients undergoing allogeneic transplantation from both matched and mismatched unrelated donor.

Conditioning regimen including fludarabine, intravenous busulfan (Bx), and 5 mg/kg total dose of rabbit antithymocyte globulin (r-ATG) (FBx-ATG) results in low incidence of graft-versus-host disease (GVHD) and non-relapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) from HLA-matched related or unrelated donors (MUD). However, whether this platform produces similar results in the setting of one mismatch unrelated donor (MMUD) Allo-HSCT is not known. We retrospectively analyzed patients aged less than 65 years who were diagnosed with hematological malignancies and received FBx-ATG regimen prior to Allo-HSCT from MUD (N = 74) or MMUD (N = 40). We compared outcome of MUD versus MMUD patients. There was no difference in the cumulative incidence of grades II-IV acute GVHD (MUD: 34% vs. MMUD: 35%, P = 0.918), but MMUD patients developed more grade III-IV acute GVHD (MUD: 5% vs. MMUD: 15%, P = 0.016). The cumulative incidences of overall chronic GVHD (MUD: 33% vs. MMUD: 22%, P = 0.088) and extensive chronic GVHD (MUD: 20% vs. MMUD: 19%, P = 0.594) were comparable. One-year NRM was similar in both groups (MUD: 16% vs. MMUD: 14%, P = 0.292); similarly, progression-free survival (MUD: 59% vs. MMUD: 55%, P = 0.476) and overall survival (MUD: 63% vs. MMUD: 61%, P = 0.762) were not different between both groups. With a median follow up of 24 months, 35 of 74 MUD patients (47%) and 19 of 40 MMUD patients (48%) were free of both disease progression and immunosuppressive treatment. We conclude that the FBx-ATG regimen results in low incidences of NRM and GVHD in both MUD and the MMUD recipients.

Long-term outcome after allogeneic stem-cell transplantation with reduced-intensity conditioning in patients with multiple myeloma.

This study examines the long-term outcomes of a cohort of patients with myeloma who were treated with reduced-intensity conditioning (RIC) regimens after a minimum follow-up of 5 years at our centre. A total of 53 patients with multiple myeloma (MM) who received allogeneic hematopoietic stem-cell transplantation (Allo-SCT) between January 2000 and January 2007 were identified. The median follow-up of living patients was 84 months (51-141). The median age of the MM patients was 50 (28-70) years. Fifty-one patients (96%) received a transplant from a sibling donor. The median time between diagnosis and Allo-SCT was 34 months (6-161), and the median time between auto-SCT and Allo-SCT was 10 months (1-89). Fifty-one patients (96%) received at least one auto-SCT; 24 patients (45%) received a tandem auto-Allo-SCT. At last follow-up, 21 patients (40%) are alive > 5 years post RIC Allo-SCT. At last follow-up, 14 (26%) are in first complete remission (CR), and four patients (8%) in second CR after donor lymphocyte infusion or re-induction with one of the new anti-myeloma drugs (bortezomib or lenalidomide) after Allo-SCT. Eight patients (38%) among these long survivors received one of these new drugs as induction or relapse treatment before Allo-SCT. Disease status and occurrence of cGvHD were significantly associated with progression-free survival (PFS); hazard ratio (HR) = 0.62 (0.30-1.29, P = 0.20). Acute GvHD was correlated with higher transplant-related mortality; HR = 4.19 (1.05-16.77, P = 0.04). No variables were associated with overall survival (OS). In conclusion, we observe that long-term disease control can be expected in a subset of MM patients undergoing RIC Allo-SCT. After 10 years, the OS and PFS were 32% and 24%, respectively. The PFS curve after Allo-SCT stabilizes in time with a plateau after 6 years post Allo-SCT.

A phase II study of lenalidomide and rituximab (R2) combination in patients with high-risk refractory/relapsed diffuse large B-cell lymphoma.

Relapsed/Refractory Diffuse Large B Cell Lymphoma have a dismal prognosis in need of innovative treatments. This prospective phase 2 study enrolled 32 patients between 2013 and 2017 with Relapsed/Refractory Diffuse Large B Cell Lymphoma treated with Rituximab and Lenalidomide (R2). Median age was 69 years (40-86), 90.1% had received at least 2 prior lines of treatment, 81% were defined as having High Risk disease according to our criteria and ECOG performance status was > 2 in 51.6%. Patients received a median number of 2 cycles of R2 (1-12). With a median follow up of 22.6 months, the objective response rate was 12.5%. Median progression free survival was 2.6 months (95% CI, [1.7-2.9]) and median overall survival was 9.3 months (95% CI, [5.1-Not estimable]). This study therefore did not achieve its primary endpoint and the R2 regimen cannot be recommended in Relapsed/Refractory Diffuse Large B Cell Lymphoma patients with High Risk features.

Primary B-CLL resistance to NK cell cytotoxicity can be overcome in vitro and in vivo by priming NK cells and monoclonal antibody therapy.

Despite recent advances with monoclonal antibody therapy, chronic lymphocytic leukemia (CLL) remains incurable. Natural killer (NK) cells are potent antitumoral effectors, particularly against hematological malignancies. Defective recognition of B-CLL leukemic cells by NK cells has been previously described. Here, we deciphered the mechanisms that hamper NK cell-mediated clearance of B-CLL and evaluated the potential of NK cells as therapeutic tools for treatment of CLL. First of all, leukemic B cells resemble to normal B cells with a weak expression of ligands for NK receptors. Conversely, NK cells from B-CLL patients were functionally and phenotypically competent, despite a decrease of expression of the activating receptor NKp30. Consequently, resting allogeneic NK cells were unable to kill leukemic B cells in vitro. These data suggest that patients' NK cells cannot initiate a proper immune reaction due to a lack of leukemic cell recognition. We next set up a xenotransplantation mouse model to study NK-CLL cell interactions. Together with our in vitro studies, in vivo data revealed that activation of NK cells is required in order to control B-CLL and that activated NK cells synergize to enhance rituximab effect on tumor load. This study points out the requirements for immune system manipulation for treatment of B-CLL in combination with monoclonal antibody therapy.

Positron emission tomography response at the time of autologous stem cell transplantation predicts outcome of patients with relapsed and/or refractory Hodgkin's lymphoma responding to prior salvage therapy.

BACKGROUND: High-dose chemotherapy followed by autologous stem cell transplantation is the standard treatment for relapsed and/or refractory Hodgkin's lymphoma although half of patients relapse after transplantation. Predictive factors, such as relapse within 12 months, Ann-Arbor stage at relapse, and relapse in previously irradiated fields are classically used to identify patients with poor outcome. Recently, 18-fluorodeoxyglucose positron emission tomography has emerged as a new method for providing information to predict outcome. The aim of this study was to confirm the predictive value of positron emission tomography status after salvage therapy and to compare single versus tandem autologous stem cell transplantation in patients with relapsed and/or refractory Hodgkin's lymphoma. DESIGN AND METHODS: We report a series of 111 consecutive patients with treatment-sensitive relapsed and/or treatment-refractory Hodgkin's lymphoma who achieved complete (positron emission tomography-negative group) or partial remission (positron emission tomography-positive group) at positron emission tomography evaluation after salvage chemotherapy and who underwent single or tandem autologous stem cell transplantation. RESULTS: Five-year overall and progression-free survival rates were 81% and 64%, respectively. There were significant differences in 5-year progression-free survival (79% versus 23%; P<0.001) and 5-year overall survival (90% versus 55%, P=0.001) between the positron emission tomography-negative and -positive groups, respectively. A complete response, as determined by positron emission tomography evaluation, after salvage therapy predicted significantly better 5-year overall survival rates in both intermediate (91% versus 50%; P=0.029) and unfavorable (89% versus 58%; P=0.026) risk subgroup analyses. In the positron emission tomography-positive subgroup, tandem transplantation improved 5-year progression-free survival from 0% (in the single transplantation group) to 43% (P=0.034). Multivariate analysis showed that positron emission tomography status (hazard ratio: 5.26 [2.57-10.73]) and tandem transplantation (hazard ratio: 0.39 [0.19-0.78]) but not risk factors at relapse (hazard ratio: 1.77 [0.80-3.92]) significantly influenced progression-free survival, while only tomography status significantly influenced overall survival (hazard ratio: 4.03 [1.38-11.75]). CONCLUSIONS: In patients with relapsed/refractory Hodgkin's lymphoma responding to prior salvage therapy, positron emission tomography response at time of autologous stem cell transplantation favorably influences outcome and enables identification of patients requiring single or tandem transplantation.

Comparable outcomes between unrelated and related donors after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation in patients with high-risk multiple myeloma.

The purpose of this study was to assess the results of allogeneic stem cell transplantation (allo-SCT) after reduced-intensity conditioning (RIC) from matched related donors (MRD) and unrelated donors (URD) in 40 patients with high-risk multiple myeloma (MM) in a single centre. Seventeen (43%) (Group 1) and 23 patients (57%) (Group 2) had URD and MRD, respectively. Thirty-nine patients (98%) received one or more autologous transplantation. The median follow-up was 22 months (1-49). None of our patient experienced a graft rejection. The cumulative incidence of grade II-IV acute GVHD was higher (47%) for the URD vs. (17%) for the MRD (P = 0.092). The cumulative incidence of chronic GVHD was no different between the two groups (24% vs. 30%, respectively). At 2 yr, the TRM probabilities were lower in the unrelated group 12% vs. 22% in the related group (P = 0.4). Also at 2 yrs, for patients receiving unrelated transplantation overall and progression-free survivals, 59% and 42%, respectively compared to patients with related donor transplantation, 66% and 44% (P = 0.241). In conclusion, these results suggest that URD in MM is feasible. The small number of patients with URD emphasizes the need to delineate indications and perform prospective protocols.

Positron Emission Tomography-Driven Strategy in Advanced Hodgkin Lymphoma: Prolonged Follow-Up of the AHL2011 Phase III Lymphoma Study Association Study.

PURPOSE: The AHL2011 study (ClinicalTrials.gov identifier: NCT01358747) demonstrated that a positron emission tomography (PET)-driven de-escalation strategy after two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) provides similar progression-free survival (PFS) and overall survival (OS) and reduces early toxicity compared with a nonmonitored standard treatment. Here, we report, with a prolonged follow-up, the final study results. METHODS: Patients with advanced Hodgkin lymphoma (stage III, IV, or IIB with mediastinum/thorax ratio > 0.33 or extranodal involvement) age 16-60 years were prospectively randomly assigned between 6 × BEACOPP and a PET-driven arm after 2 × BEACOPP delivering 4 × ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in PET2- and 4 × BEACOPP in PET2+ patients. PET performed after four cycles of chemotherapy had to be negative to complete the planned treatment. RESULTS: In total, 823 patients were enrolled including 413 in the standard arm and 410 in the PET-driven arm. With a 67.2-month median follow-up, 5-year PFS (87.5% v 86.7%; hazard ratio [HR] = 1.07; 95% CI, 0.74 to 1.57; P = .67) and OS (97.7% in both arms; HR = 1.012; 95% CI, 0.50 to 2.10; P = .53) were similar in both randomization arms. In the whole cohort, full interim PET assessment predicted patients' 5-year PFS (92.3% in PET2-/PET4-, 75.4% [HR = 3.26; 95% CI, 18.3 to 5.77] in PET2+/PET4- and 46.5% [HR = 12.4; 95% CI, 7.31 to 19.51] in PET4+ patients, respectively; P < .0001) independent of international prognosis score. Five-year OS was also affected by interim PET results, and PET2+/PET4- patients (93.5%; HR = 3.3; 95% CI, 1.07 to 10.1; P = .036) and PET4+ patients (91.9%; HR = 3.756; 95% CI, 1.07 to 13.18; P = .038) had a significant lower OS than PET2-/PET4- patients (98.2%). Twenty-two patients (2.7%) developed a second primary malignancy, 13 (3.2%) and 9 (2.2%) in the standard and experimental arms, respectively. CONCLUSION: The extended follow-up confirms the continued efficacy and favorable safety of AHL2011 PET-driven strategy, which is noninferior to standard six cycles of BEACOPP. PET4 provides additional prognostic information to PET2 and allows identifying patients with particularly poor prognosis.

Full access to medical records does not modify anxiety in cancer patients: results of a randomized study.

BACKGROUND: Information is crucial for increasing the patients' empowerment and autonomy in relevant decision-making processes, especially in malignant diseases. However, the extent to which information should be delivered is debated. The objective of this study was to assess the impact of providing systematic full access (SFA) to the medical record on anxiety, quality of life, and satisfaction. METHODS: Patients with newly diagnosed breast cancer, colon cancer, or lymphoma who had received adjuvant chemotherapy in an outpatient setting were included in a randomized controlled trial comparing those who requested access (RA) and those who provided SFA to the medical record. Anxiety was assessed using the Spielberger State-Trait Anxiety Inventory before, during, and at the end of treatment. Quality of life was evaluated using the European Organization for Research and Cancer quality-of-life questionnaire (EORTC QLQ-C30) before and at the end of treatment. Patients' satisfaction and perception of the organized medical record (OMR) were evaluated using a specifically designed questionnaire at the end of treatment. RESULTS: Most patients (98%) who had the opportunity to obtain the OMR chose to do so. Anxiety levels did not increase in the SFA arm, although they did not differ significantly compared with anxiety levels in the RA arm. The patients who had full access to their medical record were more satisfied with information (odds ratio, 1.68; 95% confidence interval, 0.98-2.9) and felt sufficiently informed more often (odds ratio, 1.86; 95% confidence interval, 1.08-3.19), but the differences were not statistically significant at the 5% level. CONCLUSIONS: Allowing full access to personal medical records increased satisfaction without increasing anxiety in patients with newly diagnosed cancer.

Features and risk factors of peripheral neuropathy during treatment with bortezomib for advanced multiple myeloma.

BACKGROUND: Bortezomib is a first-in-class proteasome inhibitor with remarkable antitumor activity that is approved for the treatment of patients with multiple myeloma. Peripheral neuropathy (PN) is a frequent adverse event reported with bortezomib use. PATIENTS AND METHODS: The aim of this retrospective, single-center study was to determine the characteristics of bortezomib-associated PN in 100 patients with advanced myeloma. Peripheral neuropathy was evaluated by investigator's assessment. RESULTS: With a median follow-up of 8 months (range, 0.1-32 months) from bortezomib initiation, bortezomib-associated PN was observed in 38 patients (38%; 95% CI, 28%-47%), with grade 3 and 4 PN occurring in 5 patients and 1 patient, respectively. Median time to onset of bortezomib-associated PN was 53 days (range, 11-182 days). Of the 38 patients with bortezomib-associated PN, resolution or improvement occurred in 20 patients (53%) at a median of 3 months (range, 1-8 months). In multivariate analysis, the total number of cycles of bortezomib (< 4 cycles or > 4 cycles; P = .03; odds ratio [OR], 2.6; 95% CI, 1.1-6.1) and a previous history of thalidomide therapy (P = .02; OR, 3.9; 95% CI, 1.2-12.6) were significantly associated with an increased incidence of bortezomib-associated PN. CONCLUSION: We conclude that, though relatively frequent, bortezomib-associated PN is reversible in a majority of patients. However, bortezomib-associated PN seems to be dependent on previous therapy with thalidomide, suggesting that bortezomib followed by thalidomide could be an optimal sequence of administration of these drugs in the salvage setting.

CDKN2A/B Deletion and Double-hit Mutations of the MAPK Pathway Underlie the Aggressive Behavior of Langerhans Cell Tumors.

Langerhans cell histiocytosis (LCH) has a mostly favorable outcome, whereas Langerhans cell sarcoma (LCS) is an aggressive tumor. It is still unclear whether any specific molecular alterations could underlie the aggressive behavior of Langerhans cell proliferations. We used targeted next-generation sequencing and array-comparative genomic hybridization to profile 22 LCH samples from different patients together with 3 LCS samples corresponding to different relapses from the same patient. The third LCS relapse was a composite tumor including both B-cell chronic lymphocytic leukemia and LCS components. The 22 LCH samples were mostly of bone origin and showed classic histophenotypical features. Array-comparative genomic hybridization showed in all 3 LCS samples a similar homozygous somatic loss affecting the CDKN2A/B locus, whereas the 17 informative LCH samples did not show any detectable abnormality. In the 3 LCS samples, targeted next-generation sequencing of 495 cancer genes detected common mutations in KMT2D/MLL2 and in both MAP2K1 and NRAS genes, whereas BRAF was not mutated. A NOTCH1 mutation was acquired in 2 LCS samples. The composite LCS/B-cell chronic lymphocytic leukemia tumor showed the same genetic profile in its 2 components. LCH samples showed mutually exclusive mutations of BRAF (8/20) and MAP2K1 (4/19), but no mutation of KMT2D, NRAS nor NOTCH1. These results suggest that CDKN2A/B deletion and/or simultaneous mutations of MAP2K1 and NRAS may underlie the aggressive behavior of Langerhans cell tumors, and thus could be useful for the diagnosis of malignancy in histiocytic neoplasms. The MAPK pathway "double hit" profile provides a basis for targeted therapy in LCS patients.

[Hodgkin and non-Hodgkin lymphoma of adolescents and young adults]. / Lymphomes hodgkiniens et non hodgkiniens des adolescents et des jeunes adultes.

Lymphoma is one of the most frequent cancers in adolescent and young adults. Hodgkin Lymphoma is curable in more than 90% of cases. Recent pediatric and adults protocols aimed to decrease long term toxicities (mostly gonadic and cardiovascular) and secondary malignancies, reducing the use of alkylating agents and limiting radiation fields. Risk-adapted strategies, using positron emission tomography staging, are about to become a standard, both in adult and pediatric protocols. These approaches allow obtaining excellent results in adolescents with Hodgkin lymphoma. On the other hand, treatment of adolescents with diffuse large B-cell lymphoma raises some questions. Even through children have good outcomes when treated with risk-adapted strategies, adolescents who are between 15 and 18 years old seem to experience poorer survivals, whereas patients older than 18 years old have globally the same outcome than older adults. This category of patient needs a particular care, based on a tight coordination between adults and pediatric oncologists. Primary mediastinal lymphomas, a subtype of BLDCL frequent in young adult population, exhibits poorer outcomes in children or young adolescent population than in older ones. Taking together, B-cell lymphoma benefited from recent advances in immunotherapy (in particular with the extended utilization of rituximab) and metabolic response-adapted strategies. In conclusion, adolescent and young adult's lymphomas are very curable diseases but require a personalized management in onco-hematological units.

Lenalidomide for the treatment of B-cell lymphoma.

INTRODUCTION: Although the combination of an anti-CD20 monoclonal antibody and chemotherapy has widely improved survival of patients with B-cell lymphoma, the disease still relapses. A better understanding of the biology of lymphomas has highlighted the role of the cell of origin in response to treatment and outcome. Lenalidomide represents an attractive therapeutic option due to its original mechanism of action. AREAS COVERED: In this review, the authors describe the pharmacological properties of lenalidomide, and the rational for its use in B-cell lymphomas; focusing on diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). They discuss the mechanism of action of the drug and its current and future clinical development. They also review the current data in relapsed/refractory situations as well as in first-line treatment. EXPERT OPINION: Lenalidomide is an oral non-chemotherapy immunomodulatory agent with an acceptable toxicity profile and manageable side-effects. Efficacy has widely been demonstrated, especially in MCL, FL and non-Germinal Center DLBCL patients. Further studies are now warranted to better define the strategy for the use of lenalidomide in B-NHL patients, and clarify which subgroup of patients will really benefit of lenalidomide as part of first-line treatment or in a relapsed/refractory setting.