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.

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.

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.

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.

Hepatitis B virus reactivation in HBsAg-negative patients is associated with emergence of viral strains with mutated HBsAg and reverse transcriptase.

BACKGROUND/AIMS: Virological factors associated with hepatitis B virus reactivation (HBV-R), following chemotherapy for cancer in hepatitis B surface antigen (HBsAg)-negative patients, are not well known. MATERIALS AND METHODS: HBV strains from 16 patients presenting HBV-R following chemotherapy were studied and compared to those obtained from 51 HBV chronically-infected patients. RESULTS: HBsAg variability was significantly increased within the major hydrophilic region, the a determinant and the C-terminal region. Amino acid substitutions were more frequently found in HBV-R patients as compared to controls at 17 and 11 positions within HBsAg and HBV-RT, respectively. This resulted in atypical serological testing in 56% of patients and detection of resistance mutation to nucleoside analogs in 12.5%. CONCLUSION: HBsAg and HBV-RT mutations are frequently encountered in patients with HBV-R, resulting in atypical serological testing and emergence of HBV strains resistant to nucleos(t)ides analogs.

Sarcoidosis Occurring After Solid Cancer: A Nonfortuitous Association: Report of 12 Cases and Review of the Literature.

The association between cancer and sarcoidosis is controversial. Some epidemiological studies show an increase of the incidence of cancer in patients with sarcoidosis but only few cases of sarcoidosis following cancer treatment have been reported. We conducted a retrospective case study from internal medicine and oncology departments for patients presenting sarcoidosis after solid cancer treatment. We also performed a literature review to search for patients who developed sarcoidosis after solid cancer. We describe the clinical, biological, and radiological characteristics and outcome of these patients. Twelve patients were included in our study. Various cancers were observed with a predominance of breast cancer. Development of sarcoidosis appeared in the 3 years following cancer and was asymptomatic in half of the patients. The disease was frequently identified after a follow-up positron emission tomography computerized tomography evaluation. Various manifestations were observed but all patients presented lymph node involvement. Half of the patients required systemic therapy. With a median follow-up of 73 months, no patient developed cancer relapse. Review of the literature identified 61 other patients for which the characteristics of both solid cancer and sarcoidosis were similar to those observed in our series. This report demonstrates that sarcoidosis must be considered in the differential diagnosis of patients with a history of malignancy who have developed lymphadenopathy or other lesions on positron emission tomography computerized tomography. Histological confirmation of cancer relapse is mandatory in order to avoid unjustified treatments. This association should be consider as a protective factor against cancer relapse.

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.

High-dose chemotherapy with carmustine, etoposide, cytarabine and melphalan followed by autologous stem cell transplant is an effective treatment for elderly patients with poor-prognosis lymphoma.

Autologous stem cell transplant (ASCT) after high-dose chemotherapy (HDT) increases overall survival when used in relapsed non-Hodgkin lymphoma (NHL) in patients under 65 years old. Limited experience is available for older patients. We present a retrospective analysis of 73 consecutive patients aged over 65 years treated for aggressive or relapsed lymphoma by HDT with carmustine, etoposide, cytarabine and melphalan (BEAM) at full dosage followed by ASCT. Patient data were obtained from medical charts from two institutions. Median age was 67 years (65-74). Significant comorbidities were present in 24.7% of patients. The median number of days for grade 4 neutropenia was 9 (5-18). The early treatment-related mortality rate (<100 days) was 2.7%. The estimated 2-year progression-free survival and overall survival rates were 67.2% and 78.5%, respectively. In conclusion, the full-dose HDT-ASCT regimen is feasible, safe and efficient in selected patients over 65 years old.

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.

[Teenage and young adult cancer: how to make effective disclosures?]. / Cancer de l'adolescent et du jeune adulte : repères pour une annonce humaine et efficace.

Announcement of diagnosis is a critical step in establishing a trust-based relationship of quality between patient and physician. Disclosing "bad news" is a difficult and sensitive task which has direct consequences on psychological, emotional and relational levels, as well as on therapeutic management. This is a potentially traumatic experience which requires a long process of integration and psychological adaptation. The hematologist-oncologist occupies a central position: He introduces the framework for a multidisciplinary care, while taking into account the personality and behavior of the teenager or young adult. We propose an analysis of doctor-patient interaction; an overview of psychological issues associate with diagnosis disclosure; suggestions to build and manage communication with patients; and a clarification of the role of the psychologist and of the psychological adjustment at the time of disclosure.

Efficacy and safety of lenalinomide combined with rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma.

Initial clinical trials demonstrated that lenalidomide monotherapy has a significant activity against some subtypes of lymphoma, but in diffuse large B-cell lymphoma (DLBCL) its activity is limited. The combination of lenalidomide with rituximab may be a promising therapeutic strategy. We retrospectively analyzed clinical outcomes in 17 patients with relapsed/refractory (R/R) DLBCL treated with lenalidomide, 25 mg/day for 21/28 days and rituximab, 375 mg/m(2) on day 7 of every lenalidomide cycle, for a maximum of 12 months. The overall response rate (ORR) was 41.2% with 35.3% complete response (CR), while median response duration was 26.5 months at a median follow-up of 24.9 months. Two patients with CR relapsed after 4 and 27 months of CR, and another four are actually in CR at + 13, + 23, + 24 and + 29 months. The estimated 24-month overall survival (OS) was 45% and progression-free survival (PFS) was 38%. Adverse events were manageable and mostly included thrombocytopenia and neutropenia. Lenalidomide-rituximab is active in R/R DLBCL with an important percentage of continuous CR.

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.

Large B-cell lymphomas in adolescents and young adults in comparison to adult patients: a matched-control analysis in 55 patients.

The aim of our study was to assess whether large B-cell lymphoma (LBCL) in adolescents and young adults (AYA) should be considered as a clinocopathological entity, and to evaluate the prognostic value of age. Fifty-five patients aged > 15-30 years were fully matched to 365 adult patients aged 31-65 years. We found a high incidence of primary mediastinal thymic LBCL subtype (33% vs. 5%), while histological transformation was rare (2% vs. 14%). LBCL in AYA presented with a bulky mediastinal mass (51% vs. 21%), and the lactate dehydrogenase (LDH) value was significantly higher (73% vs. 54%). The complete response rate to chemotherapy was similar in the two groups. Five-year overall survival (OS) and event-free survival (EFS) of AYA were 73% and 68%, respectively. The matched-control analysis showed no difference for either OS or EFS. LBCL in AYA presents with some critical features which differ from those of older adults. However, the outcome is equivalent to that observed in older patients.