Analysis of a cohort of 279 patients with hairy-cell leukemia (HCL): 10 years of follow-up.

In total, 279 patients with hairy-cell leukemia (HCL) were analyzed, with a median follow-up of 10 years. Data were collected up to June 2018. We analyzed responses to treatment, relapses, survival, and the occurrence of second malignancies during follow-up. The median age was 59 years. In total, 208 patients (75%) were treated with purine analogs (PNAs), either cladribine (159) or pentosatin (49), as the first-line therapy. After a median follow-up of 127 months, the median overall survival was 27 years, and the median relapse-free survival (RFS) was 11 years. The cumulative 10-year relapse incidence was 39%. In patients receiving second-line therapy, the median RFS was 7 years. For the second-line therapy, using the same or another PNA was equivalent. We identified 68 second malignancies in 59 patients: 49 solid cancers and 19 hematological malignancies. The 10-year cumulative incidences of cancers, solid tumors, and hematological malignancies were 15%, 11%, and 5.0%, respectively, and the standardized incidence ratios were 2.22, 1.81, and 6.67, respectively. In multivariate analysis, PNA was not a risk factor for second malignancies. HCL patients have a good long-term prognosis. PNAs are the first-line treatment. HCL patients require long-term follow-up because of their relatively increased risk of second malignancies.

Azacitidine for the treatment of relapsed and refractory AML in older patients.

The prognosis of patients older than 50 with relapsed or refractory AML is dismal. Azacitidine has been investigated in older AML patients. Here we report the outcome of 130 patients older than 50 years included in a multicenter patient named program of azacitidine after relapse (n=67) or induction failure (n=63) of intensive chemotherapy. Median age was 67 years, cytogenetic risk was high in 28% and performance status ≥2 in 15% of cases. Most (72%) patients received azacitidine at the standard schedule (75mg/m(2)/d, 7 days/month) for a median of 4 courses. The overall response rate was 17% (CR: 10%, CRi: 7%). Median overall survival was 8.4 months. Achievement of CR/CRi was associated with prolonged survival (P=0.0001), whereas hematological improvement according to MDS criteria, achieved in 36% of patients with resistant disease, did not improve survival. In multivariate analysis, high risk cytogenetics (P=0.022) and peripheral blasts >10% (P<0.0001) at onset of azacitidine were independently predictive of poor prognosis. Combining these two factors, we identified a subgroup of 48% of patients with intermediate risk cytogenetics and peripheral blasts ≤10% and a median OS of 11.3 months. These results warrant further investigation of azacitidine-based regimens in this subgroup of patients.

Long-term follow-up and second malignancies in 487 patients with hairy cell leukaemia.

A large, multicentre, retrospective survey of patients with hairy cell leukaemia (HCL) was conducted in France to determine the frequency of second malignancies and to analyse the long-term effects of the established purine nucleoside analogues (PNAs), cladribine and pentostatin. The survey retrospectively reviewed the medical history of patients and their immediate family, clinical and biological presentation at the time of HCL diagnosis, treatment choice, response to treatment, time to relapse and cause of death. Data were collected for 487 patients with HCL. Of the patients included in the survey, 18% (88/487) had a familial history of cancers, 8% (41/487) presented with malignancies before HCL diagnosis and 10% (48/487) developed second malignancies after HCL was diagnosed. An excess incidence of second malignancies was observed, with a standardized incidence ratio (SIR) of 1·86 (95% confidence interval (CI): 1·34-2·51), with no significant difference between PNAs. For second haematological malignancies alone, the SIR was markedly increased at 5·32 (95% CI: 2·90-8·92). This study highlights the high frequency of cancers in HCL patients and their family members. The frequency of second malignancies is notably increased, particularly for haematological malignancies. The respective role of pentostatin and cladribine in the development of second malignancies is debatable.

SET-NUP214 is a recurrent γδ lineage-specific fusion transcript associated with corticosteroid/chemotherapy resistance in adult T-ALL.

The SET-NUP214 (TAF1/CAN) fusion gene is a rare genetic event in T-cell acute lymphoblastic leukemia (T-ALL). Eleven (6%) of 196 T-ALL patients enrolled in the French Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) 2003 and 2005 trials harbored a SET-NUP214 transcript. SET-NUP214-positive patients were predominantly (10 [91%] of 11) T-cell receptor (TCR)-negative and strikingly associated with TCRγδ lineage T-ALLs, as defined by expression of TCRγδ, TCRδ and/or TCRγ rearrangements but no complete TCRß variable diversity joining rearrangement in surface CD3/TCR-negative cases. When compared with SET-NUP214-negative patients, SET-NUP214-positive patients showed a significantly higher rate of corticosteroid resistance (91% vs 44%; P = .003) and chemotherapy resistance (100% vs 44%; P = .0001). All SET-NUP214-positive patients but one achieved complete remission, and 9 were allografted. Despite the poor early-treatment sensitivity, the outcome of SET-NUP214-positive patients was similar to that of SET-NUP214-negative patients.

Clinical characteristics and outcome of isolated extracerebral relapses of primary central nervous system lymphoma: a case series.

There is very limited data on isolated systemic relapses of primary central nervous system lymphomas (PCNSL). We retrospectively reviewed the clinical characteristics and outcome of 10 patients with isolated systemic disease among 209 patients with PCNSL mainly treated with methotrexate-based chemotherapy (CT) with or without radiation therapy (RT). Isolated systemic relapse remained rare (4.8%, 10/209 patients). Median time from initial diagnosis to relapse was 33 months (range, 3-94). Sites of relapse were mostly extranodal. Three patients presented with early extra-cerebral (EC) relapse 3, 5 and 8 months from the beginning of initial treatment, respectively, and 7 patients had later relapses (range, 17-94 months). Treatment at relapse included surgery alone, RT alone, CT with or without radiotherapy, or CT with autologous stem cell transplantation (ASCT). Median overall survival (OS) after relapse was 15.5 months (range, 5.8-24.5) compared to 4.6 months (range, 3.6-6.5) for patients with central nervous system (CNS) relapse (p = 0.35). In conclusion, isolated systemic relapses exist but are infrequent. Early EC relapse suggests the presence of systemic disease undetectable by conventional evaluation at initial diagnosis. Patient follow-up must be prolonged because systemic relapse can occur as late as 10 years after initial diagnosis. Whether EC relapses of PCNSL have a better prognosis than CNS relapses needs to be assessed in a larger cohort.

Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study.

Extranodal NK/T-cell lymphoma, nasal type, is a rare and highly aggressive disease with a grim prognosis. No therapeutic strategy is currently identified in relapsing patients. We report the results of a French prospective phase II trial of an L-asparaginase-containing regimen in 19 patients with relapsed or refractory disease treated in 13 centers. Eleven patients were in relapse and 8 patients were refractory to their first line of treatment. L-Asparaginase-based treatment yielded objective responses in 14 of the 18 evaluable patients after 3 cycles. Eleven patients entered complete remission (61%), and only 4 of them relapsed. The median overall survival time was 1 year, with a median response duration of 12 months. The main adverse events were hepatitis, cytopenia, and allergy. The absence of antiasparaginase antibodies and the disappearance of Epstein-Barr virus serum DNA were significantly associated with a better outcome. These data confirm the excellent activity of L-asparaginase-containing regimens in extranodal NK/T-cell lymphoma. L-Asparaginase-based treatment should thus be considered for salvage therapy, especially in patients with disseminated disease. First-line L-asparaginase combination therapy for extranodal NK/T-cell lymphoma warrants evaluation in prospective trials. This trial is registered at www.clinicaltrials.gov as #NCT00283985.

Analysis of the ten-eleven translocation 2 (TET2) gene in familial myeloproliferative neoplasms.

The JAK2(V617F) mutation does not elucidate the phenotypic variability observed in myeloproliferative neoplasm (MPN) families. A putative tumor suppressor gene, TET2, was recently implicated in MPN and myelodysplastic syndromes through the identification of acquired mutations affecting hematopoietic stem cells. The present study analyzed the TET2 gene in 61 MPN cases from 42 families. Fifteen distinct mutations were identified in 12 (20%) JAK2(V617F)-positive or -negative patients. In a patient with 2 TET2 mutations, the analysis of 5 blood samples at different phases of her disease showed the sequential occurrence of JAK2(V617F) and TET2 mutations concomitantly to the disease evolution. Analysis of familial segregation confirmed that TET2 mutations were not inherited but somatically acquired. TET2 mutations were mainly observed (10 of 12) in patients with primary myelofibrosis or patients with polycythemia vera or essential thrombocythemia who secondarily evolved toward myelofibrosis or acute myeloid leukemia.

A weekly regimen with dose escalation of doxorubicin for patients with advanced Hodgkin's lymphoma: results of a phase II study of the Groupe d'Etudes des Lymphomes de l'Adulte (GELA).

This multicenter phase II study assessed the feasibility and efficacy of a weekly chemotherapy regimen with a moderately escalated dose of doxorubicin administered over 16 weeks, followed by radiation therapy (RT) to bulky sites. From July 1996 to February 1998, 44 untreated patients with stage IIIB-IV Hodgkin's lymphoma (HL), and 0 - 2 risk factors described by the Memorial Sloan-Kettering Cancer Center, were treated. Chemotherapy was a combination of increased-dose doxorubicin with conventional doses of cyclophosphamide, vinblastine, prednisone, vindesine, bleomycin, and etoposide. Patients received four cycles of the weekly regimen for 16 weeks. Forty-one patients received the planned four cycles of chemotherapy, and RT was delivered to 36 patients. The incidence of WHO grade 3 - 4 neutropenia was 90%. A total of 39 patients achieved a complete remission (88.6%). The median follow-up was 95 months. The 7-years freedom from treatment failure and overall survival estimates were 57% (95% confidence interval (CI), 41% - 70%), and 93% (95% CI, 80 - 98%), respectively. The relapse rate was related to the short duration of chemotherapy, and the failure to prevent relapses with consolidation RT. In this study population the 16-week regimen and RT to bulky sites were not sufficient for disease control.

Patterns of bone marrow involvement in 58 patients presenting primary splenic marginal zone lymphoma with or without circulating villous lymphocytes.

We studied 86 bone marrow biopsies (BMB) from 58 patients presenting with primary splenic marginal zone lymphoma (PSMZL). In 42 patients, a splenectomy was performed which enabled a histopathological diagnosis. In these patients, 44 biopsies were carried out before, and 25 after, splenectomy. In 16 recently observed patients, 17 BMB led to PSMZL diagnosis, and these patients were treated without splenectomy. Seven different patterns of infiltrates were recognized: intravascular, interstitial, nodular, massive, plasmacytic mimicking myeloma and transformation into large B-cell lymphoma (DLBCL). The association of an intravascular infiltrate and nodules with a germinal centre and/or a marginal zone favoured a diagnosis of MZL. Immunohistochemistry demonstrated the expression of B cell-associated antigens and, in 40% of the patients, a monotypic lymphoplasmacytic cell component. These patients often presented a serum M component and autoimmune disorders. In the past, such cases have been diagnosed as lymphoplasmacytic lymphoma. BM involvement was present in all patients. Successive biopsies showed progression and, after chemotherapy, a slight decrease in infiltrates. Transformation into DLBCL occurred in 11 of 34 patients. The patterns described are not specific for PSMZL and occur also in primary nodal MZL and, more rarely, in MALT-type lymphoma.