Marta Bruno Ventre

Clinical Features, Management, and Prognosis of an International Series of 161 Patients With Limited-Stage Diffuse Large B-Cell Lymphoma of the Bone (the IELSG-14 Study)

INTRODUCTION The clinical features, management, and prognosis of stage I-II diffuse large B-cell lymphoma of the bone (PB-DLBCL) included in an international database of 499 lymphoma patients with skeletal involvement were reviewed. METHODS HIV-negative patients (n = 161) with diffuse large B-cell lymphoma of the bone (PB-DLBCL) after complete staging workup were considered. The primary objective of this study was to identify the most effective treatment modality; the secondary objectives were to define the contribution of irradiation fields and doses and the pattern of relapse. RESULTS Median age was 55 years (range, 18-99 years), with a male/female ratio of 1:2; 141 (87%) patients had stage I, 14 (9%) had B symptoms, 37 (23%) had bulky lesion, 54 (33%) showed elevated lactate dehydrogenase serum levels, and 25 (15%) had fracture. Thirteen (8%) patients received chemotherapy alone, 23 (14%) received radiotherapy alone, and 125 (78%) received both treatments. The response to the first-line treatment was complete in 131 of 152 assessed patients (complete response rate, 86%; 95% confidence interval [CI], 81%-91%) and partial in 7, with an overall response rate of 91% (95% CI, 87%-95%). At a median follow-up of 54 months (range, 3-218), 107 (67%) patients remained relapse-free, with a 5-year progression-free survival of 68% (SE: 4). Four (2.5%) patients had meningeal relapse; 119 patients were alive (113 disease-free), with a 5-year overall survival of 75% (SE: 4). Patients managed with primary chemotherapy, whether followed by radiotherapy or not, had a significantly better outcome than patients treated with primary radiotherapy, whether followed by chemotherapy or not. The addition of consolidative radiotherapy after primary chemotherapy was not associated with improved outcome; doses >36 Gy and the irradiation of the whole affected bone were not associated with better outcome. CONCLUSION Patients with PB-DLBCL exhibit a favorable prognosis when treated with primary anthracycline-based chemotherapy whether followed by radiotherapy or not. In patients treated with chemoradiotherapy, the use of larger radiation fields and doses is not associated with better outcome. Central nervous system dissemination is a rare event in PB-DLBCL patients.

Safety and activity of a new intensive short-term chemoimmunotherapy in HIV-positive patients with Burkitt lymphoma

The treatment of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) patients with Burkitt lymphoma (HIV-BL) is a difficult challenge, requiring multidisciplinary efforts and demanding strategies. While the worldwide use of highly active antiretroviral therapy (HAART) resulted in improved tolerability and efficacy of standard chemotherapy in HIV-positive patients with diffuse large B-cell lymphomas, it has not been associated with better outcome in HIV-BL, with respect to the pre-HAART era, suggesting that more intensive treatments should be used (Lim et al, 2005). Currently, a few, small studies addressing feasibility and activity of dose-dense chemotherapeutic regimens in HIV-BL are available (Table S1). Reported regimens display high efficacy, but are often associated with important dose-limiting side-effects, prolonged hospitalization and treatment-related mortality (TRM) of 15–20%. A dose-dense, short-term chemotherapy program including seven active drugs and intrathecal drug delivery has showed excellent activity and safety profiles in HIV-negative patients with BL in the pre-rituximab era (Di Nicola et al, 2004). We introduced a few changes to this regimen to maintain efficacy and improve tolerability in HIV-BL. In particular, six doses of rituximab were added and methotrexate dose was reduced, from 150 and 250 mg/kg to 3 g/m, mostly to avoid mucositis, which constitutes an important route of access for infectious agents and one of the main causes of death in these patients (Galicier et al, 2007). We used this modified chemoimmunotherapy regimen in 15 consecutive HIV-BL (median age 42 years old, range 27–63) between July 2009 and July 2011 (Table S2). Treatment consisted of a 36-day induction phase including sequential doses of fractionated cyclophosphamide, high doses of methotrexate and cytarabine, doxorubicin, vincristine, and etoposide, rituximab and intrathecal prophylaxis/ treatment (Table I). Subsequent treatment was then tailored according to the objective response to induction phase (Fig. 1): patients in complete response (CR) were referred to a high-dose cytarabine-based consolidation phase (Table I); patients in partial response (PR) were referred to consolidation followed by BEAM (carmustine, etoposide, cytarabine, melphalan) plus autologous stem cell transplant (ASCT); patients with stable or progressive disease were referred to intensification phase, followed by BEAM + ASCT. At the end of chemoimmunotherapy, patients with initial bulky disease or with a residual positron emission tomography-positive single lesion were evaluated for 36-Gy involved-field irradiation. Treatment was safe and well tolerated. All patients but one completed the induction phase (median duration: 49 d; range 34–108); methotrexate and etoposide occasionally required delivery delay due to G3 transaminase increase or G4 neutropenia. Cytostatics dose reductions were recorded only in two patients. There was a single toxic death, which was due to pneumonia in a patient with extensive bone marrow infiltration and baseline CD4+ count of 0 017 9 10/l. As expected, haematological toxicity was common, but manageable (Table S3); with conventional antimicrobial prophylaxis and rHuG-CSF support, infective complications were mild and no systemic fungal infections occurred. The most relevant toxicity was recorded after consolidation: the original cytarabine-cisplatin consolidation regimen (Di Nicola et al, 2004) used in the first four patients was too toxic, with prolonged G4 neutropenia and severe infections in all cases. The exclusion of cisplatin, the change of cytarabine administration schedule and the addition of rituximab (Table I) were associated with a strikingly improved tolerability in subsequent patients, with only two cases of well-controlled febrile neutropenia. Of note, there was a single case of G4 non-haematological toxicity (transient diarrhoea). Patients with hepatitis B virus or hepatitis C virus positivity completed the planned treatment (ASCT in three), and experienced only transient G3 increase of transaminase serum level, without significant chemotherapy delay. HAART was discontinued during chemoimmunotherapy in four patients: three patients exhibited an increase of plasmatic HIV-RNA levels at day 45 followed by undetectable levels at day 90 in two cases, while the third patient needed for a further HAART line; the fourth patient was the toxic death. CD4+ cell counts remained unchanged in the three assessed patients, but were < 0 05 9 10/l in two of them. Response after induction phase was complete in six patients and partial in seven [overall response rate risk (ORR) = 87%; 95% confidence interval CI: 70–100%], one patient had meningeal dissemination and one died of sepsis (Fig. 1). Thirteen patients were referred to consolidation phase, 11 of them were referred to APBSC collection, which was successful in nine (median: 14 10 CD34+ cells/ kg; range 7 20–20 02). The six patients in CR after inducCorrespondence