Miriam Moreno

HIV-infection impact on clinical-biological features and outcome of diffuse large B-cell lymphoma treated with R-CHOP in the combination antiretroviral therapy era.

Objective:Since the introduction of combination antiretroviral therapy (cART) patients with HIV-related diffuse large B-cell lymphoma (DLBCL) show better control of immunosuppression, which may have an impact on the characteristics and prognosis of the disease. We aimed to compare the clinical presentation and prognosis of patients with HIV-related and HIV-unrelated DLBCL treated with rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP) in the cART era. Methods and design:Eighty-one HIV-infected patients included in a Spanish multicentre trial were compared with 84 HIV-uninfected patients diagnosed in a Spanish institution in the same period all treated with R-CHOP. Results:HIV-infected patients had a worse performance status, more frequent B-symptoms, and higher Ann-Arbor stages than HIV-uninfected patients, with similar frequency of extranodal involvement. The complete response (CR) rate of patients with high tumor burden was not different in HIV-infected and HIV-uninfected patients. Patients with HIV-related DLBCL showed a worse overall survival (OS) (5-year OS: 56 vs. 74%) but a similar disease-free survival (DFS) (5-year DFS: 84 vs. 73%). In the subgroup of patients with high tumor, the results regarding survival were similar to the whole series. Previous AIDS-defining illness was the strongest negative prognostic factor for OS in HIV-infected patients. Conclusion:In the cART era, HIV-related DLBCL still presents more aggressive features than HIV-unrelated DLBCL, and has a worse OS despite having a similar DFS. Prevention of HIV-related complications is essential to achieve outcomes comparable with HIV-uninfected patients with DLBCL.

Risk of, and survival following, histological transformation in follicular lymphoma in the rituximab era. A retrospective multicentre study by the Spanish GELTAMO group

The diagnostic criteria for follicular lymphoma (FL) transformation vary among the largest series, which commonly exclude histologically‐documented transformation (HT) mandatorily. The aims of this retrospective observational multicentre study by the Spanish Grupo Español de Linfoma y Transplante Autólogo de Médula Ósea, which recruited 1734 patients (800 males/934 females; median age 59 years), diagnosed with FL grades 1–3A, were, (i) the cumulative incidence of HT (CI‐HT); (ii) risk factors associated with HT; and (iii) the role of treatment and response on survival following transformation (SFT). With a median follow‐up of 6·2 years, 106 patients developed HT. Ten‐year CI‐HT was 8%. Considering these 106 patients who developed HT, median time to transformation was 2·5 years. High‐risk FL International Prognostic Index [Hazard ratio (HR) 2·6, 95% confidence interval (CI): 1·5–4·5] and non‐response to first‐line therapy (HR 2·9, 95% CI: 1·3–6·8) were associated with HT. Seventy out of the 106 patients died (5‐year SFT, 26%). Response to HT first‐line therapy (HR 5·3, 95% CI: 2·4–12·0), autologous stem cell transplantation (HR 3·9, 95% CI: 1·5–10·1), and revised International Prognostic Index (HR 2·2, 95% CI: 1·1–4·2) were significantly associated with SFT. Response to treatment and HT were the variables most significantly associated with survival in the rituximab era. Better therapies are needed to improve response. Inclusion of HT in clinical trials with new agents is mandatory.

Usefulness and safety of oral cryotherapy in the prevention of oral mucositis after conditioning regimens with high-dose melphalan for autologous stem cell transplantation for lymphoma and myeloma

Oral mucositis (OM) is a common complication of conditioning regimens with high‐dose melphalan (HDmel). This retrospective cohort study analyzes the impact of oral cryotherapy (OC) or room temperature saline rinses on the prevention of OM in patients with multiple myeloma (MM) or lymphoid neoplasias submitted to autologous stem cell transplantation (ASCT) in a single center.

Doxorrubicina liposomal no pegilada en combinación con ciclofosfamida, vincristina, prednisona y rituximab en el tratamiento de linfomas no hodgkinianos: estudio de 26 pacientes

BACKGROUND AND OBJECTIVES Non-pegylated liposomal doxorubicin is associated with lower cardiac toxicity than conventional doxorubicin, and for that reason it has been used in the treatment of non-Hodgkins lymphoma (NHL) in old patients or patients with cardiac disease. The objective of this study was to evaluate the efficacy and safety of chemotherapy schedules including non-pegylated liposomal doxorubicin in patients with NHL. PATIENTS AND METHODS Retrospective study of NHL patients treated with non-pegylated liposomal doxorubicin in two hospitals. In each patient demographic data, clinical and biological variables, as well as therapy, response and toxicity were recorded. RESULTS Twenty-six patients were included, 14 (58%) of them were women. Median age was 76 years (range 42-86). The most frequent histological diagnosis was diffuse large B cell lymphoma (DLBCL, 20 patients). The stage disease at diagnosis was III/IV in 19 (73%) patients whereas 12 (57%) of the 21 patients with DLBCL and grade 3 follicular lymphoma had a high-risk International Prognostic Index. Three patients had a left ventricular ejection fraction lower than 50% at the time of starting treatment. The most frequent cardiovascular risk factor was hypertension (50% of the patients) and 6 (23%) had previous heart disease. In all cases non-pegylated liposomal doxorubicin was administered as part of the R-COMP schedule (rituximab, cyclophosphamide, vincristin, non-pegylated liposomal doxorubicin and prednisone), in 20 cases (73%) as first-line treatment and in the remaining 6 as salvage therapy. Two patients died after the first cycle of chemotherapy (one because of sudden death and the other due to disease progression). Eleven (61%) out of the 18 patients receiving R-COMP as first-line therapy achieved a complete response (CR), 5 (28%) achieved partial response (PR) and 2 showed progression. Only one out of the 6 patients receiving R-COMP as salvage therapy achieved CR, whereas 3 had PR and 2 did not respond. Grade 3 or 4 neutropenia was observed in 11 (46%) patients and febrile neutropenia in 10 (42%), while only one patient developed grade 4 thrombocytopenia. The median overall survival was 50,7 months (95% confidence interval [95% CI] 8-93.3) and the median disease free survival was 18,4 months (95% CI 18.1-18.7). CONCLUSIONS In this cohort of patients, most of them old and with cardiovascular risk factors, the administration of non-pegylated liposomal doxorubicin as part of R-COMP regimen was effective and safe.

Refractoriness to immunochemotherapy in follicular lymphoma: Predictive factors and outcome

Follicular lymphoma is characterized by a good response to immunochemotherapy (ICT). However, a small percentage of patients responds poorly to treatment and seems to have a worse outcome. This study attempted to identify the predictive factors and outcome of refractoriness to first‐line ICT. All patients diagnosed with stage II to IV follicular lymphoma between 2002 and 2014 and treated with first‐line ICT in 4 Spanish institutions were analyzed. Those with no response or progression or relapse within 6 months of first‐line response assessment were considered ICT refractory. Three hundred forty‐three patients were included (median age 58 years, 48% male), of whom 53 (15%) were ICT refractory. On multivariate analysis, high‐risk follicular lymphoma international prognostic index (FLIPI) score, B symptoms, and elevated β2‐microglobulin were correlated with refractoriness, and refractoriness, high‐risk FLIPI score, and β2‐microglobulin were correlated with overall survival (OS). Compared with ICT‐sensitive, ICT‐refractory patients had a higher incidence of histological transformation (5‐year cumulative incidence 25% [14%‐39%] vs. 6% [3%‐10%], P < .001), a higher rate of refractoriness to second‐line therapy (16/33 [48%] vs. 13/57 [23%], P = .01), and a lower OS (5‐year OS probability 38% [95% CI 23%‐53%] vs. 87% [82%‐92%%], P < .001). In conclusion, refractoriness to ICT was seen in 15% of patients and was predicted by high‐FLIPI scores, B symptoms, and elevated serum β2‐micrglobulin. Immunochemotherapy‐refractory patients had a worse prognosis than ICT‐sensitive patients, and current treatment options for this subgroup are not satisfactory.

The long term follow-up of early stage follicular lymphoma treated with radiotherapy, chemotherapy or combined modality treatment

Local (involved-field or recently involved-site) radiotherapy is the standard therapy in limited-stage follicular lymphoma (FL). We retrospectively analyzed the value of chemotherapy in 130 patients with limited-stage FL (46 treated with radiotherapy alone [RT group], 30 with radiotherapy plus chemotherapy [COMBINED group] and 43 with chemotherapy alone [CHEMO group], 11 were managed with observation). Ninety-six percent of patients responded (RT 98%, COMBINED 100%, CHEMO 91%, p=0.179), and 37% (40/107) of patients in complete response relapsed (RT 42%, COMBINED 27%, CHEMO 41%, p=0.371). Progression-free survival (PFS) and overall survival (OS) probabilities at 10 years were similar in RT, COMBINED and CHEMO patients (PFS 41%, 61% and 39% [p=0.167], and OS 77%, 81% and 72% [p=0.821], respectively), while the COMBINED group showed a trend to better time-to-progression (TTP 43%, 72% and 47% [p=0.055]). On multivariate analysis, only a FLIPI score ≥2 showed a trend to influence PFS (HR 2.1 [95% confidence interval 0.9-4.6], p=0.067), and OS (HR 2.4 [0.9-6.5], p=0.084), while patients treated with radiotherapy plus chemotherapy (COMBINED group) showed a significantly better TTP compared with those receiving only RT (HR 0.3 [0.1-0.8], p=0.024). In our study no benefit was observed in survival with the use of systemic therapy compared with local radiotherapy.

Relapse risk after autologous stem cell transplantation in patients with lymphoma based on CD34+ cell dose

Abstract It is unclear whether higher CD34 + cell doses infused for ASCT have any influence on survival or relapse in patients with lymphoma. We analyzed the correlation of infused CD34 + cell dose with relapse, survival, and hematopoietic recovery in 146 consecutive patients undergoing ASCT for lymphoma. Higher doses (>5 × 106/kg) were significantly correlated with earlier hematopoietic recovery, fewer infectious episodes, lower transfusion needs. No differences were observed in lymphoma outcomes (4-year relapse incidence of 38% [95%CI: 29%–48%] in the lower dose group versus 51% [95%CI: 30%–69%] in the higher dose group, 10-year OS probabilities of 58% [95%CI: 48%–68%] versus 75% [95%CI: 59%–91%], 10-year DFS probabilities of 47% [95%CI: 37%–57%] versus 42% [95%CI: 23%–61%], p = NS for all outcomes). In this series, a higher infused CD34 + cell dose did not correlate with survival or relapse but correlated with earlier hematopoietic recovery and lower resource consumption.

HIV-infection has no prognostic impact on advanced-stage Hodgkin lymphoma

Objective: Classical Hodgkin lymphoma (cHL) is a non-AIDS-defining cancer with a good response to chemotherapy in the combined antiretroviral therapy (cART) era. The aim of the present study was to compare the characteristics, the response to treatment and the survival of advanced-stage cHL treated with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) between cART-treated HIV-positive and HIV-negative patients. Design and methods: We retrospectively analyzed advanced-stage cHL patients from a single institution, uniformly treated with ABVD. All HIV-positive patients received cART concomitantly with ABVD. Results: A total of 69 patients were included in the study: 21 were HIV-positive and 48 were HIV-negative. HIV-positive patients had more aggressive features at cHL diagnosis, such as worse performance status, more frequent bone marrow involvement and mixed cellularity histologic subtype. There were no differences in complete response rate (89% in HIV-positive vs. 91% in HIV-negative), P = 1; disease-free survival (DFS) [10-year DFS probability (95% CI) 70% (41–99%) vs. 74% (57–91%)], P = 0.907 and overall survival (OS) [10-year OS probability (95% CI) 73% (52–94%) vs. 68% (51–85%)], P = 0.904. On multivariate analysis, HIV infection did not correlate with worse OS. Conclusion: Although HIV-positive patients with cHL had more aggressive baseline features in this series, there were no differences in response rate or survival between HIV-positive and HIV-negative patients.

Clinico-biological features, treatment and survival of 457 patients with histological Grades 3A and 1–2 follicular lymphoma mostly treated with immunochemotherapy

Follicular lymphoma (FL) is a non-Hodgkin lymphoma (NHL) of follicle centre B-cells that grow in a follicular pattern. The 2008 World Health Organization (WHO) classification (Swerdlow et al, 2008) divides FL into three major grades: Grade 1 and 2 [<15 centroblasts/high-power field (HPF)] and Grade 3 (>15 centroblasts/HPF). FL Grade 3 is also divided into two types, 3A and 3B; Grade 3A is classified as a preserved maturation of the centrocytes. However, the prognostic value of this grading system remains controversial. Grade 3B FL is currently considered a distinct entity and managed as diffuse large B-cell lymphoma (Horn et al, 2011). It is well known that Grade 1–2, representing 75–90% of all FL cases, has an indolent evolution with a pattern of frequent relapses and is incurable with conventional therapy. However, Grade 3A FL is not yet well defined, with some characteristics of near aggressive lymphoma and others that are almost low-grade (Shustik et al, 2011; Vaidyanathan & Czuczman, 2014). The present study aimed to evaluate initial clinical and biological features, response and outcome of a large cohort of FL Grade 3A and 1–2 patients, most of whom had been treated with immunochemotherapy. Four hundred and fifty-seven patients diagnosed with FL were selected. Primary cutaneous and Grade 3B FL were excluded. In the overall cohort, median follow-up for surviving patients was 5 08 years, with a 10-year overall survival (OS) of 69% [95% confidence interval (CI): 63–75%] and 10-year progression-free survival (PFS) of 38% (95% CI: 32– 44%). Histological grade was based on the current WHO classification, assessed in all patients, and central histological review. Univariate and multivariate analysis was evaluated according to the histological grade, with all main clinical and histological data, prognostic factors, treatment strategies and response. Tumour response was assessed using International Working Group criteria for NHL (Cheson et al, 1999). The main clinical characteristics are summarized in Table I. Comparing the most important clinical differences between Grade 3A and Grade 1–2 FL, less extra nodal involvement was observed in Grade 3A patients, principally due to less bone marrow involvement in this group (Grade 3A, 35%; Grade 1–2, 54%, P = 0 003). This proportion is lower than previously described (Wahlin et al, 2012). Histological analysis did not identify significant differences between BCL2 and CD10 in both groups: 91% and 90% in Grade 3A; 95% and 92% in Grade 1–2, respectively. BCL6 expression was lower in Grade 3A patients: 77/77 (100%) and 54 out of 72 (75%) (P < 0 0001). This data was not previously described; however, this finding did not impact outcome. Ki67 index >50% was evident in Grade 3A compared with Grade 1–2 FL patients: 33/56 (59%) vs. 7/63 (11%) (P < 0 0001). Expression of Ki67 index >50% defined a small group (N = 39) in our cohort with a median survival of 1 5 years (0 7–2 3), regardless of histological subtype. Treatment was heterogeneous in both groups (Table I). Patients with FL Grade 3A were more frequently treated with anthracyclines and rituximab, and received less fludarabine, A trend towards a high complete response rate was observed in the Grade 3A FL group (Table SI). In univariate and multivariate analysis, the most important variables predicting response in FL Grade 3A patients was the FL International Prognostic Index (FLIPI) score (P = 0 009) and, included FLIPI score (P < 0 0001) and b2microglobulin (P = 0 041) for the Grade 1–2 group (Table SII). No significant differences in outcome (PFS and OS) were observed between Grades 1–2 and 3A (Fig 1). Of 270 patients that achieved CR, 121 relapsed: 21 (35%) FL Grade 3A patients and 100 (46%) FL Grade 1–2 patients (P = 0 126). At the time of this analysis, 24 (27 3%) and 91 (24 7%) FL Grade 3A and 1–2 patients, respectively, had died, mostly due to lymphoma progression. As expected, FLIPI score still remained an important prognostic factor for OS in both groups (Grade 3A, P = 0 050; Grade 1–2, P = 0 045). Univariate and Cox multivariate analysis of survival in both groups is shown in Table SIII. In our series, 95% and 70% of the Grade 3A and Grade 1–2 patients, respectively, received upfront anthracyclines (P < 0 0001). When only patients treated with anthracyclines were analysed, no differences in terms of OS and PFS were observed between the Grade 3A and Grade 1–2 cohorts (Fig S1), or when analysed for each particular group (Table SIII), and was in agreement with previous reports (Chau et al, 2003; Ganti et al, 2006). This report describes the largest number of FL patients treated with immunochemotherapy published to date. Upfront and cumulative rituximab treatment in Grade 3A and 1–2 FL patients were: 68% vs. 47% and 77% vs. 63%, respectively (P < 0 0001 and P = 0 032). OS probabilities were identical in Grades 1–2 and 3A patients treated with upfront and cumulative rituximab (Fig S2 and S3), and were the same in terms of PFS in upfront rituximab patients (Fig S2). However, PFS showed a non-significant trend for

Overall survival in patients with relapsed/refractory high grade B-cell lymphomas treated with gemcitabine, oxaliplatin with or without rituximab

In a recent article Dhanapal et al [1] retrospectively assessed the efficacy and toxicity of gemcitabine and oxaliplatin with or without rituximab (GEMOX±R) for a variety of aggressive lymphoid disorders in the relapsed setting. They report generally good tolerability but poor efficacy, underscoring the lack of satisfactory therapeutic options for these patients. Interestingly, a majority of their patients were stem cell transplant (SCT)-eligible and only a minority ultimately underwent the procedure. In our institution cisplatin-based regimens are used when aiming for stem cell transplant and GEMOX±R is used in non-eligible patients. In light of their poor results even in transplant-eligible patients, we were led to audit the results of our GEMOX±R patients. This is a retrospective study carried out in a single institution. All patients with a lymphoid malignancy who received GEMOX±R between 2002 and 2016 were considered for inclusion. In order to obtain a more homogenous sample, patients with non-B-cell lymphomas (i.e. Hodgkin lymphoma and T-cell lymphoma) or indolent Bcell lymphomas were excluded. The medical records of the selected patients were reviewed and the relevant data were extracted, including demographic (age and gender), clinical and analytical (Ann-Arbor stage, B-symptoms, serum lactate dehydrogenase) information. All lines of therapy (previous and subsequent to the GEMOX±R) were registered, as was the response and progressionfree survival (PFS) to those given front-line and to that before GEMOX±R. Regarding GEMOX±R, we gathered the number of cycles administered, toxicity related to the treatment, response, progression-free survival and overall survival (OS) (time from the beginning of GEMOX±R until progression or death from any cause, respectively). Frequencies (and percentages) and median (and range) were used for categorical and quantitative variables, respectively. The Kaplan–Meier method was used to draw the PFS and OS curves. Twenty-two patients were included, 73% male, with a median age of 60 years (range 34–75). Table 1 shows the baseline characteristics of the patients included. Thirteen (59%) patients were diagnosed with diffuse large B-cell lymphoma (DLBCL), and most of them (72%) received RCHOP as initial treatment. Fifteen (68%) patients had primary refractory disease and 16 (73%) patients were refractory to the previous line of treatment. The median number of GEMOX±R cycles received was 4 (range 1–6). Six patients (29%) achieved a complete response to GEMOX±R, and 16 (73%) patients were refractory to this treatment. The six months probability of PFS was 21% (95% CI: 7–40), and six months probability of OS was 48% (95% CI: 26–67). (Supplementary Figures 1 and 2) Ten (45%) patients experienced grade 3 hematological toxicity (grade 3 neutropenia in 8 [36%] patients, grade 3 anemia in 5 [23%] patients and grade 3 thrombocytopenia in 5 [23%] patients). Three patients (14%) had at least one febrile episode requiring hospitalization. There were nine patients (41%) who had nonhamatological toxicities, none of them of grade 3, except anaphylactic reaction to gemcitabine in one case. Grade <3 toxicities included gastrointestinal toxicity (vomiting, diarrhea, gastroesophageal reflux), fever, and peripheral neuropathy. No renal toxicity or treatmentrelated deaths were reported. Similar to Dhanapal et al [1] we found that GEMOX±R offered very poor response rate and survival in a population of non-transplant eligible patients with relapsed/ refractory high-grade B-cell lymphomas. Our series includes a very high-risk population, particularly due to the high rate of refractoriness to frontline therapy, a relevant prognostic factor [2]. However, response and survival were almost uniformly poor, regardless of the response to previous therapy. These results are in part concordant with the available series, which show that patients with relapsed/refractory