Marc Sorigue

Expression of CD43 in chronic lymphoproliferative leukemias

CD43 has been used on histological samples for the differential diagnosis of lymphoproliferative disorders but there is scarce data on its use by flow cytometry (FC). We set out to characterize the expression of CD43 by FC in B‐cell lymphoproliferative disorders and to determine its possible role in the differential diagnosis of these malignancies.

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.

The role of T-cell phenotype and T-cell receptor rearrangement in the diagnosis of T-cell malignancies

We read with interest the article by Flammiger et al. [1] on the study of a series of patients with aberrant T-cell phenotype of unclear significance by flow cytometry (FC). They divided their cases into mature T-cell malignancies (TCM) and reactive (non-TCM) cases, focusing on the phenotypes that pose a diagnostic challenge, having excluded those cases whose clinical evolution and further testing did not allow for a clear diagnosis, as well as those cases with obviously aberrant phenotypes. After analyzing their FC reports they argue that an aberrant T-cell phenotype of unclear significance is of little help in the diagnosis of TCM. They only found a correlation with a loss of expression of CD7, more frequent and marked in TCM, but also present in up to 30% of the non-TCM cases (which, notably, included B-cell malignancies in 50% of cases). The authors conclude that, in those cases without an obviously aberrant phenotype, FC can only be a part of a much larger set of diagnostic tools, which include cytogenetics, the study of T-cell receptor (TCR) rearrangements, clinical course and histological examination whenever possible. However, it is well established that TCR clonality is often detected in reactive cases or simply with aging [2–8]. It has been our experience that, indeed, T-cell FC analysis often shows abnormal markers that ultimately do not reflect an underlying TCM [3]. Thus, we set out to analyze the role of T-cell phenotype and TCR rearrangements in the diagnosis of TCM. From October 2007 to December 2014, there were 452 TCR rearrangement studies performed at our institution. After exclusion of all patients who had previously been tested for TCR clonality and those not simultaneously studied by FC, 120 cases were left and were the object of this study. Samples tested were primarily peripheral blood but also bone marrow, lymph node biopsies, lymph node fine needle aspiration and pleural or ascitic exudates. Demographic, clinical and diagnostic data were collected and, based on the FC results, four groups were established: (1) those with an obviously aberrant phenotype, including T-cell expression of CD30, CD10 or CD1a, loss of CD26, expression of gammadelta chains and CD4  CD8 co-expression ( 5% of the lymphocytic population); (2) those with an aberrant T-cell phenotype of unclear significance, as described by Flammiger et al. [1]. In our series, those abnormalities included diminished expression of CD7, CD5 or alpha-beta chains and expression of CD56 or CD57 by T-cells (Table I); (3) those with an abnormal CD4/CD8 ratio, defined as CD4/CD8  3 or CD4/CD8  1; and (4) those with a normal T-cell phenotype in whom TCR rearrangement testing was ordered to study absolute lymphocytosis or lymphopenia. Concerning diagnosis, we divided TCM into aggressive T-cell lymphomas (TCL), i.e. those high-grade lymphomas that required chemotherapy, including Sézary syndrome (SS), all diagnosed by histological tissue examination, and indolent TCM, which in our series were limited to T-cell large granular lymphocyte leukemias (TLGL), diagnosed by peripheral blood smear and according to WHO criteria. We diagnosed as reactive those cases that were clearly related to a non-hematological disorder as well as those that eventually resolved, even without a specific diagnosis. Cases with unclear clinical course and diagnosis were excluded and labeled as unclassified There were 20 patients in group 1, 17 (85%) of them with a clonal TCR, 23 patients in group 2, 15 (65%) of them with a clonal TCR, 47 patients in group 3, 18 (38%) of them with a clonal TCR and 30 patients in group 4, 6 (20%) of them with a clonal TCR (p  0.001). Table I shows for each of the phenotype groups the number of TCM, non-T-cell hematological malignancies (mostly B-cell lymphomas), non-malignant hematological disorders (mostly bone marrow aplasia) and reactive cases. Of note, not only do clearly aberrant phenotypes almost always reflect a hematological disorder (mostly TCL, but also TLGL or B-cell malignancies), but TCL and SS were mostly found in the group with clearly aberrant phenotypes (9/11 and 3/6, respectively). However, TLGL were found in all four groups. Furthermore, aberrant phenotypes

Highly variable mutational profile of ASXL1 in myelofibrosis

Somatic mutations in ASXL1 seem to have a negative prognostic impact in patients with several myeloid neoplasms, including myelofibrosis (MF). The aim of this work was to determine the prevalence and profile of ASXL1 mutations in MF.

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

The clinical dilemma of grade 3 follicular lymphoma

ABSTRACT The recommended treatment of grade 3 (or grade 3B) follicular lymphoma patients is that of diffuse large B-cell lymphoma rather than that of follicular lymphoma. These recommendations are not supported by randomized evidence. While RCHOP is a good therapeutic option for both follicular lymphoma and diffuse large B-cell lymphoma, the advent of targeted therapies is likely to change the optimal first-line regimen in both of these entities or, at least, some subset of patients. If that becomes the case, the current consensus-based (rather than evidence-based) approach to grade 3 follicular lymphoma will become a clinical concern to which we are, at present, unable to provide a satisfactory solution.

CD200 in High-Grade Lymphoma, Chronic Lymphocytic Leukemia, and Chronic Lymphocytic Leukemia–Phenotype Monoclonal B-Cell Lymphocytosis

To the Editor CD200 has become an essential marker for the study of low-grade lymphoproliferative disorders by flow cytometry (FC) because of its high discriminative power between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). However, its behavior in high-grade lymphomas remains unknown. Thus, we read with interest the recently published article by Challagundla et al,1 in which they examine CD200 in 505 samples, of both healthy individuals and patients with lymphoproliferative disorders, including 52 cases of diffuse large B-cell lymphoma (DLBCL) and six cases of Burkitt lymphoma (BL). Also very interestingly, and previously unreported, Challagundla et al1 found that CD200 in CLL, while always positive, was dimmer in those cases with trisomy 12. In this setting, we report our experience regarding the expression of CD200 by FC in high-grade lymphomas and CLL as well as CLL-phenotype monoclonal B-cell lymphocytosis (MBL), with emphasis on their cytogenetic aberrations. From November 2012 onward, we have used CD200 (clone MRC-OX104; Becton Dickinson) as part of the basic antibody panel for the study of lymphoproliferative disorders. From that date until December 2014, we studied by FC 44 samples suggestive of high-grade lymphoma (34 lymph node biopsy specimens, three lymph node fine-needle aspirations, three cavity exudates, three peripheral blood, and one bone marrow), 36 of which have been confirmed by histologic tissue examination according to World Health Organization …