Gonzalo Gutiérrez-García

Gene expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy

Diffuse large B-cell lymphomas (DLBCLs) can be divided into germinal-center B cell-like (GCB) and activated-B cell-like (ABC) subtypes by gene-expression profiling (GEP), with the latter showing a poorer outcome. Although this classification can be mimicked by different immunostaining algorithms, their reliability is the object of controversy. We constructed tissue microarrays with samples of 157 DLBCL patients homogeneously treated with immunochemotherapy to apply the following algorithms: Colomo (MUM1/IRF4, CD10, and BCL6 antigens), Hans (CD10, BCL6, and MUM1/IRF4), Muris (CD10 and MUM1/IRF4 plus BCL2), Choi (GCET1, MUM1/IRF4, CD10, FOXP1, and BCL6), and Tally (CD10, GCET1, MUM1/IRF4, FOXP1, and LMO2). GEP information was available in 62 cases. The proportion of misclassified cases by immunohistochemistry compared with GEP was higher when defining the GCB subset: 41%, 48%, 30%, 60%, and 40% for Colomo, Hans, Muris, Choi, and Tally, respectively. Whereas the GEP groups showed significantly different 5-year progression-free survival (76% vs 31% for GCB and activated DLBCL) and overall survival (80% vs 45%), none of the immunostaining algorithms was able to retain the prognostic impact of the groups (GCB vs non-GCB). In conclusion, stratification based on immunostaining algorithms should be used with caution in guiding therapy, even in clinical trials.

Comparison of four prognostic scores in peripheral T-cell lymphoma

BACKGROUND To compare the usefulness of four prognostic scores in patients with peripheral T-cell lymphoma (PTCL) from a single institution. PATIENTS AND METHODS One hundred twenty-one patients (77 male/36 female, median age 53 years) with PTCL [anaplastic large-cell lymphoma (ALCL) 21, PTCL not otherwise specified 56 and other 44)]. Complete response (CR) rate and 5-year overall survival (OS) were 41% and 31%, respectively. International Prognostic Index (IPI), Prognostic Index for T-cell lymphoma (PIT), International peripheral T-cell lymphoma Project score (IPTCLP) and modified Prognostic Index for T-cell lymphoma (mPIT) were calculated as in the original references. mPIT was only assembled to 41 patients in whom Ki-67 immunostaining was available. ALCL patients were analyzed separately. RESULTS Concordance among IPI, PIT and IPTCLP was 52% for low-risk group, 27% for low/intermediate-risk group, 20% for high/intermediate-risk group and 14% for high-risk group. IPI, PIT and IPTCLP predicted CR, with IPI being the best score in logistic regression. Neither Ki-67 immunostaining nor mPIT predicted CR. Five-year OS (low-risk versus intermediate- or high-risk categories) according to IPI, PIT, IPTCLP and mPIT were 52% versus 45%, 75% versus 49%, 58% versus 20% and 39% versus 0%, respectively. IPTCLP was the best score for OS in multivariate analysis. CONCLUSION All the scores demonstrated their usefulness to assess the outcome of patients with PTCL, with IPTCLP being the most significant to predict OS.

Clinico-biological characterization and outcome of primary nodal and extranodal diffuse large B-cell lymphoma in the rituximab era.

To study the main clinico-biological characteristics and the outcome of patients with diffuse large B-cell lymphoma (DLBCL) according to the primary site (nodal vs. extranodal), we included 262 patients consecutively diagnosed with DLBCL in a single institution, 5 years before and after immunochemotherapy was considered as the standard treatment. Altogether 116 patients received CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone) and 146 rituximab plus CHOP (R-CHOP). The primary site was the lymph node in 140 patients (53%), Waldeyers ring (WR) in 22, gastrointestinal (GI) in 33, and other extranodal in 67. The addition of rituximab significantly improved the CR rate in nodal, but not in extranodal, lymphomas. Patients receiving R-CHOP showed higher OS than those treated with CHOP alone (5-year OS: 71% vs. 48%). This difference was maintained in primary nodal (5-year OS: 69% vs. 37%, p < 0.0001), but was not observed in primary extranodal (75% vs. 65%, p = 0.45) lymphomas. The IPI, treatment, and primary site were the main variables for OS in multivariate analysis. In nodal cases, IPI and treatment maintained value, whereas only IPI predicted OS in extranodal cases. In conclusion, immunochemotherapy treatment dramatically improved the outcome of patients with nodal DLBCL; however, its effect was less in primary extranodal cases, so the prognosis of patients with nodal and extranodal lymphomas has been equalized in the rituximab era.

Fatal Immune Hemolytic Anemia Following Allogeneic Stem Cell Transplantation: Report of 2 Cases and Review of Literature

Immune hemolytic anemia is a well-recognized complication after allogeneic hematopoietic stem cell transplantation (HSCT). There are 4 possible causes for this complication. First, antibodies present in the recipient destroy donor cells. Second, donor red cell antibodies at the time of stem cell infusion are transferred to the recipient. Third, sometimes, engrafted donor lymphocytes cause active production of red cell antibodies. Fourth, another cause of hemolysis after allogeneic HSCT is autoimmune hemolytic anemia (AIHA). It is thought to be due to antibodies produced by the donors immune system against antigens on red cells of donor origin. Autoimmune hemolytic anemia after allogeneic HSCT is rare, it is still not well characterized, and it represents a life-threatening situation. We describe 2 patients with acute myeloid leukemia treated with intensive chemotherapy and umbilical cord blood stem cell transplantation (UCBT). One patient developed AIHA at day +182 and the other at day +212 after receiving UCBT. Patients received 5 and 7 line treatment options, respectively, including continuous corticosteroids, intravenous immunoglobulin, splenectomy, cyclophosphamide, plasma exchange, rituximab, bortezomib, and eculizumab. However, both patients died because of massive hemolysis after 85 and 106 days of intensive treatment, respectively. These cases reflect the extreme difficulty in the therapeutic management of patients with AIHA following UCBT. After an extensive review of the literature, the exact physiopathologic mechanisms of AIHA after allogeneic HSCT in general, and after UCBT in particular, and therefore an effective treatment remain unknown.

Initial features and outcome of cutaneous and non-cutaneous primary extranodal follicular lymphoma

Follicular lymphoma (FL), a typically nodal disease, can arise in extranodal sites in about 10% of cases. The present study aimed to analyse the main differential features of patients with primary extranodal FL. Thirty‐nine patients with primary extranodal FL were identified from a series of 354 patients with FL diagnosed at a single institution and their main clinicobiological features were analysed. Twenty patients (5·6%) had a primary extranodal non‐cutaneous FL, and 19 (5·4%) a cutaneous FL. BCL2+ and CD10+ expression and BCL2/IGHJ@ rearrangement were less frequently observed in cutaneous FL. Absence of ‘B’‐symptoms, early stage, absence of bone marrow involvement and low‐risk Follicular Lymphoma International Prognostic Index (FLIPI) were more frequent in extranodal FL. Five‐year overall survival (OS) was 100%, 83% and 78% for cutaneous, non‐cutaneous and nodal FL, respectively. When stage I patients were analysed separately, no differences were seen in terms of OS. In multivariate analysis, FLIPI was the most important variable to predict outcome. In conclusion, extranodal FLs, particularly cutaneous, have particular clinico‐biological features, which differentiate them from nodal cases. Nevertheless, primary site of the disease is not the main issue to predict outcome.

Role of radiotherapy in patients with early-stage diffuse large B-cell lymphoma of Waldeyer's ring in remission after anthracycline-containing chemotherapy.

Consolidation radiotherapy (cRT) in patients with stage I/II diffuse large B-cell lymphoma of the Waldeyers ring (WR-DLBCL) in complete remission (CR) after induction chemotherapy (CHT) is often associated with relevant acute and chronic toxicity, and its impact on survival remains to be defined. A total of 184 patients in CR after anthracycline-based chemotherapy were retrospectively analyzed: 62 underwent CHT alone (CHT group), while 122 (66%) patients were referred to cRT (CHT + RT group). After a median follow-up of 54 months, 36 patients (20%) experienced relapse: 19% in the CHT group and 20% in the CHT + RT group. At the time of analysis 47 (76%) CHT patients and 97 (80%) CHT + RT patients were alive. Five-year overall survival (OS), disease-free survival (DFS) and lymphoma-specific survival (LSS) were 80%, 74% and 86%, respectively. Five-year OS was significantly prolonged in the CHT + RT group, while DFS and LSS were similar between groups. This discrepancy was attributed to a high percentage of deaths due to unrelated causes in CHT patients. cRT does not prolong LSS in patients with early-stage WR-DLBCL in CR after anthracycline-containing chemotherapy. An international confirmatory trial is warranted.

Allogeneic hematopoietic SCT in multiple myeloma: long-term results from a single institution

The role of allogeneic hematopoietic SCT (allo-HCT) in multiple myeloma (MM) remains controversial. A total of 58 patients received an allo-HCT (25 of them with myeloablative conditioning—allo-MAC—and 33 with reduced-intensity conditioning—allo-RIC) at our institution over a 28-year period. The CR rate for allo-MAC was 36%. The incidence of grade III–IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) was 28% and 39%, respectively The TRM at any time was 60% and the main causes of death were aGVHD or infectious complications not directly related to GVHD. The estimated PFS and OS at 15 years were 8% and 15%, respectively. The CR rate with allo-RIC was 45%. The incidence of grade III–IV aGVHD and cGVHD were 24% and 41%, respectively. The TRM at any time was 33% and was mainly related to aGVHD. The estimated PFS and OS at 5 years were 22% and 38%, respectively. Despite its high TRM, a proportion of patients with high-risk myeloma (early relapse and newly diagnosed ultrahigh risk) may obtain long-term disease control with allo-HCT. New approaches aimed at decreasing the incidence of aGVHD, and consequently to decrease the TRM, are needed.

Current immunochemotherapy strategies in follicular lymphoma

Nowadays, there is no consensus about the best treatment for patients with follicular lymphoma (FL) in differing situations. In frontline treatment, a watchful waiting policy remains a good option if the patient has no risk criteria; the role of rituximab is under investigation in this setting. In patients needing therapy, immunotherapy or immunochemotherapy are the best options; although it has not been established which chemotherapy, including cyclophosphamide, vincristine, and prednisone (CVP); cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP); fludarabine, or bendamustine combinations, is the best partner for rituximab. Following frontline treatment, recent and still unpublished data strongly suggest a role for maintenance with rituximab, instead of observation only. At relapse, immunochemotherapy is the standard induction approach. The role of maintenance after induction is well established, although comparative studies with autologous stem-cell transplantation (ASCT) or other combinations are warranted. The role of ASCT in this setting is a matter of discussion. Other monoclonal antibodies, as well as vaccines and other immunotherapies, are currently under investigation. Finally, allogeneic transplantation should be reserved for a very select group of young high-risk patients in the setting of clinical trials.

Innovative strategies minimize engraftment syndrome in multiple myeloma patients with novel induction therapy following autologous hematopoietic stem cell transplantation

Autologous stem cell transplantation (PBSCT) is standard for young patients in MM and its TRM has decreased after the 2000s. Bortezomib and immunomodulatory agents (IMiDs) in MM have improved the outcome. However, they seem to boost pro-inflammatory stage increasing the incidence of engraftment syndrome (ES). Favorable factors in PBSCT such as G-CSF could increase inflammatory stage during transplant. Corticosteroids have shown an excellent response of ES and some authors propose them as prophylaxis for ES. The aim was to analyze the impact of G-CSF avoidance and corticosteroids’ prophylaxis in 170 patients diagnosed of MM treated with bortezomib/IMiDs that underwent PBSCT. We established three groups: Group-I [(G-CSF_administration), 60 patients (35%)], group-II [(nonG-CSF), 60 patients (35%)] and group-III [(nonG-CSF plus corticosteroid’s prophylaxis), 50 patients (30%)]. A decreased ES incidence among groups was observed: 62, 42, and 22% (P < 0.0001). The incidence of symptoms mimicking a capillary leak syndrome associated with ES dropped: 43, 32, and 0% (P = 0.03). The G-CSF avoidance and corticosteroids had impact over admission 24, 21, and 20 days (P = 0.001). The most important variables related to ES were HCT-CI >2 (p < 0.0001; HR 8.5) and risk groups (p < 0.0001; HR 7.2). Hence, G-CSF avoidance and corticosteroid’s prophylaxis decrease morbidity in patients undergoing PBSCT with MM treated with bortezomib/IMiDs.

At-home autologous stem cell transplantation in multiple myeloma with and without G-CSF administration: a comparative study

Severe neutropenia remains the main cause of morbidity and mortality after autologous stem cell transplantation (ASCT). Improvements in this procedure, such as the use of peripheral blood progenitor cells and the administration of an oral antibiotic prophylaxis, have reduced the incidence of infections during the time of neutropenia and have made ASCT safer. The use of G-CSF after ASCT with the intention of reducing the duration of neutropenia and minimising the risk of severe infection is a common practice in most transplantation centres. In addition, because of a faster neutrophil recovery, G-CSF administration may also be associated with a reduction in the incidence and severity of oral and intestinal mucositis after ASCT. However, it has been reported that G-CSF administration after ASCT does not reduce the incidence or duration of febrile neutropenia or the infectious mortality rate. Moreover, G-CSF administration has been associated with a higher incidence of clinical complications such as engraftment syndrome (ES) and capillary leak syndrome. For these reasons, its use after ASCT is controversial. Thus, in May 2011, our centre discontinued the administration of post-transplant G-CSF in patients with multiple myeloma (MM). We hypothesised that the use of G-CSF in these patients does not provide any significant clinical benefit as compared with not using G-CSF. Here we report the results of this policy by comparing two cohorts of patients; one cohort received post-transplant G-CSF, whereas the other cohort did not receive G-CSF. One hundred ninety-five patients with MM underwent an ASCT between November 2000 and October 2014. Of them, 131 (67%) were not included in an at-home ASCT programme because of ECOG 42 (35%), patient decision (27%), geographic distance (21%) and no caregiver available (17%). Finally, 64 (33%) patients were included. The hospital ethics committee approved this programme and all patients signed a written informed consent. Patient-, diseaseand transplant-related variables are described in Table 1. All patients received high-dose melphalan (200 mg/m) and a peripheral blood stem cell infusion in the hospital and were discharged on day +1. Specialised nurses in Hematology looked after the patients daily, either at home or by phone. They checked patients’ vital signs, oral intake, central venous catheter status and presence of mucositis; they administered IV medications and they took blood samples. If necessary, medical assistance was provided in the hospital by a designated physician or by the haematologist on call. Patients who underwent an ASCT between November 2000 and April 2011 (n= 32) received G-CSF (5 mcg/kg per day) starting on day +7 until their ANC reached 1× 10/L for two consecutive days. The second cohort beginning in May 2011 (n= 32), received no G-CSF. All patients received antimicrobial prophylaxis with quinolone, fluconazole, aerosolized pentamidine and low-dose acyclovir if herpes serology was positive. Patients also received ceftriaxone (1 g per day IV) from day +1 until the first day of febrile neutropenia or until attaining an ANC of 1 × 10/L. Transfusions were administered when the haemoglobin concentration and platelet count were below 8 g/dL and 10× 10/L, respectively.