Different Clinical Features but Not Outcome in SLL Patients Compared to CLL,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3896-3896
Author(s):  
Alejandra Martinez-Trillos ◽  
Eva Gine ◽  
Jordina Rovira ◽  
Marcos González ◽  
Maria Jose Terol ◽  
...  
Keyword(s):  
B Cells ◽  
Median Time ◽  
Who Classification ◽  
Conflicts Of Interest ◽  
Statistical Significance ◽  
Biological Features ◽  
Biological Variables ◽  
Richter Syndrome ◽  
Biological Studies

Abstract Abstract 3896 Chronic lymphocitytic leukaemia/Small lymphocytic lymphoma (CLL/SLL) is a neoplasm composed of monomorphic small neoplastic B cells that usually co-express CD5 and CD23. The current WHO classification considers CLL/SLL as the same entity being SLL the non-leukemic lymphoma presentation of CLL. The criteria for SLL include the presence of lymphadenopathy with less than 5×109/L peripheral blood B cells. Patients with SLL usually develop PB involvement during the evolution of the disease. The aim of this study was to analyze the main clinico-biological features and outcome of a series of SLL patients and compare them with the CLL patients diagnosed in the same period of time.Patients and methods: we have included 588 patients (353M/ 233F; median age 61 years) diagnosed with CLL or SLL according to the WHO classification criteria in the same period of time.The main clinico-biological features and the outcome were recorded and analysed according to the CLL/SLL diagnosis. Results: five hundred forty-five patients (93%) fulfil the criteria for CLL and 43 patients (7%) for SLL. The main clinico-biological variables according to the CLL/SLL criteria are detailed in the table. No differences were observed in gender distribution, age at diagnosis or ECOG. Patients with SLL had more frequently Binet C stage, low haemoglobin levels and platelet counts. 320 patients eventually received therapy, including purine analogues containing regimens (159 patients), chlorambucil (113), CHOP-like regimens (31), and other therapies (17). Sixty-nine patients received rituximab in combination. SLL patients received more frequently CHOP-like regimens than CLL patients, but this difference did not reach statistical significance. During the follow-up, 58% of the SLL patients eventually developed leukemic presentation, after a median time from diagnosis of 4.6 years (0.2–15 years). Patients with SLL not receiving treatment progressed to PB involvement sooner than treated SLL (median time, 1 year vs 6 year, respectively; p=0.06).Twenty four of the 588 patients eventually developed Richter syndrome, with this proportion being higher in the SLL than in CLL patients (13.1% vs 3.5%; p=0.001). Moreover, the proportion of second neoplasm (excluding non melanoma skin cancer) was higher for SLL patients than for CLL patients. After a median follow-up for surviving patients of 7.4 years (range, 0.1 to 28), 207 patients eventually died with no differences in overall survival between the two groups of patients. In addition, the causes of death were also similar (50% in SLL and 43% in CLL due to disease progression). In conclusion, although the outcome is similar in SLL and CLL groups, SLL patients more frequently had cytopenias as well as higher risk to develop Richter syndrome and second neoplasias. Genetic and other biological studies are warranted to elucidate the particular presentation and features of SLL.Patients (n=588)CLL (=545)SLL (n=43)pMedian age (years)6161Gender (Male/female)324/21929/14Binet C27/536 (5%)8/43 (18%)<0.001Hemoglobin <110 g/L26/526 (5%)7/39 (18%)0.001Platelets <100x109/L22/525 (4%)4/39 (10%)0.08High serum LDH (%)57/496 (11%)7/37 (18%)n.s.High B2 microglobuline191/442 (43%)17/32 (53%)n.s.High CD 38 expression135/484 (27%)18/38 (47%)0.011High ZAP 70 expression138/527 (26%)14/41 (34%)n.s.Unmutated IGHV160/335 (48%)10/15 (66%)n.s.Presence of Monoclonal Paraprotein28/545 (5%)4/43 (9%)n.s.Second Neoplasia (excluding Skin)74/545 (14%)11/43 (25%)0.03110-year risk of Richter Syndrome5.3%32.8%0.00110-year OS59%53.1%n.s. Disclosures: No relevant conflicts of interest to declare.

Quantitative Imaging of Femoral Bone Marrow Microenvironments Reveals a Heterogenous Distribution of Hematopoietic Stem and Progenitor Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1455-1455
Author(s):  
Cesar Nombela-Arrieta ◽  
Brendan Harley ◽  
Gregory Pivarnik ◽  
John E Mahoney ◽  
Elena Levantini ◽  
...  
Keyword(s):  
Stem Cells ◽  
B Cells ◽  
Cell Biology ◽  
Conflicts Of Interest ◽  
Statistical Significance ◽  
Quantitative Imaging ◽  
Cell Types ◽  
Immunofluorescent Staining ◽  
Cell Populations ◽  
Hematopoietic Stem

Abstract Abstract 1455 Poster Board I-478 Sustained production of all mature blood cell types relies on the continuous proliferation and differentiation of a rare population of self-renewing, multipotent hematopoietic stem cells (HSCs). HSC maintenance and lineage differentiation are thought to be regulated by spatially confined niches, defined by cellular components, soluble regulators, and the extracellular matrix immediately surrounding stem cells. Identification of these microenvironments in which endogenous and transferred HSCs reside within the BM is a major challenge in stem cell biology with relevant clinical implications. Yet the extreme rarity of HSCs, their dynamic nature, and the lack of specific markers to identify them, have precluded an accurate definition of HSC niches to date. Quantitative imaging technologies such as Laser Scanning Cytometry (LSC) are designed for the automated analysis of large cell numbers at a single cell level with high resolution while preserving the morphological information lost in flow cytometry, therefore providing data of statistical significance even for rare cell populations such as HSCs. We have employed LSC to analyze the localization of both adoptively transferred and endogenous hematopoietic stem and progenitor cell (HSPC) populations inside whole longitudinal sections of murine femoral BM cavities. Our results indicate that, as previously suggested, purified HSPC (Lin−c-kit+Sca-1+) significantly accumulate in endosteal regions (ER) of BM cavities (within 100μm of inner bone surface) upon transplantation. Nevertheless, analysis of sufficient numbers of more differentiated cell subsets (Lin−c-kit+Sca-1− progenitors, pro B cells and mature B cells) indicated that these areas serve as homing sites for most hematopoietic cells, highlighting the limitations of any conclusions drawn on HSC niche identity from studies performed with transferred HSPC populations. Immunofluorescent staining of endogenous cell populations revealed a gradient in distribution of early hematopoietic progenitors (c-kit+), which accumulated in but were not restricted to ER regions. Of note, a vast majority (>80%) of HSPC (Bmi-GFPhic-kit+, or Lin−c-kit+Sca-1+),were found inside ER, although not directly adjacent to endosteal surfaces. Our studies define endosteal areas as tissue regions where HSPC reside in close proximity, but not necessarily in direct contact with a dense vascular network, osteoblastic cells and other potential niche cell types and growth factors currently under investigation. Disclosures No relevant conflicts of interest to declare.

Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) in Patients with Haematological Lymphoid Malignancies: Long Term Follow-up in a Single Centre Series.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4326-4326
Author(s):  
Malek Benakli ◽  
Redhouane Ahmed nacer ◽  
Amina Talbi ◽  
Rachida Belhadj ◽  
Farih Mehdid ◽  
...  
Keyword(s):  
Complete Remission ◽  
Hodgkin Lymphoma ◽  
Median Time ◽  
Conflicts Of Interest ◽  
Late Onset ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Lymphoid Leukaemia ◽  
Autologous Transplant

Abstract Abstract 4326 Background Patients (pts) with recurrent and refractory haematological lymphoid malignancy (HLM) have a very limited survival expectance. RIC allo-SCT has been proposed as a strategy for retaining the graft versus malignancy effect of allo-SCT while decreasing transplant related mortality (TRM). Here, we retrospectively studied a series of 32 pts treated by RIC allo-SCT. Patients and methods Between April 2001 and November 2007, 32 pts with HLM underwent RIC allo-SCT with an HLA-identical sibling donor. Fifteen pts with multiple myeloma, 7 pts with Non-Hodgkin lymphoma, 6 pts with Chronic lymphoid leukaemia, 3 pts with Hodgkin lymphoma and 1 pt with Waldenstrom disease. At time of allo-SCT, 10 pts were in complete remission (3 received prior autologous transplant) and 22 in refractory/progressive disease (6 received prior autologous transplant). Median age was 38 years (range, 28-60) and the sex-ratio (M/F) 2,2. Median time from diagnosis to RIC allo-SCT was 18 (range,6-76) months. The conditioning regimen included Fludarabine 150mg/m2 and Melphalan 140mg/m2. GVHD prophylaxis consisted of association cyclosporine (cSA) and mycophenolate (MMF). All pts received G-CSF mobilised peripheral blood stem cells, with a median CD34+ cell count: 6,2.106/kg (range, 1.9-13,6). Results Neutropenia occurred in all pts (100%) and the median duration of aplasia was 9 (range, 5-16) days. Only 10 pts (31 %) required red blood cells transfusions and 23 pts (71 %) needed platelets transfusions. Acute GVHD was observed in 15 cases (47 %) including 10 cases of grade II-IV. Fifteen pts (75 %) had chronic GVHD, of whom 9 with an extensive form. Four pts (12 %) had CMV reactivation at a median time 60 (range, 52-80) days after transplantation. Six pts (18 %) had late onset relapse at a median time of 13 (range, 4-45) months. TRM was 43 % at one year after RIC allo-SCT. With a median follow-up of 60 (range 18-97) months, 12 pts (37,5 %) are still alive in complete remission with full donor chimerism. Twenty pts (62,5 %) have died (5 early severe infections, 10 GVHD, 3 after relapse, one myocardial infarction, and one accident). Overall and progression-free survivals at 8 years are 31 % and 30 % respectively. Conclusion This study, after a large follow-up, suggests that RIC allo-SCT is a potential therapy for refractory or progressive HLM. However, TRM is still high likely due to the inclusion of refractory and heavily pretreated pts with many comorbid conditions. Disclosures: No relevant conflicts of interest to declare.

Efficacy of Lenalidomide-Based Regimens in Multiple Myeloma Complicated by Extramedullary Plasmacytomas at Relapse or Progression.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4952-4952 ◽  
Author(s):  
Jose Manuel Calvo-Villas ◽  
Adrian Alegre ◽  
Ricarda García-Sánchez ◽  
Miguel T Hernández ◽  
Pilar Giraldo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Median Time ◽  
Light Chain ◽  
Conflicts Of Interest ◽  
Bone Lesions ◽  
Complete Disappearance ◽  
Toxicity Profile ◽  
Small Series ◽  
Extramedullary Plasmacytomas

Abstract Abstract 4952 Background Current clinical observations on extramedullary myeloma (EM) are based on small series of relapsed myeloma patients (pts) and, in this situation, results suggest that the disease course is often aggressive. Among novel therapies for extramedullary involvement, thalidomide has provided poor results and bortezomib is emerging as a possible useful drug. The role of lenalidomide for treatment of multiple myeloma (MM) with EM is still under investigation. Aim A multicenter retrospective study was performed by PETHEMA (Spanish Myeloma Group, Spain) to evaluate the response rate and toxicity profile of lenalidomide-based regimens in myeloma patients with extramedullary involvement at relapse or progression. All the cases were evaluated for response of MM and improvement of extramedullary plasmacytoma. Patients and Methods From October 2007 to March 2009, thirteen patients (median age 67 years; range 61–87; 7 females) treated with lenalidomide-containing regimens were recorded. Patients with bone disease without extramedullary manifestations were excluded. Response of MM was evaluated according to the new international criteria and the response of EM by measuring size changes by physical examination, CT scans and/or MR imaging. Adverse events were graded based on the WHO toxicity scale. The M-protein type was IgG in 7 cases, IgA in 5 and light chain in 1. The type of light chain was κ in 7 pts and l in 6. In eight patients the soft-tissue plasmacytomas may have developed from underlying bone lesions [(skull (n=2), rib cage (n=4) and paravertebral (n=2)], two patients had subcutaneous nodules and three had visceral involvement (liver (n=1), lung and kidney (n=1) and pleura (n=1). Multiple localizations were present in 4 pts (30.7%). Six cases (79.6%) received previous antimyeloma treatment for EM before lenalidomide therapy and the incidence of prior bone plasmacytomas was 61.5%. Median time from initial antimyeloma therapy to treatment with lenalidomide was 34 months (range 5 - 115). Median number of prior lines of chemotherapy regimens was 3 (range 1 – 4), including autologous stem cell transplantation in 2 pts, bortezomib-containing regimens in 12 (92.3%) and previous exposure to thalidomide in 1 patient. Ten pts received standard lenalidomide dose (25 mg/day every 4 weeks) plus dexamethasone (40 mg/d PO ranging from 1 to 12 doses/cycle) every 3-week; and three patients received lower doses of lenalidomide and/or different schedules. Involved-field radiotherapy was given in 2 cases. Thirty percent of patients required lenalidomide dose reduction, because of toxicity or intolerance. Results Median duration of lenalidomide treatment was 3.6 months (1 – 15). One case was not evaluable for response because of death from disease progression after one cycle. In nine out of twelve evaluable patients (75%), MM responded to lenalidomide regimens according to EBMT criteria. Three (25%) achieved complete response, five (41.6%) partial response and 1 (8.3%) minimal response. Median time to response was 63 days (range 37 – 180). Regarding EM, nine patients showed response in the size of extramedullary plasmacytomas. Seven (58.3%) achieved complete disappearance of EM and two pts reduction of the size. Response of EM was also achieved in 75% of pts previously exposed to bortezomib, and in 4/9 cases who received therapies for prior extramedullary involvement. Median follow-up period was 6.3 months (1 – 15.8). Median overall survival from the start of lenalidomide therapy was 4.7 months. At the time of analysis, seven patients were still on therapy, and ten (76.9%) were alive. Only one out of the 9 patients who had achieved a response has relapsed so far. Toxicity profile (grade 3/4) was: thrombocytopenia, 4 (30.7%); anemia, 2 (15.3%); neutropenia, 5 (46.4%); neutropenic fever, 1 (7.6%) and others, 3 (11.8%). No deep venous thrombosis (DVT) was reported. Thrombosis prophylaxis was used in most cases (92%) patients. Conclusions We report one of the first investigations specifically evaluating the activity of lenalidomide on EM. Lenalidomide-containing regimens could be an alternative promising approach to achieve clinical response in heavily treated MM patients with extramedullary disease. The duration of response and the best regimen or combination are at present unknown. These preliminary observations require further analysis and longer follow-up. Disclosures No relevant conflicts of interest to declare.

Outcome of Patients with CML Treated with Dasatinib or Nilotinib after Failure of Second Prior TKIs

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2294-2294
Author(s):  
Antonella Russo Rossi ◽  
Massimo Breccia ◽  
Fausto Castagnetti ◽  
Luigiana Luciano ◽  
Antonella Gozzini ◽  
...  
Keyword(s):  
Median Time ◽  
Conflicts Of Interest ◽  
Cell Uptake ◽  
Second Line ◽  
The Third ◽  
Line Therapy ◽  
Third Line ◽  
New Mutations

Abstract Abstract 2294 Background. The TKIs Nilotinib and Dasatinib offer additional therapeutic options for patients with CML who are resistant or intolerant to Imatinib. These agents, active against the majority of Imatinib resistant BCR-ABL mutated clones, have a different pattern of kinase target selectivity, pharmacokinetics parameters, cell uptake, efflux properties and adverse events profiles. Preliminary results suggest that some patients may respond to a second TKI used as third line therapy, but little is known about the long term benefit of such an approach.Aim of this collaborative Italian study was to verify the response (rate and duration) and the clinical outcome in patients with CML treated with a third TKI after sequential failure of the previous ones. Methods. We evaluated 66 patients with CML, resistant/intolerant to Imatinib and treated with Dasatinib or Nilotinib, then switched to a third- line TKI after treatment failure. Of these, 29 patients were treated with dasatinib after imatinib/nilotinib failure and 37 with nilotinib after imatinib/dasatinib failure. Patients were monitored with complete blood counts, cytogenetic analysis, bone marrow aspiration RT-PCR and mutational analysis. Results. A total of 66 patients (median age 63 years, range, 33–85 years) were treated with sequential TKIs; 40 (61%) patients had received interferon-a before starting Imatinib; 26 (39%) patients received imatinib as first line therapy. The median time on imatinib therapy was 47.5 months (range 4–101 months). At the start of nilotinib as second line, 27/29 (93%) patients were in CP, 1 (3.5%) in AP, and 1 (3.5%) in BP. 9 patients (31%) had developed mutations before starting treatment. The median time on second line TKI was 8 months (range 2–36 months). In the resistant patients 4 new mutations were identified (F359V in two patients, T315I, Y253H+F359V). At the start of dasatinib as second line, 33/37 (89.2%) patients were in CP, 4 (10.8%) in AP. 7 patients (18.9%) had developed mutations before starting treatment. The median time on second line TKI was 14 months (range 4–59 months).In the resistant patients 5 new mutations were identified (F137L in three pts, M318T, M244V+F317L). At the start of the third TKI, 60/66 (90.9%) patients were in CP, 5 (7.6%) in AP, and 1 (1.5%) in BP. Of these, 7 patients (18.9%) on dasatinib and 7 (24.1%) on nilotinib had mutations before starting treatment. The best response to the third line treatment with TKI was 10 (15.2%) MMR, 10 (15.2%) CCyR, 8 PcyR (12.1%), 5 (7.5%) mCyR, 24 (36.4%) CHR and 9 (13.6%) No Response (NR). In the dasatinib group, 9 (31%) patients discontinued treatment because of toxicity versus 17 (45.9%) patients in the nilotinib group.Two new mutations (F317L, E255V) emerged with dasatinib as third line therapy.After a median follow up of 13 months (range 2–37 months) 50 patients (48 CP, 2 AP) are continuing therapy (33 on nilotinib, 17 on dasatinib).Since the start of the third TKI, 61 patients (92.4%) are still alive for a median overall survival of 110 months (range 15–300) (52 CP, 7 AP, 2 NA); the 5 deaths (7.6%) were caused by disease progression and spread of the gene mutation T315I. Discussion. In our study, about one third of patients derived benefit from the use of three sequential TKIs; patients with better, longer response (28.7%) to third TKI were the same patients with a better response to the Imatinib and 2TKIs therapy. All these patients had taken interferon therapy before the Imatinib. In this subset of patients (good responders: CCyR and MMR) 5 patients developed mutations that were sensitive to the sequential treatment.The lack of a durable cytogenetic remission could be explained by the emergence of new kinase domain mutations as patients are exposed to sequential TKI; a change of therapy resulted in an adequate response. In our series, patients with poor prognosis showed mutations not sensitive to the TKIs treatment. Conclusions. Although allogeneic SCT is the treatment of choice in all patients failing 2 TKIs who are suitable candidates for this approach, alternative strategies are required for ineligible patients. The use of a third TKI after failure of two previous TKIs induces response in some patients. Longer follow up of a larger series of patients is needed to determine the long term impact of the response. Disclosures: No relevant conflicts of interest to declare.

Rituximab In Allogeneic Hematopoietic Stem Cell Transplantation for Advanced Chronic Lymphocytic Leukemia with Fludarabine + Total Body Irradiation Conditioning: Results of a Phase II Prospective Multicenter Study (ITAC 02-02)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3520-3520
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Stephane Morisset ◽  
Mohamad Mohty ◽  
Gerard Socie ◽  
...  
Keyword(s):  
Median Time ◽  
Total Body Irradiation ◽  
Cumulative Incidence ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Lymphocytic Leukemia ◽  
Positive Trend ◽  
Hematopoietic Stem ◽  
Total Body

Abstract Abstract 3520 Background: CLL remains incurable with standard therapies. Myeloablative allogeneic SCT (allo-HSCT) is still associated with high TRM and few late relapses. Recently, the major focus of transplantation in CLL has been with reduced-intensity conditioning (RIC) allo-HSCT, which is applicable to the more elderly patient population and which attempts to exploit the graft-versus-leukemia (GVL) effect that was proved in CLL Objective: To evaluate the efficacy and toxicity a RIC regimen including fludarabine and total body irradiation (TBI) with the introduction of rituximab for allo-HSCT in patients with a CLL stage B or C diagnosis. Materials and methods: This prospective study included adult CLL patients with age < 65 years in stage B or C in response after a salvage treatment either following at least 2 treatment lines (1 including fludarabine) or after a progressive disease after auto-HSCT, having a HLA identical sibling donor and a good performance status (Karnfosky >70%). Donors were mobilized by G-CSF and in case of collection failure, bone marrow aspiration was authorized. The conditioning included: rituximab 375mg/m2 on day -5, fludarabine 30 mg/m2 from day-4 to day-2, TBI 2grays (6-7 cGrays/minute) on day 0 and rituximab 500mg/m2 on day1 and day8. GVHD prophylaxis used cyclosporine A (IV 3mg/kg/day) from day-2 and mycomofetil fenolate oral (2g/day) from day 1. Results: Between April 2003 and December 2008, 40 patients were included, 34 (85%) males and 6 females with a median age of 54 years (35-65), 38 (95%) were in B stage at diagnosis and 2 in stage C. Among 23 explored for cytogenetics, 8 were abnormal (3 del17, 1 trisomy12, 1 t(8-11) & 1 del13). Before transplantation, 17 patients received 2 lines treatment, 10 three lines, 5 four lines, and 8>4. Only 1 patient received a previous auto-HSCT. Among 18 explored for Matutes status, 1 was in score 1, 1 in score 2, 3 in score 3, 5 in score 4 & 9 in score 5. At time of allograft, 7 (17%) patients were in complete response (CR), 29 (73%) in partial response (PR) and 4 (10%) < PR. For sex-matching, 59% were mismatched (27%of them were F>M). For ABO matching, 68% were compatible, 19% major incomp. & 13% minor incopm. The median interval diagnosis-allo-HSCT was 58 months (6-177). Median CD34+ number was 7.64 (3.1-18.7). Seven (17%) patients did not receive rituximab during conditioning because the protocol did not include it at the beginning and has been amended later. Thirty-nine (98%) patients engrafted with a median time to neutrophils recovery of 20 days (11-70), 79% of patients reached a total donor chimerism at day 90. Seventeen patients developed aGVHD grade ≥II (8 grII, 8 grIII & 1 grIV) with a cumulative incidence at 3 months of 44% (36-52). The cumulative incidence of cGVHD was, at 12 months: 29% (21-36) for limited and extensive; at 18 months: 32% (24-40) limited and 42% (34-50) extensive. After a median follow-up of 28 months (3-71), the median OS was not reached with 3 and 5-years probability of 55%(41-74). The median time of EFS was 30 months (15 - 70) with a 5-years probability of 46%(33-66). The cumulative incidence of relapse at 1 and 3 years was 17% (11-23) and 22% (15-29) respectively. The cumulative incidence TRM at 1 and 3 years was 10% (5-15) and 27% (20-35) respectively. At the last follow-up, 17 patients died, 6 due to relapse and 11 due to TRM. We noticed a high severe infection rate (56%) and 4% of deaths related only to infection. The univariate analysis showed a positive trend of rituximab on OS and relapse, and a significant protective effect on aGVHD>=2 (p=0.02). The multivariate analysis studying age, interval diagnosis-allo-HSCT, ABO and sex matching, disease status at allo-HSCT, CD34+ number, and rituximab, showed a positive significant impact of this last factor (rituximab) on OS and EFS [HR=0.1 [0-0.6] p=0.02 & HR=0.1[0-0.4] p=0.035 respectively]. Conclusion: We showed interesting results in terms of OS, relapse and TRM in patients with advanced CLL after Fludarabine/TBI allo-HSCT. The introduction of rituximab allowed a better outcome especially a significant reduction of incidence and severity of acute GVHD. Nevertheless there was still a high incidence of cGVHD, already known following the Fludarabine/TBI conditioning, leading us to propose either to increase the number of rituximab injections after allo-HSCT, or to test Fludarabine/busilvex/ATG associated to rituximab. Disclosures: No relevant conflicts of interest to declare.

PET -CT Adapted Therapy After 3 Cycles of ABVD for All Stages of Hodgkin Lymphoma. Preliminary Results in 193 Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1619-1619 ◽  
Author(s):  
Astrid Pavlovsky ◽  
Isolda Fernandez ◽  
Virginia Prates ◽  
Miguel A Pavlovsky ◽  
Lucia Zoppegno ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Progressive Disease ◽  
Conflicts Of Interest ◽  
Statistical Significance ◽  
Cell Transplant ◽  
Bulky Disease ◽  
Radio Therapy ◽  
Anatomic Reduction ◽  
Pet Ct

Abstract Abstract 1619 Background: Positron emission tomography using 18F-fluoro-2-deoxy-d-glucose (FDG-PET-CT) is an important tool for treatment response assessment in Hodgkin Lymphoma (HL) treated with ABVD. It can predict response and overall outcome. The negative predictive value for PET-CT in patients (pts.) with HL is 90–94%. New recommendations define complete remission (CR) for HL as the lack of signs and symptoms of lymphoma with a negative PET-CT. OBJECTIVES: Reduce therapy in pts. who achieve early CR with negative PET-CT. Intensify treatment, only in pts. with positive PET-CT after 3 cycles of ABVD. Achieve CR, event free survival (EFS) and overall survival (OS), as good as in our historical control, when we used 3 or 6 cycles of ABVD plus involved field radio therapy (IFRT) in all pts.(LH-96) PATIENTS AND METHOD: Since October 2005, 200 newly diagnosed pts. with HL have been included in a prospective multicenter clinical trial (LH-05) All pts. received 3 cycles of ABVD and were then evaluated with a PET-CT (PET-CT +3) Pts. with a negative PET-CT+3 and absence of other signs or symptoms of lymphoma were considered in CR and received no further therapy. Pts with more than 50% of anatomic reduction of initial masses but persistent hyper metabolic lesions were considered in partial response (PR) and completed 6 cycles of ABVD and IFRT on PET-CT positive areas. Pts with less than PR received high doses of chemotherapy and an autologous stem cell transplant (ASCT). All pts were re-evaluated at the end of treatment with a new PET CT. One hundred and ninety three pts. have been evaluated. The median age at diagnosis was 29 years. One hundred and twenty five (65%) had localized stage (I-II) non bulky and 68 (35%) presented with advanced stage (III-IV), or bulky disease, 33 (17%) had bulky disease. RESULTS: One hundred and forty-eight (77%) achieved CR with negative PET-CT + 3. Forty-five (21%) were PET-CT+3 positive, 5 showed progressive disease. The other 40 pts. were in PR and completed a total of 6 ABVD + IFRT in PET-CT positive areas. Twenty eight achieved CR and 12 persisted with hypermetabolic lesions. Three died of progressive disease. After finishing planned treatment 178 pts. (92%) were in CR. With a median follow up of 39 months the EFS and OS at 36 months is 80% and 97% respectively. Patients with negative PET-CT +3 have an EFS of 86% compared to 61% for pts. with positive PET-CT+3 (P=0,001). We perform a multivariate analysis for EFS which included age, stage, IPS, bulky disease, extranodal areas and the result of the PET –CT+ 3. This last parameter together with age were the only ones with statistical significance (p=0.001 and 0.046 respectively). When comparing the results LH-05 with LH-96 there is no difference in EFS and OS at 36 months (83% vs. 85% and 97 vs. 96%) but in LH-05 only 23% received 6 cycles of ABVD and IFRT compared to 61% and 100% in LH-96. This reduces the exposure to chemo and radiotherapy. CONCLUSION: With PET-CT adapted therapy after 3 cycles of ABVD, 148 pts.(77%) received only 3 cycles of ABVD as initial therapy with an EFS and OS of 80% and 97% at 36 months. In the Cox regression model, PET-CT at completion of treatment was the most significant factor associated to EFS. In this interim analysis of PET-CT adapted therapy to all stages of HL, treatment with 3 cycles of ABVD can be adequate for pts. with negative PET-CT+3. Continuing with ABVD after a positive PET-CT +3 can be considered insufficient. A longer follow-up and a larger number of pts. are necessary to confirm these results. Disclosures: No relevant conflicts of interest to declare.

Impaired Precursor B-Cell Maturation/Production In The Bone Marrow: Association With Molecular and Immunophenotypic Markers Of Myeloid Dysplasia In Suspected Low-Grade MDS

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4943-4943
Author(s):  
Charles Repetti ◽  
Hsueh-Hua Chen ◽  
Yongbao Wang ◽  
Vanessa A Jones ◽  
Albert K Ho ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
B Cells ◽  
B Cell ◽  
Somatic Mutation ◽  
Conflicts Of Interest ◽  
Statistical Significance ◽  
Sequence Variant ◽  
Low Grade ◽  
Precursor B Cells

Abstract Rationale Myelodysplastic syndromes (MDS) are clonal stem cell disorders that disrupt orderly maturation of multiple hematopoietic lineages. Several studies have suggested that maturation of precursor B cells (hematogones) is also abnormal in MDS. As a result, the presence of normal numbers or increased precursor B cells in bone marrow (BM) is frequently used as a diagnostic feature arguing against a diagnosis of MDS. We compared the presence of myeloid-associated gene mutations and myeloid maturation abnormalities with qualitative and quantitative precursor B cell findings in BM samples submitted for workup of cytopenias or MDS. Methods Seventeen BM aspirate samples with <5% blasts submitted for cytopenia or MDS evaluation were compared with 10 samples having 5% or more blasts and changes diagnostic of MDS or AML. Mutation analysis was performed on genomic DNA using a targeted exome sequencing assay. This assay employs a TruSeq custom amplicon design on the MiSeq platform (Illumina, San Diego, CA). The assay covers the commonly mutated areas of 19 myeloid-associated genes. Somatic mutation status was assigned based on mutation levels, previous association with myeloid neoplasia, and no prior identification in public or internal databases as a normal sequence variant. Flow cytometry using 6-color (CD19/CD34) and 8-color (CD19/10) formats was used to assess lymphoblasts; CD34/13 was used to assess myeloblasts; and CD11b, CD13, CD16, and CD38 were used to assess abnormalities in myelopoiesis. Results  Among the 17 BM samples submitted for cytopenia or MDS evaluation that had <5% blasts, 7 (41%) had immunophenotypic myeloid maturation abnormalities. Ten (59%) of the 17 cases had at least one myeloid-associated somatic mutation, with TET2 and ASXL1being the most commonly mutated genes. The ratio of myeloblasts to B-lymphoblasts, calculated using either CD10 or CD19, was >10:1 in 10/17 (59%) cases. Nine of the 17 (53%) cases had virtually no precursor B cells detected. Discrete abnormalities in more mature myeloid forms were seen in 7/10 (70%) cases with low numbers of B-lymphoblasts but in none of the 7 cases with significant numbers of B-lymphoblasts. MDS-associated mutations were more common in cases with rare B-lymphoblasts (7/9) than in those with higher percentages of precursor B cells (3/8), but the difference did not reach statistical significance (P = 0.15).  Genes mutated in the group with B-lymphoblasts present included ASXL1 (3 cases), DNMT3A (2), TET2 (1) and TP53 (2). Two of these mutated cases presented with isolated thrombocytopenia. By comparison, myeloblast/lymphoblast ratios were >50:1 in all 10 unequivocal MDS/AML samples (>5% blasts); 8 (80%) of these cases had MDS-associated mutations, and 4 (50%) had mutations in multiple genes. Conclusions Decreases in BM precursor B cells in cases of possible low-grade MDS were usually, but not always, associated with the presence of MDS-associated mutations. However, cases with normal or increased precursor B cell numbers also showed MDS-associated mutations although immunophenotypic evidence of myeloid maturation abnormalities was not seen in this group. The identification of a subgroup of cytopenic patients with likely pathogenic mutations in bone marrow precursors but minimal phenotypic evidence of myeloid dysplasia may indicate clonal abnormalities primarily located outside the granulocyte or common stem precursor populations, e.g. restricted to the megakaryocytic lineage. Therefore, the presence of intact precursor lymphoblast and myeloid maturation by higher-dimensional flow cytometry as a primary criterion to argue against a diagnosis of low-grade MDS needs further evaluation, especially when granulocytopenia is absent. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Dysfunction of CD27+IgD+B Cells Correlates With Aggravated Systemic Lupus Erythematosus

2021 ◽  
Author(s):  
wei zhang ◽  
YF Wang ◽  
Fanlei Hu ◽  
Fuai Lu ◽  
Tao Wu ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Statistical Significance ◽  
Systemic Lupus ◽  
Follow Up Study ◽  
Healthy Control ◽  
Natural Igm

Abstract Objective：The apoptotic signaling pathway is obviously disordered in systemic lupus erythematosus (SLE). Natural IgM (nIgM) is important in clearing apoptotic cells and preventing them from triggering deleterious autoimmunity. B-1- and innate-like B- (ILBs) cells are the main nIgM producers. Human CD27+IgD+B cells (un-switched memory B cells) are considered ILBs. However, their functional properties in SLE remain undefined.Methods：Peripheral blood samples of 50 SLE patients and 50 healthy control were collected, and twelve SLE patients were assessed in a follow-up study. The amounts of CD27+IgD+ B cell was analyzed by flow cytometry. The IgM and IL-10 levels of CD27+IgD+ B cell were assessed by ELISPOT and qRT-PCR. SPSS 17.0 (SPSS, USA) was employed for data analysis. P<0.05 indicated statistical significance.Result：92.0% were females, 17-67 years. CD27+IgD+B cell amounts are significantly decreased in SLE patients than healthy control (p<0.01). CD27+IgD+B cell amounts were positively correlated with WBC(r=0.337, p=0.017), platelet count(r=0.396, p=0.004) and serum C3 levels(r=0.415, p=0.003), CD27+IgD+B cell amounts showed negative correlations with serum creatinine levels(r=-0.285, p=0.045), SLEDAI(r=-0.724, p=0.000), anti-dsDNA(r=-0.477, p=0.000) and CRP(r=-0.398,p=0.004). The IgM and IL-10 levels of CD27+IgD+B in SLE were decreased than healthy control (p<0.001), moreover CD27+IgD+B cells are increased in SLE cases after treatment in SLE patients than before treatment(p<0.001).Conclusion：CD27+IgD+B cell amounts are significantly decreased and it was correlated with clinical and immunological features in SLE patients. CD27+IgD+B cells had impaired function regarding IgM and IL-10 production in SLE, however, CD27+IgD+B cells amounts are recovered in SLE cases with treatment-related disease remission.

scholarly journals LB6. EDP-938, a Novel RSV N-Inhibitor, Administered Once or Twice Daily Was Safe and Demonstrated Robust Antiviral and Clinical Efficacy in a Healthy Volunteer Challenge Study

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S995-S995 ◽  
Author(s):  
Eoin Coakley ◽  
Alaa Ahmad ◽  
Kajal Larson ◽  
Ty McClure ◽  
Kai Lin ◽  
...  
Keyword(s):  
Viral Load ◽  
Conflicts Of Interest ◽  
Statistical Significance ◽  
Rt Pcr ◽  
Nasal Wash ◽  
Double Blind ◽  
Challenge Study ◽  
Populations At Risk ◽  
Financial Relationships

Abstract Background Respiratory syncytial virus (RSV) represents an important global health challenge with significant morbidity and mortality in infants, elderly, and immunocompromised adults. No effective therapy is currently available. EDP-938 demonstrates potent in vitro activity against RSV Subtypes A and B. We report data from EDP 938-101, a double-blind, placebo-controlled, Phase 2a study that evaluated EDP-938 in adult volunteers inoculated with RSV-A Memphis 37b. Methods Subjects were healthy volunteers, 18–45 years, who were sero-suitable (i.e., lower 25th percentile). After RSV inoculation on Study Day 0, subjects had 12 hourly nasal wash monitored for RSV infection by qualitative RSV RT–PCR. On Study Day 5 or previously if qualitative RT–PCR was RSV+, subjects were randomized to receive 5 days of EDP-938 600 mg once daily (QD arm) or 500 mg loading dose then 300 mg twice daily (BID arm), or placebo twice daily. Assessments included 12 hourly nasal wash for quantitative RSV viral load, 8 hourly RSV Total Symptom Scoring (TSS) and daily mucus weights. Safety assessments were continued though Day 28 (last follow-up). The primary endpoint was the RSV viral load area under the curve (AUC) from first dose through Day 12 among RSV-infected subjects, defined as the Intent To Treat-Infected (ITT-I) population. The study was fully powered for both RSV viral load and TSS endpoints. Results A total of 115 subjects were randomized and inoculated; 86 were included in the ITT-I analysis. The primary and secondary efficacy endpoints were achieved with high statistical significance in QD and BID arms (figure and table). Among EDP-938 recipients all adverse events (AEs) were mild except for a single AE of moderate dyspepsia in the BID arm and events of moderate headache (n = 2) and hypoacusis (n = 1) in the placebo arm. All AEs resolved in follow-up. Conclusions In the RSV Challenge study, EDP-938 administered once or twice daily achieved primary and key secondary endpoints with robust reductions in RSV viral load (by both qRT–PCR and plaque assays), symptom scores and mucus weights. These data support the further clinical evaluation of EDP-938 in populations at risk of severe RSV disease. Disclosures Eoin Coakley, MD, Enanta Pharmaceuticals (Employee), Alaa Ahmad, PhD, Enanta Pharmaceuticals (Employee), Kajal Larson, PhD, Enanta Pharmaceuticals (Employee), Ty McClure, PhD, Enanta Pharmaceuticals (Employee), Kai Lin, PhD, Enanta Pharmaceuticals (Employee), Kursten Tenhoor, n/a, Enanta Pharmaceuticals (Consultant), Kingsley Eze, n/a, hVIVO Services Ltd. (Employee), Nicolas Noulin, PhD, No financial relationships or conflicts of interest, Veronika Horvathova, MBChB, MSc, hVIVO Services Limited (Other Financial or Material Support, Employed by hVIVO during the conduct of the study), Bryan Murray, MBBS, No financial relationships or conflicts of interest, Mark Baillet, PhD, S-CUBED (Employee), Julie Mori, PhD, hVIVO (Employee, Shareholder) Nathalie Adda, MD, Enanta Pharmaceuticals (Employee).

HAART Does Not Improve the Outcome of HIV-Related Multicentric Castleman Disease: Results of a Multicentric Retrospective Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4918-4918 ◽  
Author(s):  
Chiara Cattaneo ◽  
Emanuela Vaccher ◽  
Alessandro Re ◽  
Salvatore Casari ◽  
Erika Borlenghi ◽  
...  
Keyword(s):  
Median Time ◽  
Conflicts Of Interest ◽  
Primary Effusion Lymphoma ◽  
Case Series ◽  
Central Nervous System Lymphoma ◽  
Castleman Disease ◽  
Time Interval ◽  
Female Ratio ◽  
Multicentric Castleman Disease

Abstract Abstract 4918 Background. Multicentric Castleman Disease (MCD) is a rare lymphoproliferative disorder, strictly related to Kaposi Sarcoma (KS) as both associated to HHV-8 infection. Like other HIV-related diseases, such as Non Hodgkin Lymphoma (NHL) and Primary Central Nervous System Lymphoma, MCD prevalence is known to be increased in HIV-pos subjects. However, limited case series among this subset of patients (pts) are reported and data regarding epidemiological variations in the pre and post HAART era are often non conclusive. In order to evaluate possible differences between pre- and post-HAART era, we retrospectively evaluated epidemiological and clinical characteristics of all pts affected by HIV-pos MCD afferent to two Italian Institutions. Patients and Methods. Data concerning biological, clinical and prognostic factors of HIV-pos MCD pts were collected and reported on a database. Pts were grouped according to the date of diagnosis in pre- (before 1997) and post-HAART (after 1997) era. Results. During a 21-year period (1990-2011), 35 HIV-pos MCD pts were observed at our Institutions, nine in the pre- and 26 in the post-HAART era. Male/Female ratio was 30/5; median age 37y (23-65). Histological subtype in 34 evaluable cases was hyaline-vascular in 6, plasmacytic in 20 and mixed cellularity in 8. Median time interval from HIV-pos detection to MCD diagnosis was 24 months (range 0–157) and CD4 count at MCD diagnosis 233/mcL (26-839). All these MCD baseline characteristics were not statistically different between pre- and post-HAART era. A concomitant diagnosis of KS was made in 18/35 (51.4%) cases, all but one in the post-HAART era. NHL was diagnosed concurrently with MCD in 2/35 (5.7%) pts (1 Primary Effusion Lymphoma, PEL, and 1 Plasmablastic Lymphoma, PBL); in 8/35 (22.8%) cases NHL developed after MCD diagnosis (2 PEL, 1 PBL, 2 Diffuse Large Cell, DLC, 1 unspecified, respectively). Median time from MCD to NHL was 19 mo (0-71). Evolution toward NHL was observed in 3 (33%) cases in the pre-HAART era and in 5 (19%) in the post-HAART era (p=0.39, Fisher's exact test). Six pts did not receive any type of treatment, 6 were treated with HAART only and 23 with different therapies, including antivirals, steroids, chemotherapy and rituximab (alone in 1 pt, in combination with chemotherapy in 5). Nineteen/23 pts received HAART together with other therapies. Two pts treated with rituximab developed NHL (1 PEL and 1 DLC). A complete or partial radiological response, together with clinical improvement was observed in 19/25 of evaluable pts (76%). Thirty pts were evaluable for relapse/progression, mainly in the post-HAART era. Overall, 19/30 pts showed MCD progression or transformation to NHL; median PFS was 15 months. Nineteen pts died and 5 were lost to follow-up. Overall survival (OS) of the entire series was 28 months, without significant differences between pre and post-HAART era (18 and 28 months, OR 0.643 [CI 0.2406–1.045], median follow-up 18 and 9 months, respectively). Causes of death were evaluable in 18 cases: NHL (7), MCD (6), opportunistic infections (1), liver cyrrhosis (1), acute myocardial infarction (1), KS (1) and therapy-related toxicity (1). NHL and MCD were the most frequent cause of death in the post-HAART era (4 and 5 of the 10 cases, respectively). Although no differences in OS between MCD pts without or with NHL were seen (19 vs 28 months, OR 0.6786 [CI 0.2763–1.081], median follow-up 13 and 23 months, respectively), eight/10 pts with NHL died, in comparison with 11/21 pts without NHL evaluable for outcome and median time from NHL diagnosis to death was 2 months (0-31). Conclusions. Our data confirm that the prognosis of HIV-related MCD remains poor even after the advent of HAART. Unlike other lymphoproliferative disorders, HAART did not impact on outcome of HIV-related MCD, suggesting that MCD can “escape” immune reconstitution. A concomitant diagnosis of NHL and uncontrolled MCD seem to be the main reason for an unfavourable outcome, particularly in the post-HAART era. New therapeutic approaches, including rituximab, should therefore aim at avoiding NHL transformation and controlling “MCD-related cytokine storm”. Disclosures: No relevant conflicts of interest to declare.

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