Short-term absolute B-cell counts monitoring in systemic sclerosis patients treated with rituximab

Objective. To evaluate B-cell counts in circulation of SS patients prior to initiation and one year after completion of RTM therapy.Subjects and methods. The study included 71 patients. Median follow up was 13,2±2,0 months (11-18 Mo.). Average cumulative RTM dose during the follow up period was 1,43±0,60 g, with 48 patients receiving < 2 g RTM (Group 1, mean dose 1,1±0,1 g) and 23 patients receiving ≥ 2 g RTM (Group 2, mean dose 2,2±0,6 g). CD19+ lymphocyte counts in peripheral blood were determined using flow cytometry in PSS patients and 20 healthy volunteers matched by sex and age. In SS patients B-cell counts were obtained before initiating RTM, within first month after first administration, then after 6 months and at the end of this study.Results. Baseline absolute and proportional В-lymphocyte counts in peripheral blood was almost similar in SS patients and healthy subjects. Highest counts were observed in SS patients with <3 years disease duration, showing inverse correlation between baseline absolute (R – 0,36, р=0,003) and proportional (R – 0,48, р=0,001) B cell counts and duration of the disease. Complete B-cell depletion from peripheral circulation was documented one month after RTM administration. It persisted in 79% 6 months later, although initiation of B- cell repopulation was documented in some patients. In one year after RTM initiation В-cell counts were significantly lower than at baseline. Complete or partial depletion was still there in the majority of patients with normal counts achieved only in 10% of SS patients. Inverse correlation was found between absolute B-cell count and cumulative RTM dose (R=-0,237, p=0,048).Conclusion. Higher RTM doses resulted in more pronounced В-lymphocytes depletion and more evident improvement of lung function. Current state of practice requires further research to identify most optimal regimens in the context of personalized therapy for SS and other immune-mediated inflammatory diseases.

Download Full-text

Allotransplantation with Reduced Intensity Conditioning Regimens Modified To Lessen Transplant-Related Mortality Is a Useful Treatment for High-Risk Myeloid Diseases.

Blood ◽

10.1182/blood.v106.11.5328.5328 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5328-5328

Author(s):

Carolyn L. Bigelow ◽

Stephanie L. Elkins ◽

Cheryl L. Hardy ◽

Joe C. Files

Keyword(s):

High Risk ◽

Cord Blood ◽

Peripheral Blood ◽

Conditioning Regimens ◽

Group 3 ◽

Group 2 ◽

One Year ◽

Reduced Intensity ◽

Group 1

Abstract Our stem cell transplant program treats a spectrum of hematologic malignancies that includes a number of patients with high risk myeloid disease. These challenging patients have lead our adult allotransplant program to employ alternative approaches to standard conditioning over the last three years using reduced intensity conditioning. The regimens are amenable to modification, allowing a goal of maximizing length of remission or period of low tumor burden while minimizing transplant-related mortality. We have conducted a retrospective study of patients receiving modified reduced intensity regimens of fludarabine, melphalan and Campath. Incidence of relapse, survival, tempo of engraftment and incidence of grades I–II and III–IV acute GVHD were compared. Three modifications of the regimen were: fludarabine 30 mg/m2 x 5d, melphalan 140 mg/m2 x 1d, Campath 20 mg/d x 5 days (Group 1); fludarabine and melphalan the same and Campath 20 mg/d x 3d (Group 2); fludarabine and melphalan the same and Campath 20 mg/d x 1d (Group 3). Fifteen patients with a median age of 48, range 24 to 58 years, were in the study. Twelve patients had AML, two had CML and one had MDS. Six patients were in CR at time of transplant and nine had detectable tumor or disease. Patients were not randomized for a conditioning group but were transplanted in a consecutive fashion; seven patients were in Group 1, five patients in Group 2 and three patients in Group 3. Stem cell sources were related BM for four recipients, related peripheral blood for one, unrelated BM for four, unrelated peripheral blood for four, a combination of related BM and peripheral blood for one, and one cord blood. All patients received an adequate CD34+ cell dose and none of the products was manipulated. Match grade was 6/6 for 13 transplants, 5/6 for one and 4/6 for the cord blood transplant. GVHD prophylaxis was the same for all recipients (standard dose cyclosporine or tacrolimus and MMF) tapering after day 30. No failures to achieve a WBC graft, including the cord blood recipient, occurred. Neutrophils (ANC >500/dl) engrafted at a median of day 13 (range 10 – 48 days). Median follow-up was seven months (range 1.5 – 30 months). Two patients in Group 1 had grade I aGVHD and one continued to chronic GVHD. One patient in Group 2 had grade II and one had grade III aGVHD. None in Group 3 had aGVHD. Relapse occurred in three patients in Group 1 and they received DLI immunotherapy; no relapse occurred in Group 2 or 3. Twelve patients survived to day 100; three from Groups 1 or 2 did not. Four were alive at one year and four others who are still alive have not reached the one year mark. Four of the seven patients who have died were from residual disease; the other three were from treatment-related toxicity within the first 100 days. Eight of 15 patients remain in follow-up. We conclude that the application of fludarabine, melphalan, Campath conditioning regimens has been successful in this high risk group of patients. The cell source from an unrelated or related donor does not impact outcomes. There was a very low incidence of toxicity related to aGVHD, no failure to engraft and no unexpected complications. Lastly, this regimen has allowed modification to enhance its tumoricidal properties to the extent that these patients with myeloid disease have experienced a low 20% incidence of relapse. We will continue to modify and expand the patient selection criteria to elderly (< 70 years old) AML in remission.

Download Full-text

Reduced fluence corneal cross-linking in mild to moderate keratoconus: One year-follow-up

European Journal of Ophthalmology ◽

10.1177/1120672120966560 ◽

2020 ◽

pp. 112067212096656

Author(s):

Seyed Reza Ghaffari ◽

Saeed Khaheshi ◽

Fateme Alipour ◽

Somayye Mashhadi Farahani ◽

Amir-Hooshang Beheshtnejad ◽

...

Keyword(s):

Visual Acuity ◽

Eligible Patient ◽

Case Series ◽

Control Group ◽

Data Analyst ◽

Cell Counts ◽

Group 2 ◽

One Year ◽

And Control

Purpose: To evaluate the safety and efficacy of reduced fluence CXL (lower dose of UV-A irradiation) in mild to moderate keratoconus. Setting: Farabi Eye Hospital, Tehran, Iran. Design: Non-randomized prospective comparative interventional case series. Every eligible patient included in the study (mild to moderate progressive keratoconus) was randomly allocated to case (reduced fluence) and control (standard) groups, except for bilateral patients. In these patients the eye with more advanced disease was allocated to control group and the other eye was randomly assigned in either case or control group. Operators performing refraction and images and the data analyst were masked, but patients and physicians were not. Methods: Forty-six eyes of 38 patients were recruited. Group 1 received 7 min (fluence of 3.8 J/cm2), while group 2 received 10 min of 9 mW/cm2 UV-A (fluence of 5.4 J/cm2). Visual, keratometric and biomechanical outcomes were compared between groups. Results: At last follow-up (mean12 months, range 6–24 months), there were no statistically significant differences in changes in uncorrected visual acuity, best corrected distance visual acuity, Kmax, Kmean, corneal hysteresis, corneal resistance factor, endothelial cell counts, demarcation line depth, and intraoperative pain scores between groups (all p-values < 0.05). Conclusion: The results of this study show comparable one-year outcomes between 3.8 and 5.4 J/cm2 accelerated CXL in mild to moderate keratoconus. Should the results of this study be confirmed in longer follow-ups, using a reduced fluence setting could be considered as an alternative to standard treatment in these patients.

Download Full-text

CD19 Cell Count at Baseline Predicts B Cell Repopulation at 6 and 12 Months in Multiple Sclerosis Patients Treated with Ocrelizumab

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18158163 ◽

2021 ◽

Vol 18 (15) ◽

pp. 8163

Author(s):

Gianmarco Abbadessa ◽

Giuseppina Miele ◽

Paola Cavalla ◽

Paola Valentino ◽

Girolama Alessandra Marfia ◽

...

Keyword(s):

B Cell ◽

Cell Count ◽

Considerable Proportion ◽

Cell Counts ◽

Time Scheduling ◽

Magnetic Resonance Imaging Mri ◽

Multiple Sclerosis Patients ◽

Kinetics Of ◽

Cell Repopulation

Background: The kinetics of B cell repopulation in MS patients treated with Ocrelizumab is highly variable, suggesting that a fixed dosage and time scheduling might be not optimal. We aimed to investigate whether B cell repopulation kinetics influences clinical and radiological outcomes and whether circulating immune asset at baseline affects B cell repopulation kinetics. Methods: 218 MS patients treated with Ocrelizumab were included. Every six months we collected data on clinical and magnetic resonance imaging (MRI) activity and lymphocyte subsets at baseline. According to B cell counts at six and twelve months, we identified two groups of patients, those with fast repopulation rate (FR) and those with slow repopulation rate (SR). Results: A significant reduction in clinical and radiological activity was found. One hundred fifty-five patients had complete data and received at least three treatment cycles (twelve-month follow-up). After six months, the FR patients were 41/155 (26.45%) and 10/41 (29.27%) remained non-depleted after twelve months. FR patients showed a significantly higher percentage of active MRI scan at twelve months (17.39% vs. 2.53%; p = 0,008). Furthermore, FR patients had a higher baseline B cell count compared to patients with an SR (p = 0.02 and p = 0.002, at the six- and twelve-month follow-ups, respectively). Conclusion: A considerable proportion of MS patients did not achieve a complete CD19 cell depletion and these patients had a higher baseline CD19 cell count. These findings, together with the higher MRI activity found in FR patients, suggest that the Ocrelizumab dosage could be tailored depending on CD19 cell counts at baseline in order to achieve complete disease control in all patients.

Download Full-text

Pulsed Radiofrequency for Chronic Inguinal Neuralgia

January 2018 - Pain Physician ◽

10.36076/ppj/2015.18.e147 ◽

2015 ◽

Vol 2;18 (2;3) ◽

pp. E147-E155

Author(s):

Yasser M. Amr

Keyword(s):

Pain Relief ◽

Nerve Root ◽

Small Sample ◽

Pulsed Radiofrequency ◽

Group 2 ◽

One Year ◽

The One ◽

Inguinal Neuralgia ◽

Group 1

Background: Chronic inguinal neuralgia has been reported after inguinal herniorrhaphy, caesarean section, appendectomy, and trauma to the lower quadrant of the abdomen or inguinal region. Objectives: This study was designed to evaluate the efficacy of pulsed radiofrequency in management of chronic inguinal neuralgia. Study Design: Randomized, double-blind controlled trial. Setting: Hospital outpatient setting. Methods: Twenty-one patients were allocated into 2 groups. Group 1 received 2 cycles of pulsed radiofrequency (PRF) for each nerve root. In Group 2, after stimulation, we spent the same time to mimic PRF. Both groups received bupivacaine 0.25% + 4 mg dexamethasone in 2 mL for each nerve root. Visual Analogue Scale (VAS) was assessed. Duration of the first block effective pain relief was reported. Repeated PRF blockade was allowed for any patient who reported a VAS > 30 mm in both groups during the one year follow-up period. The number and duration of blocks were reported and adverse effects were also reported. Results: Significantly longer duration of pain relief was noticed in Group 1 (P = 0.005) after the first block, while the durations of pain relief of the second block were comparable (P = 0.59). In Group 1 the second PRF produced pain relief from the twenty-fourth week until the tenth month while in Group 2, pain relief was reported from the sixteenth week until the eighth month after the use of PRF. All patients in Group 2 received 3 blocks (the first was a sham PRF) during the one year follow-up period. Meanwhile, 2 PRF blocks were sufficient to achieve pain relief for patients in Group 1 except 4 patients who needed a third PRF block. No adverse events were reported. Limitations: Small sample size. Conclusion: For intractable chronic inguinal pain, PRF for the dorsal root ganglion represents a promising treatment modality. Key words: Radiofrequency, chronic, inguinal neuralgia

Download Full-text

Peripheral Blood CD3+CD4+ and CD3−CD56+ Cell Counts and Circulating Lymphoma Cells Are Significant Predictors of Overall Survival in Newly Diagnosed Follicular Lymphoma.

Blood ◽

10.1182/blood.v110.11.2607.2607 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2607-2607

Author(s):

Danielle Shafer ◽

Mitchell R. Smith ◽

Samuel Litwin ◽

Tianyu Li ◽

Hossein Borghaei ◽

...

Keyword(s):

Overall Survival ◽

Cell Count ◽

Peripheral Blood ◽

Lymphocyte Subsets ◽

Nk Cell ◽

Cd4 Count ◽

Newly Diagnosed ◽

Original Diagnosis ◽

Cell Counts

Abstract BACKGROUND: Interaction between the immune system and follicular lymphoma (FL) is well recognized from immunohistochemical as well as microarray studies, but is not yet fully elucidated. A recent report suggested that a higher absolute lymphocyte count (ALC) predicted a longer time to progression and improved response to rituximab in FL (Behl et al, Br J Haem2007). The GELA group reported a correlation between peripheral blood natural killer cell count and event free survival in diffuse large B cell lymphoma (Plonquet et al Ann Oncol2007). The influence of lymphocyte subsets in the peripheral blood (PB) on FL outcome has not been reported. PATIENTS AND METHODS: We retrospectively analyzed the immunophenotype from peripheral blood flow cytometry (PBFC) at Fox Chase Cancer Center in FL patients (pts). We identified 127 pts (82 newly diagnosed and 45 previously treated). We recorded the presence or absence of circulating monoclonal B cells (CLC) and survival in all as well as a complete PBFC panel in > 90% of pts. FLIPI and IPI scores were calculated from data at the time of diagnosis. Overall survival and time to treatment from date of original diagnosis and from date of PBFC were analyzed in relation to ALC, CLC, the lymphocyte subsets CD3+CD4+, CD3+CD8+, CD3−CD56+/CD16+ (NK cells) and FLIPI and IPI scores. A low CD4 count was defined as <500 cells/mm3, a low NK cell count as <150 cells/mm3 and a low ALC as <1500 cells/mm3. RESULTS: There were 63 females and 64 males; median age at presentation was 56 yrs (range 31–88). Median follow up intervals from original diagnosis and from PBFC were 46 months (range 3.5 – 207) and 24 months (range 0.7–138), respectively. This abstract deals principally with the 82 newly diagnosed pts. Median follow up in the newly diagnosed subset was 27.8 months (range 0.7 to – 138); thirty-five pts were subsequently treated, and 47 pts remained under observation. FLIPI scores at diagnosis were: low - 48 pts, intermediate - 25, high - 7 and unknown - 2. IPI scores were: low - 52 pts, low-intermediate - 24, high-intermediate/high - 4 and unknown - 2. CLC were present in 21% of pts. At last follow up, 74 pts were still alive. By univariate analysis, the most significant predictors for inferior overall survival (OS) from time of PBFC were low CD4 count (P = 0.03), low NK cell count (P = 0.02), and presence of CLC (P = 0.03). There was insufficient power for significance in multivariate analysis. At last follow up, survival for the low vs. high CD4 and NK cell groups was 85% vs. 97% and 85% vs.98%, respectively. FLIPI and IPI scores, low ALC, and low CD8 did not correlate with OS from time of diagnosis or time of PBFC. With respect to time to initial treatment, only a low ALC (P<0.001) and FLIPI (P<0.001) were significant. In multivariate analysis for OS of all 127 pts, low NK cell count remained significant (P = 0.03), while low CD4 count was marginally significant (P = 0.08). CONCLUSION: Analysis of PB lymphocytes by PBFC has prognostic value in previously untreated FL pts. Low CD4 and NK cell counts as well as the presence of CLC are the most significant predictors for OS in newly diagnosed FL. Our findings suggest the importance of an intact immune system. They merit further prospective studies to ascertain the impact of treatment on subsets of pts with specific immunophenotypes and may prove useful in FL management.

Download Full-text

Effect of T-Cell Dose On Outcomes After Peripheral Blood Allogeneic Hematopoietic Cell Transplantation in Hematological Malignancies.

Blood ◽

10.1182/blood.v114.22.1171.1171 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1171-1171

Author(s):

Abraham S Kanate ◽

Farhad Khimani ◽

Aaron Cumpston ◽

Kathy Watkins ◽

Sonia Leadmon ◽

...

Keyword(s):

T Cell ◽

Peripheral Blood ◽

Hematological Malignancies ◽

Acute Gvhd ◽

Hematopoietic Cell ◽

Cell Dose ◽

All Cause Mortality ◽

Cd8 Cell ◽

One Year

Abstract Abstract 1171 Poster Board I-193 Purpose: Peripheral blood allogeneic hematopoietic cell transplant (HCT) is used to treat various types of hematological malignancies. Current knowledge supports that increased CD34 + cell dose in the infusate is associated with earlier leukocyte recovery. The dose of CD3 +, CD4 + and CD8 + cells is largely disregarded except in T-cell depleted transplant. The correlation between various cell doses and outcomes is an area of great interest in HCT. Our analysis focuses on the impact of T-cell subset dosing, on outcomes after HCT, such as acute graft versus host disease (GVHD) and mortality. Methods: Retrospective analysis was conducted on 134 consecutive patients who underwent peripheral blood allogeneic HCT for various hematological malignancies in our institution between January 2003 and December 2008. Statistical analysis was performed using SPSS 15.0. The Chi - square test was used to determine any association between cell doses and the incidence of acute GVHD and all-cause mortality at one year of follow-up after transplant. Results were also compared with the association between CD3+ and CD8+ cell doses and incidence of acute GVHD as reported in 2007 by our institution. Results: A total of 134 patients were included in our analysis, consisting of 49 females and 85 males. The median age was 49 years (range 17-69). HCT was from matched related donors in 68 and from matched unrelated donors in 66 patients. A variety of conditioning regimens were used in preparation for the HCT. Overall survival at 1 year of follow-up was 60%, the incidence of acute GVHD was 52%, and chronic GVHD was 29%. All-cause mortality at one year follow up was found to be significantly higher when the CD3+ cell dose was < 30.5 × 107/kg IBW (49% vs. 29%, P = 0.018). All-cause mortality was also significantly increased when CD8+ cell dose was < 9.2 × 107/kg IBW (50% vs. 33%, P= 0.05). A CD8+ cell dose of < 9.2 × 107/kg IBW was also associated with an increased risk of grades 2-4 acute GVHD (48% vs. 22%, P = 0.026). There was no association of statistical significance between CD3+ and CD4+ cell doses and the incidence of acute GVHD. Conclusion: The data suggests a statistically significant inverse association between mortality and CD3+ cell dose of <30.5 × 107/kg IBW. A CD8+ cell dose of <9.2 × 107/kg IBW was also associated with increased all-cause mortality and acute GVHD (grades 2-4). Our institution reported in 2007, a significant association between the incidence of acute GVHD (grades 2-4) and CD3+ cell dose < 33.5 × 107/kg IBW and CD8+ cell dose of < 6.2 × 107/kg IBW, based on series of 66 patients. As we increased the sample size to 134, the association between CD3+ cell dose and acute GVHD was no more present. We conclude that T-cell dose is an important factor in terms of outcomes after all allogeneic HCT irrespective of preparative regimen. T-cell subsets likely play a pivotal role in transplant results, though it is not well described. Analysis of larger databases is required to substantiate our results. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Risk Adjusted Management of Newly Diagnosed High and Intermediate FLIPI Follicular Lymphoma Using (90)Y Ibritumomab Tiuxetan

Blood ◽

10.1182/blood.v128.22.1794.1794 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1794-1794

Author(s):

Neil L Berinstein ◽

Nancy M Pennell ◽

Rashmi Weerasinghe ◽

Matthew C. Cheung ◽

Eugenia Piliotis ◽

...

Keyword(s):

High Risk ◽

Follicular Lymphoma ◽

B Cell ◽

International Prognostic Index ◽

Prognostic Index ◽

Newly Diagnosed ◽

Ibritumomab Tiuxetan ◽

Cell Counts ◽

Post Therapy

Abstract Background: Although the natural history of follicular lymphoma is indolent with a median overall survival of about 12-15 years, the disease is heterogeneous. The 5 and 10 year overall survival (OS) of low, intermediate and high risk FLIPI is 91%, 78% and 53% and 71%, 51% and 36% using standard rituximab-based treatment. 5-year progression-free survival (PFS) is 80%, 70% and 48% respectively. Methods: Based upon this we conducted an investigator-initiated single-centre Phase II trial of intensified therapy with CHOP-R followed by (90)Y ibritumomab tiuxetan consolidation and 24 months of rituximab maintenance as treatment for patients with intermediate and high-risk newly diagnosed symptomatic follicular lymphoma. 33 patients were enrolled. Results: The addition of (90)Y ibritumomab tiuxetan was well tolerated but resulted in asymptomatic grade 3 or 4 thrombocytopenia and neutropenia in11-36% and 10-24% of patients between weeks 2-8 post (90) Y. After 9 years of follow-up (median follow-up 61 months) the 0S for intermediate and high risk FLIPI was 95% and 78%. The 5 year PFS was 79% and 64% for intermediate and high risk FLIPI, respectively. Responses at three months post consolidation were as follows: 3/33 (9%) achieved CR, 25/33(76%), achieved CRU, 1/33(3%) had PR, and 1/33(3%) had PD. Three patients did not receive (90)Y ibritumomab tiuxetan due to disease progression 2/33(6%), or death 1/33(3%). Of 19 patients who had a molecular marker for their lymphoma, 18 (95%) achieved molecular remissions in peripheral blood with CHOP-R therapy. Nine (47%) of these patients have been recently assessed for MRD and remain in molecular remission. The therapy resulted in decreased levels of IgG, IgM and IgA below the lower normal level in 33%, 40% and 23% of patients respectively post therapy. These levels did not recover in most of these patients. B cells were depleted to undetectable levels during therapy including rituximab maintenance. In 18 evaluable patients only 11 recovered normal B cell counts post maintenance rituximab. There was no correlation between normal B-cell recovery and Ig levels. Many patients with low or no B cell counts had normal IgG levels, whereas some patients who regained normal B cell counts were still unable to reach normal Ig levels. No patient developed human anti-mouse antibody. Immunity to measles, mumps, or rubella was retained post therapy. Patients did not have significant infections or opportunistic infections (although 2 developed Grade 1 shingles post (90)Y ibritumomab tiuxetan) and none required IVIG. Conclusions: We conclude that this intensified regimen is highly active in cyto-reducing lymphoma in high and intermediate risk FLIPI follicular lymphoma patients. The toxicity is tolerable although a significant percentage of patients will end up with persistent asymptomatic reductions in B cells and serum Ig. Only randomized trials will determine whether this regimen enhances outcome over standard of care in this higher risk follicular lymphoma population. References: 1.Examination of the follicular lymphoma international prognostic index (FLIPI) in the National LymphoCare study (NLCS): a prospective US patient cohort treated predominantly in community practices. Nooka AK, Nabhan C, Zhou X, Taylor MD, Byrtek M, Miller TP, Friedberg JW, Zelenetz AD, Link BK, Cerhan JR, Dillon H, Sinha R, Shenoy PJ, Levy D, Dawson K, Hirata JH, Flowers CR. Ann Oncol. 2013 Feb;24(2):441-8. doi: 10.1093/annonc/mds429. Epub 2012 Oct 5 2.Validation, revision and extension of the Follicular Lymphoma International Prognostic Index (FLIPI) in a population-based setting. van de Schans SA, Steyerberg EW, Nijziel MR, Creemers GJ, Janssen-Heijnen ML, van Spronsen DJ. Ann Oncol. 2009 Oct;20(10):1697-702. doi: 10.1093/annonc/mdp053. Epub 2009 Jun 23. PMID: 19549712 Disclosures Buckstein: Novartis: Honoraria; Celgene: Honoraria, Research Funding.

Download Full-text

Memory persistence and differentiation into antibody-secreting cells accompanied by positive selection in longitudinal BCR repertoires

10.1101/2021.12.30.474135 ◽

2022 ◽

Author(s):

Artem I. Mikelov ◽

Evgeniia I. Alekseeva ◽

Ekaterina A. Komech ◽

Dmitriy B. Staroverov ◽

Maria A. Turchaninova ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Peripheral Blood ◽

Plasma Cells ◽

Inflammatory Diseases ◽

Affinity Maturation ◽

Memory B Cells ◽

Immune Memory ◽

Memory B Cell ◽

Antibody Secreting Cells

B-cell mediated immune memory holds both plasticity and conservatism to respond to new challenges and repeated infections. Here, we analyze the dynamics of immunoglobulin heavy chain (IGH) repertoires of memory B cells, plasmablasts and plasma cells sampled several times during one year from peripheral blood of volunteers without severe inflammatory diseases. We reveal a high degree of clonal persistence in individual memory B-cell subsets with inter-individual convergence in memory and antibody-secreting cells (ASCs). Clonotypes in ASCs demonstrate clonal relatedness to memory B cells and are transient in peripheral blood. Two clusters of expanded clonal lineages displayed different prevalence of memory B cells, isotypes, and persistence. Phylogenetic analysis revealed signs of reactivation of persisting memory B cell-enriched clonal lineages, accompanied by new rounds of affinity maturation during proliferation to ASCs. Negative selection contributes to both, persisting and reactivated lineages, saving functionality and specificity of BCRs to protect from the current and future pathogens.

Download Full-text

Preliminary Safety and Efficacy Results with an Intermittent Schedule of the PI3kδ Inhibitor ME-401 Alone or in Combination with Rituximab for B-Cell Malignancies

Blood ◽

10.1182/blood-2018-99-115670 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2893-2893 ◽

Cited By ~ 7

Author(s):

Andrew D. Zelenetz ◽

Jacob D. Soumerai ◽

Deepa Jagadeesh ◽

Nishitha Reddy ◽

Anastasios Stathis ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Objective Response ◽

Intermittent Schedule ◽

Safety And Efficacy ◽

Group 2 ◽

Grade 3 ◽

Expansion Cohort ◽

Group 1

Abstract Background: ME-401, a potent and selective oral PI3kδ inhibitor, achieved a high rate of early and durable responses in patients with follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) when administered once daily in 28-day cycles on a continuous schedule (CS) in a dose escalation Phase 1b study (Soumerai et al, ASCO 2018:#7519). The most common adverse events (AEs) were the delayed onset (beyond Cycle 2) of grade 3 diarrhea and rash, which were reversible with drug interruption and/or corticosteroids. These delayed AEs were thought to be due to pathway inhibition in regulatory T cells (Treg) leading to a disruption in immune homeostasis. We hypothesized that an intermittent schedule (IS) beyond Cycle 2 might mitigate or reduce the incidence of significant delayed AEs. The IS tested was selected based on the kinetics of Treg repopulation, and consists of ME-401 administered on days 1-7 of a 28-day cycle. We report preliminary results of this strategy. Methods: Group 1 included 31 patients with relapsed FL (n = 22) or CLL/SLL (n = 9) who received ME-401 on a CS at doses ≥60 mg per day. 11/29 patients (38%) who received >2 cycles of therapy had developed delayed grade 3 AEs on CS and could be re-challenged with either the CS or IS (from December 2017 onward) following recovery from toxicity. The other 18/29 patients (62%) had not developed a grade 3 AEs of interest on CS and, beginning in December 2017, were switched to IS after a median of 26 weeks (range, 8-49) of daily dosing. Group 2 included 15 patients with relapsed FL (n = 9), diffuse large B-cell lymphoma (n = 4), marginal zone lymphoma (MZL, n = 1), and CLL (n = 1) who received rituximab 375 mg/m2 x 8 doses over 6 months and ME-401 at 60 mg daily x 2 cycles then switched to the IS. Group 3 includes 30 patients with relapsed FL/CLL/SLL enrolling in an expansion cohort of ME-401 alone at 60 mg daily x 2 cycles then switching to IS. Results: Group 1: Of the 11 patients who developed a delayed grade 3 AE on CS, 6 were never re-challenged, 2 were re-challenged with CS with recurrence of their AE, and 3 were re-challenged with IS without recurrence of their AE. Of the 18 patients switched to the IS, and with a median follow-up of 5.2 months (range, 2.3-6.6) on IS, 3 developed grade 3 diarrhea on IS, 2 in the first cycle and 1 in the second cycle after the switch to IS, of whom 2 have been re-treated with IS for 1+ and 5+ months without recurrence of the AE. One patient was not evaluable for response due to discontinuation on Day 28 for personal reasons and 27/30 (90%) evaluable patients achieved an objective response. With a median follow-up of 9.4 months (range, 2.2-17.5) from enrollment, only 2/27 (7%) responders had disease progression (PD) on CS and were discontinued. Of the 18 patients who were switched to IS, only 1 SLL patient with a partial response (PR) achieved on CS developed PD on IS and was successfully rescued with switch back to CS. Another CLL patient in PR on CS had 10% increase in SPD from nadir in Cycle 5 on the IS and was switched back to CS. Group 2: 10/15 patients have completed 2 cycles of daily dosing at the time of analysis and were systematically switched to IS. With a median follow-up of 3.4 months (range, 1.5-5.7) on IS, only 1/10 patients developed delayed grade 3 diarrhea in the first cycle after switch to IS. 7/10 patients (70%) with FL/MZL achieved an objective response and no PD was reported with a median follow-up of 5.2 months (range, 3.1-7.5) from enrollment. Conclusions: Preliminary data suggest that switching to an intermittent schedule consisting of ME-401 administered on days 1-7 of a 28-day cycle following 2 cycles of continuous daily dosing was associated with a low rate of delayed grade 3 AEs and was associated with preservation of response in the vast majority of patients. All delayed grade 3 AEs of interest on IS occurred within 1-2 cycles of switching from CS to IS, suggesting that these might have represented a delayed effect of daily dosing. IS may also be a suitable re-treatment strategy in patients with delayed AEs on CS. Safety and efficacy data for the expansion cohort of 30 patients treated with ME-401 at 60 mg for 2 cycles then switched to IS will be presented at the meeting. A randomized study comparing CS and IS in FL is planned. Disclosures Zelenetz: Abbvie: Research Funding; Celgene: Consultancy; AstraZeneca: Consultancy; Novartis/Sandoz: Consultancy; Amgen: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding. Reddy:MEI Pharma: Research Funding. Stathis:Oncology Therapeutic Development: Research Funding. Ghalie:MEI Pharma: Employment, Equity Ownership; Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy.

Download Full-text

Prevalence of Hospital PCR Confirmed COVID-19 Cases in Patients with Chronic Inflammatory and Autoimmune Rheumatic Diseases

10.1101/2020.05.11.20097808 ◽

2020 ◽

Cited By ~ 2

Author(s):

José L. Pablos ◽

Lydia Abasolo-Alcázar ◽

José M. Álvaro-Gracia ◽

Francisco J. Blanco ◽

Ricardo Blanco ◽

...

Keyword(s):

Rheumatic Diseases ◽

Lupus Erythematosus ◽

Inflammatory Diseases ◽

Age Distribution ◽

Reference Population ◽

Disease Modifying Antirheumatic Drugs ◽

Antirheumatic Drugs ◽

Immune Mediated ◽

Specific Factors

ABSTRACTBackgroundThe susceptibility of patients with rheumatic diseases, and the risks or benefits of immunosuppressive therapies for COVID-19 are unknown.MethodsWe performed a retrospective study with patients under follow-up in rheumatology departments from seven hospitals in Spain. We matched updated databases of rheumatology patients with SARS-CoV-2 positive PCR tests performed in the hospital to the same reference populations. Rates of PCR+ confirmed COVID-19 were compared among groups.ResultsPatients with chronic inflammatory diseases had 1.32-fold higher prevalence of hospital PCR+ COVID-19 than the reference population (0.76% vs 0.58%). Systemic autoimmune or immune mediated diseases (AI/IMID) patients showed a significant increase, whereas inflammatory arthritis (IA) or systemic lupus erythematosus (SLE) patients did not. COVID-19 cases in some but not all diagnostic groups had older ages than cases in the reference population. IA patients on targeted-synthetic or biological disease-modifying antirheumatic drugs (ts/bDMARD), but not those on conventional-synthetic (csDMARD), had a greater prevalence despite a similar age distribution.ConclusionPatients with AI/IMID show a variable risk of hospital diagnosed COVID-19. Interplay of aging, therapies, and disease specific factors seem to contribute. These data provide a basis to improve preventive recommendations to rheumatic patients and to analyze the specific factors involved in COVID-19 susceptibility.

Download Full-text