Evaluating the association between absolute lymphocyte count (ALC) after 6 months of dimethyl fumarate treatment and risk of relapse at one year

2017 ◽  
Author(s):  
Kyle E. Smoot
Keyword(s):  
Lymphocyte Count ◽  
Absolute Lymphocyte Count ◽  
Dimethyl Fumarate ◽  
One Year ◽  
Risk Of Relapse

scholarly journals Safety and Tolerability of Subcutaneous Cladribine Therapy in Progressive Multiple Sclerosis

1998 ◽  
Vol 25 (4) ◽  
pp. 295-299 ◽  
Author(s):  
R. Selby ◽  
J. Brandwein ◽  
P. O'Connor
Keyword(s):  
Multiple Sclerosis ◽  
Lymphocyte Count ◽  
Antineoplastic Agent ◽  
Absolute Lymphocyte Count ◽  
Progressive Multiple Sclerosis ◽  
Disability Status ◽  
Chronic Progressive Multiple Sclerosis ◽  
Clinically Significant ◽  
One Year ◽  
Post Therapy

ABSTRACT:Objective:To evaluate the safety and tolerability of subcutaneous (s.c.) cladribine therapy in patients with chronic progressive multiple sclerosis (CPMS), and to evaluate the effects on lymphocyte subsets.Background:Cladribine, a synthetic antineoplastic agent with immunosuppressive effects, may favourably affect the course of CPMS. However results of a previous reported clinical trial showed significant myelosuppression in some patients.Design/Methods:19 patients with severe (mean extended disability status score [EDSS] = 6.7) CPMS were treated on a compassionate basis with cladribine 0.07 mg/kg/ day s.c. for 5 days per cycle, repeated every 4 weeks for a total of 6 cycles. Patients underwent clinical evaluation, EDSS, and hematologic analysis before, during, and following therapy.Results:The treatment was very well tolerated with no clinically significant side effects observed. Between baseline and the end of cycle 6, mean decreases were noted in absolute lymphocyte count from 1697 to 463 (p = 0.000012), CD4 count from 865 to 187 (p = 0.0000008), CD8 from 418 to 165 (p = 0.005) and CD19 from 197 to 26 (p = 0.000002). Platelet, granulocyte and RBC counts were unaffected. Approximately one year after completion of therapy, some recovery of CD4 and CD8 counts had occurred although both counts remained suppressed compared to baseline (302 and 227 respectively); the CD19 count had recovered essentially to normal by one year. EDSS scores post-therapy revealed some deterioration in 8 patients and stable scores in the remaining 11. Global patient evaluations of the treatment were mixed.Conclusions:Cladribine therapy, at lower doses than previously reported, was remarkably well tolerated in CPMS, with no significant myelosuppression. Profound effects occurred in total lymphocyte count and CD4, CD8 and CD19 subsets.

scholarly journals Effect of dimethyl fumarate on lymphocyte subsets in patients with relapsing multiple sclerosis

2020 ◽  
Vol 6 (2) ◽  
pp. 205521732091861 ◽  
Author(s):  
Guy Buckle ◽  
Daniel Bandari ◽  
Jeffrey Greenstein ◽  
Mark Gudesblatt ◽  
Bhupendra Khatri ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Confidence Interval ◽  
Cd8 T Cells ◽  
Lymphocyte Count ◽  
Absolute Lymphocyte Count ◽  
Dimethyl Fumarate ◽  
T Cell Subsets ◽  
Routine Practice ◽  
Patients At Risk

Background In patients treated with dimethyl fumarate, absolute lymphocyte count decline typically occurs during the first year and then plateaus; early drops have been associated with the development of severe prolonged lymphopenia. Objective We investigated the effect of dimethyl fumarate on absolute lymphocyte counts and CD4+/CD8+ T cells in patients with relapsing–remitting multiple sclerosis treated with dimethyl fumarate in routine practice. Methods Lymphocyte data were collected via medical chart abstraction. Primary endpoint: change from baseline in absolute lymphocyte count and CD4+/CD8+ counts at 6‐month intervals following dimethyl fumarate initiation. Results Charts of 483 patients were abstracted and 476 patients included in the analysis. Mean baseline absolute lymphocyte count (2.23 × 109/l) decreased by ∼39% (95% confidence interval: –41.1 to –37.2) by month 6 and 44% (95% confidence interval: –46.6 to –42.1) by month 12. CD4+ and CD8+ T-cell subsets strongly correlated with absolute lymphocyte count, with greater decreases from baseline to 6 months vs 6–12 months, and in CD8+ vs CD4+ T cells. Prior natalizumab was not a risk factor for lymphopenia. Conclusion Dimethyl fumarate-associated decline in absolute lymphocyte count in the first 12 months correlated with decline in CD4+ and CD8+ T cells and was independent of prior natalizumab. Absolute lymphocyte count monitoring continues to be an effective strategy to identify patients at risk of prolonged lymphopenia.

scholarly journals Identification of Patients Who May Benefit From Prophylactic Immunotherapy After Bone Marrow Transplantation for Acute Myeloid Leukemia on the Basis of Lymphocyte Recovery Early After Transplantation

Blood ◽  
1998 ◽  
Vol 91 (9) ◽  
pp. 3481-3486 ◽  
Author(s):  
Ray Powles ◽  
Seema Singhal ◽  
Jennifer Treleaven ◽  
Samar Kulkarni ◽  
Clive Horton ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Bone Marrow Transplantation ◽  
Lymphocyte Count ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Absolute Lymphocyte Count ◽  
Gvhd Prophylaxis ◽  
Risk Of Relapse ◽  
Acute Myeloid

Two hundred and one patients (median age, 29 years) with acute myeloid leukemia (AML) underwent bone marrow transplantation (BMT) from HLA-identical sibling donors after conditioning with melphalan-total-body irradiation (TBI) (57%), cyclophosphamide-TBI (35%), or chemotherapy alone (8%). Graft-versus-host disease (GVHD) prophylaxis included cyclosporine alone (68%), cyclosporine-methotrexate (26%), or T-cell depletion (6%). The probability of relapse was calculated as a function of the absolute lymphocyte count (109/L) on days 27 to 30 posttransplant (<0.1 v ≥0.1, <0.2 v ≥0.2, and <0.3 v≥0.3). In each of these 12 comparisons, the probability of relapse was higher for the group with the lower lymphocyte count. Because the difference was most significant (P = .004) for an absolute lymphocyte count of <0.2 on day 29 (3-year relapse probability, 42%) versus ≥ 0.2 (16%), this variable was included in a Cox model to determine factors independently affecting relapse. Multivariate analysis showed that conditioning regimens other than melphalan-TBI, a low lymphocyte count on day 29, French-American-British (FAB) subtypes M4-7, and a nucleated cell dose of > 2.42 × 108/kg was associated with a higher risk of relapse. We conclude that slow lymphocyte recovery after allogeneic BMT, to < 0.2 × 109/L 29 days in this analysis, appears to be associated with a higher risk of relapse in patients with AML. This group of patients may benefit from posttransplant immune manipulations such as abbreviated GVHD prophylaxis, or donor cell or cytokine administration to enhance graft-versus-leukemia reactions to reduce relapse.

scholarly journals Identification of Patients Who May Benefit From Prophylactic Immunotherapy After Bone Marrow Transplantation for Acute Myeloid Leukemia on the Basis of Lymphocyte Recovery Early After Transplantation

Blood ◽  
1998 ◽  
Vol 91 (9) ◽  
pp. 3481-3486 ◽  
Author(s):  
Ray Powles ◽  
Seema Singhal ◽  
Jennifer Treleaven ◽  
Samar Kulkarni ◽  
Clive Horton ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Bone Marrow Transplantation ◽  
Lymphocyte Count ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Absolute Lymphocyte Count ◽  
Gvhd Prophylaxis ◽  
Risk Of Relapse ◽  
Acute Myeloid

Abstract Two hundred and one patients (median age, 29 years) with acute myeloid leukemia (AML) underwent bone marrow transplantation (BMT) from HLA-identical sibling donors after conditioning with melphalan-total-body irradiation (TBI) (57%), cyclophosphamide-TBI (35%), or chemotherapy alone (8%). Graft-versus-host disease (GVHD) prophylaxis included cyclosporine alone (68%), cyclosporine-methotrexate (26%), or T-cell depletion (6%). The probability of relapse was calculated as a function of the absolute lymphocyte count (109/L) on days 27 to 30 posttransplant (<0.1 v ≥0.1, <0.2 v ≥0.2, and <0.3 v≥0.3). In each of these 12 comparisons, the probability of relapse was higher for the group with the lower lymphocyte count. Because the difference was most significant (P = .004) for an absolute lymphocyte count of <0.2 on day 29 (3-year relapse probability, 42%) versus ≥ 0.2 (16%), this variable was included in a Cox model to determine factors independently affecting relapse. Multivariate analysis showed that conditioning regimens other than melphalan-TBI, a low lymphocyte count on day 29, French-American-British (FAB) subtypes M4-7, and a nucleated cell dose of > 2.42 × 108/kg was associated with a higher risk of relapse. We conclude that slow lymphocyte recovery after allogeneic BMT, to < 0.2 × 109/L 29 days in this analysis, appears to be associated with a higher risk of relapse in patients with AML. This group of patients may benefit from posttransplant immune manipulations such as abbreviated GVHD prophylaxis, or donor cell or cytokine administration to enhance graft-versus-leukemia reactions to reduce relapse.

Important Role for Absolute Lymphocyte Count in Predicting Risk of Relapse in Pediatric Acute Lymphoblastic Leukemia Post Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3669-3669
Author(s):  
Mohammed Kashif Ishaqi ◽  
Samina Afzal ◽  
Annie Dupuis ◽  
John Doyle ◽  
Adam Gassas
Keyword(s):  
Complete Remission ◽  
Lymphocyte Count ◽  
Lymphoblastic Leukemia ◽  
Absolute Lymphocyte Count ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Graft Versus Leukemia ◽  
Conditioning Regimens ◽  
Risk Of Relapse ◽  
Graft Versus Leukemia Effect

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) is currently an established treatment for children with relapsed or high risk acute lymphoblastic leukemia (ALL). Relapse is a major risk post HSCT and an important cause of treatment failure with abysmal outcome. An important therapeutic mechanism of allogeneic HSCT is the immune-mediated destruction of recipient leukemic cells by donor lymphocytes, the graft-versus-leukemia-effect (GVL). Our hypothesis was to determine if delayed lymphocyte recovery measured by the absolute lymphocyte count (ALC) at two time points post HSCT at day 21 and day 30 correlates with leukemia relapse. We reviewed 136 consecutive paediatric patients with ALL who received allogeneic HSCT between 1994 and 2005 in the Hospital for Sick Children, Toronto, Canada. All patients were in complete morphological remission prior to HSCT and remission status at time of HSCT were as follows; Complete remission 1 (CR1, n=36); Complete remission 2 (CR2, n=79); Complete remission 3 (CR3, n=21). Conditioning regimens included single dose of VP16 (60mg/kg infused over 4 hours) and fractionated total body irradiation (TBI; 1200cGy) in six fractions over 3 days (VP16/TBI) in 49 patients (1994–1998) and cyclophosphamide 50mg/kg infused over 1 hour daily for 4 days followed by the same dose of fractionated TBI (CY/TBI) in 83 patients (1999–2005) and 4 patients received other conditioning regimens. Fifty-six patients received matched sibling donor (MSD), 12 patients received one antigen mismatched related donor (MMRD), 64 received unrelated donors and 4 patients received cord progenitor stem cells. Two groups were identified based on absolute lymphocyte count at day 21 and day 30 post HSCT. Patients with absolute lymphocyte count <0.3×109/L at day 21 (n=104) had more than 5 times risk of relapse compared to those with ALC count >0.3 × 109/L (n=32) (Hazard ratio 0.19; P=0.0004). Patients with ALC <0.3×109/L (n=48) at day 30 were more than twice likely to relapse compared to those with ALC >0.3×109/L (n=88) (Hazard ratio 0.46; P=0.01). Conclusion: ALC, at day 21 and day 30 post HSCT identifies a patient population of pediatric ALL with delayed lymphocyte recovery and a significant risk of relapse post HSCT. Such patients could be considered for early intervention targeted to prevent relapse such as reduction of immunosuppressive therapy or other means of immunotherapy to enhance the graft versus leukemia effect.

scholarly journals Characterizing absolute lymphocyte count profiles in dimethyl fumarate–treated patients with MS

2016 ◽  
Vol 6 (3) ◽  
pp. 220-229 ◽  
Author(s):  
Robert J. Fox ◽  
Andrew Chan ◽  
Ralf Gold ◽  
J. Theodore Phillips ◽  
Krzysztof Selmaj ◽  
...  
Keyword(s):  
Lymphocyte Count ◽  
Absolute Lymphocyte Count ◽  
Dimethyl Fumarate

scholarly journals Increased multiple sclerosis disease activity in patients transitioned from fingolimod to dimethyl fumarate: a case series

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Silvia Delgado ◽  
Jeffrey Hernandez ◽  
Leticia Tornes ◽  
Kottil Rammohan
Keyword(s):  
T Lymphocytes ◽  
Disease Activity ◽  
Lymphocyte Count ◽  
Opportunistic Infections ◽  
Severe Disease ◽  
Case Series ◽  
Absolute Lymphocyte Count ◽  
Dimethyl Fumarate ◽  
Lymphoid Tissues ◽  
Receptor Modulator

Abstract Background Fingolimod is a S1P1 receptor modulator that prevents activated lymphocyte egress from lymphoid tissues causing lymphopenia, mainly affecting CD4+ T lymphocytes. Withdrawal from fingolimod can be followed by severe disease reactivation, and this coincides with return of autoreactive lymphocytes into circulation. The CD8+ T cytotoxic population returns prior to the regulatory CD4+ T lymphocytes leading to a state of dysregulation, which may contribute to the rebound and severity of clinical relapses. On the other hand, dimethyl fumarate (DMF) preferentially reduces CD8+ T lymphocytes, has the same efficacy as fingolimod, and therefore, was expected to be a suitable oral alternative to reduce the rebound associated with fingolimod withdrawal. Case presentation We present six patients with relapsing-remitting MS who developed an unexpected increase in disease activity after transitioning from fingolimod to DMF. All patients were clinically and radiologically stable on fingolimod for at least 1 year. The switch in therapy was due to significantly low CD4+ T lymphocyte count ≤65 cells/ul (normal range 490–1740 cells/ul), after discussing the results with the patients and the potential risk for opportunistic infections including cryptococcal infections. DMF was introduced following a washout period of 5 to 11 weeks to allow reconstitution of the immune system and for the absolute lymphocyte count to reach ≥500 cells/ul. Every patient who experienced a relapse had several enhancing lesions in the brain and/or spinal cord between 12 to 23 weeks after cessation of fingolimod and 1 to 18 weeks after starting DMF. All relapses were treated with intravenous methylprednisolone with good clinical responses. Conclusion The anticipated beneficial response of DMF treatment to mitigate rebound after fingolimod therapy cessation was not observed. Our patients experienced rebound disease despite being on treatment with DMF. Additional studies are necessary to understand which treatments are most effective to transition to after discontinuing fingolimod.

scholarly journals Dimethyl fumarate induces changes in B- and T-lymphocyte function independent of the effects on absolute lymphocyte count

2017 ◽  
Vol 24 (6) ◽  
pp. 728-738 ◽  
Author(s):  
Erin E Longbrake ◽  
Claudia Cantoni ◽  
Salim Chahin ◽  
Francesca Cignarella ◽  
Anne H Cross ◽  
...  
Keyword(s):  
T Cell ◽  
Lymphocyte Count ◽  
Mononuclear Cells ◽  
Absolute Lymphocyte Count ◽  
Dimethyl Fumarate ◽  
Cell Phenotype ◽  
Lymphocyte Function ◽  
Functional Changes ◽  
Viral Peptide ◽  
Peptide Stimulation

Background: Dimethyl fumarate (DMF) is used to treat relapsing multiple sclerosis and causes lymphopenia in a subpopulation of treated individuals. Much remains to be learned about how the drug affects B- and T-lymphocytes. Objectives: To characterize changes in B- and T-cell phenotype and function induced by DMF and to investigate whether low absolute lymphocyte count (ALC) is associated with unique functional changes. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from DMF-treated patients, untreated patients, and healthy controls. A subset of DMF-treated patients was lymphopenic (ALC < 800). Multiparametric flow cytometry was used to evaluate cellular phenotypes. Functional response to non-specific and viral peptide stimulation was assessed. Results: DMF reduced circulating memory B-cells regardless of ALC. Follicular T-helper cells (CD4+ CXCR5+) and mucosal invariant T-cells (CD8+ CD161+) were also reduced. DMF reduced T-cell production of pro-inflammatory cytokines in response to polyclonal (PMA/ionomycin) and viral peptide stimulation, regardless of ALC. No differences in activation-induced cell death or circulating progenitors were observed between lymphopenic and non-lymphopenic DMF-treated patients. Conclusion: These data implicate DMF-induced changes in lymphocytes as an important component of the drug’s efficacy and expand our understanding of the functional significance of DMF-induced lymphopenia.

Lymphocyte Recovery Kinetics in Patients Undergoing Myeloablative Conditioning and Allogeneic Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5467-5467
Author(s):  
David Jared Kobulnicky ◽  
Roy T Sabo ◽  
Ali S Shubar Ali ◽  
Catherine H. Roberts ◽  
Allison F Scalora ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Clinical Outcomes ◽  
Cell Transplantation ◽  
Lymphocyte Count ◽  
Absolute Lymphocyte Count ◽  
Kaplan Meier ◽  
Type C ◽  
One Year ◽  
Survival Plot

Abstract Immune reconstitution following stem cell transplantation (SCT) may be considered as a dynamical system in which future events are predicated on all the preceding past events. In turn, lymphoid reconstitution over time will determine the clinical trajectory an individual patient might take. Lymphoid recovery following myeloablative stem cell transplantation (SCT) displays a logistic (sigmoidal) pattern of exponential growth followed by a plateau. This study aims to understand whether logistic modeling of lymphocyte recovery following SCT can be used to predict outcomes and thus guide therapies to minimize the competing pathologies of graft vs. host disease (GVHD) and relapse. A retrospective analysis of allogeneic SCT performed from 2008 to 2011 was undertaken to compare lymphoid recovery and clinical outcomes in 82 patients with acute myelogenous leukemia, acute lymphocytic leukemia and myelodysplastic syndromes. Using Prism software, a logistic curve was successfully fitted to the absolute lymphocyte count recovery in all patients. Patients were classified according to the magnitude and rate of lymphoid recovery; Type A achieved an absolute lymphocyte count (ALC) of > 1000/mcrL by day 45; Type B an ALC 500 < x < 1000 /mcrL and Type C, an ALC <500/mcrL. There was a significant difference in overall survival (Kaplan-Meier p=0.002) and one-year survival whereby 32/45 (71%) of Type A, 15/26 (58%) of Type B and 2/11 (18%) of Type C remained alive (p=.006). There was no difference in cGVHD (p=0.22) or relapse (p=0.52) incidence between patients with patterns A and B; all patients with pattern C experienced death, relapse or cGVHD within one year. Acute Lymphoblastic Leukemia as initial diagnosis (p=0.04), unrelated donor (p=0.007), mycophenolate mofetil GVHD prophylaxis (p=0.04) predicted type C pattern. Within this logistic framework, cellular recovery is characterized by the parameters R (slope of ascent), a (time of maximal ascent) and K ( plateau), the 'steady state' lymphocyte count. Mean K was significantly different between pattern type whereby pattern A had mean ALC of 1760 /mcrL, pattern B an ALC of 868 and pattern C, an ALC of 262 (p=0.0029) respectively. Neither parameters, a nor R were significantly different between pattern types. CMV, acute GVHD and relapse all were associated with deviation from logistic behavior. Weaning of tacrolimus post-transplant was associated with a second, separate phase of logistic expansion of ALC in some patients. Low K or steady state lymphocyte count is a risk factor for relapse and early death. Pattern B have no increased risk of GVHD compared to Pattern A. Assesing lymphoid reconstitution as a logistic function of time allows dynamic association of donor immune recovery with clinical outcomes and may allow for preemptive adjustments in immune suppresssion or use donor lymphocyte infusions to optimize clinical outcomes. Figure 1. Kaplan-Meier survival plot of patients grouped according to ALC recovery pattern. Figure 1. Kaplan-Meier survival plot of patients grouped according to ALC recovery pattern. Figure 2. Figure 2. Disclosures Neale: CHRB: Research Funding.

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